1W1 - semspub.epa.gov

1W1APPENDIX H

TOXICOLOGY PROFILES

ArsenicBariumBenzeneBeryllium

2(2-Chloroethyl)etherChloroformChromium

1.4-Dichlorobenzene1,1-Dichloroethane1,2-Dichloroethane1,1 -Dichloroethene1,2-Dichloroethene2,4-Dlchlorophenoi

bls(2-Ethylhexyl)phthalateHeptachlor Epoxide

Manganese2-Methylnaphthalene

NaphthalenePhenol

Polynuclear Aromatic HydrocarbonsTetrachloroethene

1,2,4-Trichloroben2eneTrlchloroethene

VanadiumZinc

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C

CAS No.: 7440-38-2Synonyms: gray arsenic, metallic arsenic

A. Physical and Chemical Properties

Chemical Formula: AsForm: grayf shiny, brittle, metallic-looking

rhombohedra

Chemical Class: metalAtomic Weight: 74.92Boiling Point: 61.3°CMelting Point: 818°C at 36 atm.

Specific Gravity: 5.727 at 25/4°CSolubility in Water: insoluble, some salts are soluble

Solubility in Organics: Not attacked by cold H2SO4 or HC1;converted by HNO3 or hot H2SO4 intoarsenous or arsenic acid

Organic CarbonPartition Coefficient: NALog Octanol/Water

Partition Coefficient: NAVapor Pressure: 0Vapor Density: NA

Henry's Law Constant: NABioconcentration Factor: 44 (Fish L/kg)

B. Regulations and Standards

Safe Drinking Water ActMaximum Contaminant Level Goal(MCLG for Drinking Water (mg/L): 0.05

Maximum Contaminant Level (MCL)for Drinking Water (mg/L): 0.05

Clean Water ActAmbient Water Quality Criteria (mg/L)Human Health

Water and Fish Consumption: 2.20E-06Fish Consumption Only: "1 .75E-05

Aquatic Organisms (mg/L)Fresh Water:

Acute: 3.60E-01Chronic: 1.90E-01

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MarineAcute: 6.90E-02

Chronic: 3.60E-02

ReferencesSax and Lewis 1989. Verschueren 1983, The Merck Index 1983.SPHEM 1986. EPA 1986NA - Not Available

C. Fate and Transport

The major environmental fate processes of arsenic are sorption.bloaccumulation, and biodegradation/btotransformation. The cyclingof arsenic through the environment is dominated by its sorption anddesorption on soils and sediments. Some arsenic compounds tend tobioaccumulate in lower levels of the food chain and to a certain extent.in fish. Arsenic is readily biotransformed in aquatic environments tomethylated forms. In these forms arsenic becomes more mobile andenters the water and subsequently the food chain. Thus, mobilitycould bring increasing concentrations of arsenic to the aquaticenvironment from contaminated sediments. Based upon the limitedquantative data available for arsenic, photolysis, oxidation.volatilization, and hydrolysis are considered to be environmentallyinsignificant fate processes.

IX Ecotoxicology

Although the human health effects of arsenic are well documented,analyses of the ecotoxic properties are limited to single species testswhich primarily Identify acute effects. Arsenic is mobile in theenvironment and is readily transported to biotic and abioticcomponents of ecosystems; however, no data was identified regardingthe potential effects on the higher levels of organization.The available literature indicates arsenite (As*3) is more toxic toaquatic organisms than arsenate (As+5). In the aquatic environment,toxicity could be abated by the oxidation of As*3 to As*5 under aerobicconditions or increasing pH. In general, arsenic is characterized by ahigh affinity for sulfhydryl groups in proteins and may interfere withenzymatic reactions {EPA 1978. EPA 1980, Moore & Ramamoorthy1984). However, As+5 does not bind as readily to sulfhydryl groups,but it may uncouple oxidative phosphorylation (EPA 1980). Arsenic is

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a lipophilic substance, but it has also been detected in muscle tissue.* The half-life of arsenic In the muscle tissue of green sunfish (Lepomisj cyanellus) was reported as seven days (EPA 1978, EPA 1980). Overall,

arsenic does not usually accumulate at appreciable levels In freshwaterspecies. However, saltwater invertebrates appear to concentrate aconsiderable amount of arsenic.Arsenic's use as an herbicide indicates it is ecotoxic to certain plantspecies. The available data suggest both arsenite and arsenate aretoxic to certain algae. Arsenate produced adverse effects in aquaticplants at test concentrations as low as 48 ng/1 (EPA 1986).The LC50 values for freshwater crustaceans exposed to arsenite rangefrom 812 to 97.000 jig/1 (EPA 1980. EPA 1986). A 96-hour LC50 of3,490 iig/l.was reported for bay scallops (Argopecton irradians)exposed to arsenate. The LCSO values for freshwater fish exposed toarsenite range from 13.340 to 41,760 jig/L Similar to other heavymetals, salmonid species (I.e., Salveltnus fontinalis, Salmo gatrdneri)were the most sensitive fish tested while bluegills (Lepomismacrochirus) were the most tolerant (EPA 1980). Inglis and Davis(1972) conducted toxicity tests at three hardness levels and reportedhardness had no apparent effect on toxicity. Although toxicity testsusing arsenate are very limited, studies using a cladoceran (D, magna)and brook trout (S. fonttnalis) indicated that As*5 demonstrated a

f similar level of toxicity as As*3. In saltwater tests using As*3- the 96-i hour LCso. were 15 mg/1 and 16 mg/1 for the fourspine stickleback

(Apeitus quadracus) and atlantic silverside (Monidia monidia),respectively. Typical of most heavy metals, the early life stages aremost sensitive to arsenic.Chronic toxicity data is deficient for arsenic. In a lifecycle test using a.cladoceran (D. magna), reproduction, growth and enzymatic activitywere inhibited at aresenite levels between 633 and 1,315 ng/1 (EPA1980). -} .No data regarding arsenic's effect on terrestrial species was identifiedin the literature.

E. Human Toxicology

Chemical and physical properties: Elemental arsenic exists in severalallotropic modifications; the ordinary form is metallic or gray arsenic.It forms a steel gray crystalline mass with a metallic luster, is brittleand rather soft, and is insoluble in water. The Inorganic compounds(+3 or +5) are usually colorless, water soluble crystalline solids orpowders; the trioxide, the calcium salts as well as the yellow-orange/

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Arsenic

sulphides have a limited to low water solubility. Elemental arsenicsublimes at 613C without melting and is easily volatilized in variouscombustion processes involving arsenic containing materials.

Hie arsenic compounds are often unstable, and are in many-cases notwell-defined materials. For example, the arsenites of alkali metals areslowly converted in solution to arsenates by atmospheric oxygen.

Environmental Levels and Exposure

Arsenic occurs occasionally native, as "Scherbenkobalt", but is foundchiefly in the form of its compounds with metals (arsenides), whichusually occur in isomorphous mixture with sulphides. The mostcommonly found is arsenopyrlte with the approximate compositionFeAsS. Naturally occurring sulphides are realgar (AsS) and orpiment(AS2S3). High levels of arsenic may be present in some coals, e.g.those mined in Czechoslovakia with levels up to 1.500 ppm. Peat mayalso contain appreciable quantities.

As a result of its natural occurrence, exposure to arsenic is universal(WHO/IPCS, 1981). It is present in most foodstuffs in concentrationsbelow 1 ppm. However, marine fish may contain up to 5 ppm and thearsenic concentration in some Crustacea and bottom-feeding fish mayreach several tens of milligrams per kg. However, in marineorganisms arsenic is predominantly present as organic arsenic, whichhas a totally different toxicological profile than the inorganic forms. Ithas been estimated that 5 - 10% of the total concentration of arsenicin marine organisms exist in the inorganic state. In the environmenta number of organisms (e.g. fungi and bacteria in soil) have thecapacity to methylate inorganic mercury with the formation ofdimethyl- and trimethylarsines. Fish from arsenic polluted watersappears to accumulate organic arsenic compounds via the food chain(Norin and Vahter. 1984).

Arsenic can be found in some natural waters in high concentrations.Whereas a survey of the drinking water In 18.000 communities in theU.S. (McCabe et al.. 1970) indicated that less than 1% has arseniclevels exceeding 10 ig/L, levels of 70 - 1.700 ig/L have been found Inwells in Oregon (Goldblatt. et al.. 1963). It has been estimated thatmore than 100.000 people in the U.S. are receiving drinking waterfrom public water supplies with arsenic levels above 50 tig/L, the

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current Maximum Contamination Level Goal (MCGL), of whichapproximately 84% consume water from ground-water supplies {EPA.1986). In several areas - like Cordoba. Argentina (900 - 3.400 \ig/L)and the Tainan province in Taiwan ( up to 1.800 ug/L) the naturalhigh arsenic content of the drinking water has caused endemicchronic arsenic poisoning. Airborne concentrations of arsenic inurban areas may range from a few nanograms to a few tenths of amicrogram per cubic meter.

In man the total daily intake of arsenic is greatly Influenced by theamount of seafood in the diet, but is usually less than 200 ug/day(normally about 50 jig/day).

Summary of Toxicity Data

Arsenic has a high acute as well as chronic toxicity. Systemic chronicpoisoning is primarily characterized by skin lesions such as asdermatoses, which may include eruptions, pigmentation, orhyperkeratosis. that may ultimately lead to the development of skincancer. Effects on the nervous system (e.g. peripheral nervousdisturbance) as well as on the heart and circulatory system (e.g.abnormal electrocardiograms, and peripheral vascular disturbanceswith gangrene of the extremities - the Blackfoot disease) have alsobeen reported following chronic exposure to arsenic. Hematologicalchanges following arsenic exposure are characterized by anemia andleukopenia.

In man various forms of arsenic-induced skin cancer have beendetected in populations chronically exposed to arsenic via drinkingwater, drugs, etc. Clearly, the risk of lung cancer is also increased incertain populations occupationally exposed to high levels of airbornearsenic. In the latter case, carcinogenlcity action Is strongly enhancedby smoking and possibly also by other environmental factors.

Acute and Chronic Toxicology

The acute toxicity of inorganic arsenic is dependent on the solubilityof the administered compound. In man the smallest recorded fataldose is in the range of 70-180 mg. but recovery has been reportedafter much larger doses. Death occurs after a period of 12 to 48 hrs

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(Stokinger. 1981). Common acute symptoms include gastritis, fever.insomnia, anorexia, liver swelling, and disturbed heart function.Peripheral nervous disturbances, primarily of sensory type, arefrequently encountered in individuals surviving poisoning, and theremay also be transient effects on the blood. Irritant and vesicantarsenical compounds, such as arsenic trtoxide, arsenic trichloride, andthe arsenical war gases* have been known to cause severe damage tothe respiratory system upon inhalation.

Signs of chronic arsenic toxicity are chiefly related to the skin,mucous membranes, lungs, gastrointestinal and nervous systems.Involvements of the circulatory system and liver are less common.

Chronic arsenic poisoning from ingestlon of contaminated food.beverages, and water has been reported in many countries. Anincident in the United Kingdom involved 6000 people who hadingested beer contaminated by arsenic. Reports of regional endemicchronic arsenism caused by drinking water with high concentrationsof arsenic in and around Cordoba. Argentina, date back as far as 1931.The primary criteria for diagnosis of chronic poisoning weresymmetrical palmar and plantar hyperkeratosis. Similar skin lesionshave also been observed in populations exposed to arsenic-contaminated drinking water in Chile. An endemic disease, alsoassociated with arsenic in drinking water, was discovered in Taiwan in1963. The major manifestation was hyperkeratotic skin lesions aswell as a vascular disorder resulting in gangrene of the lowerextremities - commonly called Blackfoot disease - which has not beenobserved among the people with skin lesions in Chile. Clinicaldifferences between populations with endemic arsenic exposureappear to be mediated by other as yet undefined environmental factors(Ishinishi, et al., 1986).

The skin is a common critical organ in humans exposed to inorganicarsenicals. The accumulation of arsenic in skin is probably related tothe abundance of proteins containing sulfhydryl groups, with whicharsenic readily reacts. Eczematoid symptoms develop with varyingdegrees of severity. In occupational exposure, skin lesions arefrequently found in the palm of the hand and on the sole of the foot.An allergic type of contact dermatitis is also frequently seen amongworkers who are exposed to arsenic trioxide. Chronic dermal lesionsmay follow this type of initial reaction, depending on theconcentration and duration of exposure. Hyperkeratosis. warts, andmelanosis of the skin are the most commonly observed lesions in

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chronic exposure. Grossly, the hyperkeratoses are usually small, non-tender corn-like elevations, 0.4 to-1 cm in diameter. The 'smallnodules may coalesce to form plaques, diffuse keratosls or largeverrucous growths. Skin lesions may develop long after cessation ofexposure, when dermal arsenic concentrations have returned tonormal levels.

Conjunctivitis characterized by redness, swelling and pain has oftenbeen associated with occupational exposure to arsenic-containing dust.Perforation of the nasal septum as a result of irritation of the upperrespiratory organs by arsenic dust is a common finding among arsenic-exposed workers. Like lesions caused by other chemical irritants suchas chromium, the perforation is confined to the cartilaginous portionof the septum and does not lead to deformity of the nose. There areno other apparent subjective symptoms once inflammation hassubsided.

Peripheral neuritis affecting mainly the upper and lower extremities isone of the symptoms of chronic arsenical poisoning. This neuritis ismostly symmetrical, widespread and painful. Abnormalelectromyograms (EMGs) have been reported among people who hadlived near an arsenic mine and smelter and who showed no subjectivesymptoms. Abnormal EMGs have also been reported among peopledrinking well water with high arsenic contents (Ishinlshi, et al..1986). The neurotoxic action of arsenic, involving demyelinatlon ofperipheral nerves, optic nerves and optic tracts, has also beendemonstrated in pigs given doses of arsanilic acid In excess of about100 ppm (Ledet et al.. 1973).

Anemia and disturbance of the hematopoietic system have beenobserved in chronic occupational exposure to arsenic and in treatmentwith arsenical drugs. Chronic arsenic poisoning with skin lesions isoften accompanied by moderate anemia and leukopenia.

Inorganic arsenic compounds have long been considered capable ofdamaging the liver under certain circumstances, but there are only afew reports of this occurring in arsenic-exposed workers. Alcoholconsumption may have been a complicating factor in cirrhosis amongvineyard workers who used arsenic as a pesticide.

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The epldemiological and clinical evidence for primary cardiac injury inarsenic workers is not very definite, but electrocardiograms have Irevealed abnormalities. Abnormal electrocardiograms indicating a \ j'toxic myocardlal effect were also seen in vineyard workers who usedarsenical insecticides and suffered from chronic arsenical poisoning.The Blackfoot disease of Taiwan is due to a peripheral vasculardisorder, and Raynaud's syndrome has been reported to occur in Chilein people drinking water with a high arsenic content.

Dose-response relationships for non-neoplastic effects are difficult toestablish on basis of available epldemiological data, but it appears thatingestlon of 3 mg of inorganic arsenic per day, over a period of a fewweeks, may give rise to severe poisoning in Infants and symptoms oftoxicity In adults (WHO/IPCS, 1981). The MED (non-carcinogeniceffects) of 1 mg/kg listed by the EPA Superfund Public HealthEvaluation Manual is. therefore, to high.

Carcinogenic Activity

There has been no consistent demonstration of carcinogenicity in testanimals for various chemical forms of arsenic administered by the oralroute or by skin application to several species (IARC, 1980). However,there are some data to indicate that arsenic may produce animaltumors. If retention time in the lung can be increased. Thus, arsenictrloxlde produced lung adenomas in mice after perinatal treatmentand induced low incidences of carcinomas, adenomas, papillomas andadenomatoid lesions of the respiratory tract in hamsters afterIntratracheal instillation. A high incidence of lung carcinomas wasinduced in rats following a single intratracheal instillation of apesticide mixture containing calcium arsenate (IARC, 1987)..

Arsenic may also act as a promotor. Oral administration of sodiumarsenite enhanced the incidence of renal tumors Induced in rats byintraperitoneal injection of N-nitrosodiethylamine (Kroes. R., et al..1974) As outlined below for skin carcinogenesls via keratosis, arsenicby Ingestion may predominantly act by the in a promotor vs. theinitiator route. This realization has potentiated adoption of athreshold concept for arsenic by ingestion.

Among the several types of skin cancer induced by arsenic.epithelioma developing at the site of keratoses is the most common. \

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oArsenic

The keratotic lesions may exist for many years before they change to amalignant form of epithelioma which is usually of the squamous type.Basal cell carcinoma of a low-grade malignancy, in situ, accompaniedby chronic "precancerous dermatitis" (Bowen's disease) is also foundIn cases of chronic arsenical dermatitis. In people exposed toInorganic arsenic via medication. Insecticides, contaminated wine ordrinking water, malignant tumors have developed in other organs.frequently accompanied by skin cancers. However, the relationshipbetween arsenic exposure and a higher risk of cancer In organs otherthan skin and lungs Is unclear (IARC. 1980)

A cross-sectional study of 40,000 Taiwanese exposed to arsenic indrinking water found significant excess skin cancer prevalence bycomparison to 7500 residents of Taiwan and Matsu who consumedrelatively arsenic-free water (Tseng, 1977). Arsenic-induced skincancer has also been attributed to water supplies in Chile, Argentinaand Mexico No excess skin cancer incidence has been observed inU.S. residents consuming relatively high levels of arsenic in drinkingwater (Morton et al., 1976). These U.S. studies, however, are notinconsistent with the existing findings from the foreign populations.The statistical powers of the U.S. studies are considered to beInadequate because of small sample size.

Studies of smelter worker populations (Tacoma, WA; Magma, UT;Anaconda, MT; Rinnskor, Sweden; Saganoseki-Machii, Japan) have allfound an association between occupational arsenic exposure and lungcancer mortality (Enterline and Marsh. 1982; Lee-Feldstein, ,1983;Axelson et al., 1978; Tokudome and Kuratsune, 1976; Rencher et al..1977). Both proportionate mortality and cohort studies of pesticidemanufacturing workers have also shown excess lung cancer deathsamong exposed persons (Ott et al., 1974; Mabuchi et al.. 1979). Casereports of arsenical pesticide applicators have further demonstratedan association between arsenic exposure and lung cancer (Roth,1958). There seems little doubt that .exposure to arsenic by inhalationincreases the risk of lung cancer. However, a strong multiplicativeeffect of arsenic exposure and smoking has been unequivocallyestablished (Pershagen et al., 1981) and poses special problems inrisk asessment.

Carcinogenic Risk Assessment

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Arsenic

In its initial evaluation of cancer risk based on epidemiologic evidenceand using standard EPA procedures, a carcinogenic slope factor of 15(mg/kg/day)"1 was determined (EPA, 1984), or a risk of 4.3E-04 forlifetime exposure to 1 jig arsenic/L in the drinking water. Assuming adally Intake of Inorganic arsenic of 30 jig/day for all sources (based onexcretion of inorganic and simple methylated arsenic; Smith et al..1977), this would correspond to an incidence of arsenic induced skincancers of about 40,000 cases per year in the U.S. population.Although the normal rate of skin cancer of different types is difficult toestablish (except for melanoma) due to underreporting, such anincidence would account for a major part of all skin cancers whichoccur in the U.S. This estimate lacks credibility, especially in view ofthe fact that arsenic-induced skin cancer is distinguishable from sun-induced skin cancer (EPA, 1986).

The EPA Risk Assessment Forum has completed a reassessment of thecarcinogenic risk associated with ingestion of inorganic arsenic. Riskestimates were adjusted for survival times and for the larger waterconsumption of Taiwanese as compared with U.S. males. Further.instead of using upper bound estimates based on the the linearizedmultistage model, a maximum likelihood approach was utilizedtogether with the Weibull model. The report concluded, that the mostappropriate basis for an oral estimate was the study by Tseng et al.(1977), which reported Increased prevalence of skin cancers inhumans as a consequence of arsenic exposure in drinking water.Based on this study a unit risk of 5.0E-05/ng/L was proposed, which isan order of magnitude lower than the previous estimate (carcinogenicslope factor of 1.75). However, it should be noted, that even whenapplying this lower estimate, practically no drinking water consumedIn the U.S. will fulfill the l.OE-06 risk goal. Imminently (mid-1990).USEPA may promulgate a once again lowered oral carcinogenic slopefactor for arsenic and, in addition, introduce a threshold below whichingested arsenic is not carcinogenic.

*

A recent memorandum by the Administrator of the EPA recommendedthat the above slope factor be adopted. The memorandum furthercounsels that "in reaching risk management decisions In a specificsituation, risk managers must recognize and consider the qualities anduncertainties of risk estimates. The uncertainties associated withIngested Inorganic arsenic are such that estimates could be modifieddownwards as much as an order of magnitude, relative to riskestimates associated with most other carcinogens. In such instances.the management document must clearly articulate this fact and statethe factors that influenced such a decision." (IRIS, 1988). \

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For workers exposed by inhalation to arsenic a geometric mean hasbeen calculated for data sets obtained within distinct exposedpopulations which Included exposure assessments based on airconcentration measurements for the Anaconda smelter and both airmeasurements and urinary arsenic for the ASARCO smelter (U.S. EPA,1984). The estimates were based on the assumption that the increasein age-specific mortality rate of lung cancer was a function only ofcumulative exposures. A slope factor of 5.0E+01 (mg/kg/day)"1, orunit risk of 4.3E-03/|ig/m3, was calculated assuming a 70 kg humanbody weight. 20 m3 air inhaled/day and 30% absorption of inhaledarsenic.

Due to the the fact that differences in smoking habits was notadequately taken into account as well as the exposure of these workersto a host of other potentially carcinogenic/potentiating factors, thevalidity of the EPA estimates for Inhalation exposure must bequestioned. In particular, the strong multiplicative effects betweenarsenic exposure and smoking mentioned above must be considered asan Important confounding factor.

Genotozlc effects and adverse effects on reproduction

Conflicting results have been obtained from Investigations of thegenotoxlc action of arsenic and arsenic compounds (for review, seeIARC 1980 and 1987). However, it is widely believed that these.agents exert their action by interfering with the normal repair andsynthesis of DNA. Thus, arsenic can inhibit DMA synthesis by bindingto thiol groups of the enzyme DNA polymerase. Several investigationshave demonstrated, that arsenic compounds inhibit DNA repair inbacteria as well as in human epidermal grafts following ultra-violetirradiation.

Results from bacterial mutation tests - like the Ames' test - havelargely been negative. Trivalent arsenic has been reported to inducegene conversion in yeast. A low Increase number of chromosomalaberrations (chromatid breaks, chromatid exchanges) in culturedhuman peripheral lymphocytes and in human diploid fibroblastinduced by sodium arsenate has been reported (Paton and Allison.1972). Equivocal results have been obtained in assays for theinduction of sister chromatid exchanges.

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In one study of people exposed to trivalent arsenic in drinking-water, jno increase in the incidence of sister chromatid exchanges or ""chromosomal aberrations was observed. A number of other studiespublished of occupational exposure to arsenic or patients treated witharsenic have shown increased levels of chromosomal aberrations orsister chromatid exchanges. The interpretation of these resultsremains uncertain because of methodological problems.

Trivalent arsenic did not induce dominant lethal mutations in mice,but It produced a small increase in the incidence of chromosomalaberrations and micronuclei in bone-marrow cells of mice treated invivo. It induced transformation in Syrian hamster embryo cells andgene conversion in yeast, but did not induce mutations or DNA strandbreaks In cultured rodent cells or mutations In bacteria.

Teratogenic effects (anencephaly. renal agenesis and ribmalformations) have been shown to occur after a single intravenousadministration of high doses (6-10 mg As/kg body weight) of sodiumarsenate to pregnant Syrian golden hamsters. Similar effects havebeen induced upon intraperitoneal injection of sodium arsenate inmice and rats .

F. Phannacokinetics and Metabolism

Studies in experimental animals as well as in man have shown thatover 90% of an ingested dose of dissolved inorganic trivalent orpentavalent arsenic is absorbed from the gastrointestinal tract.Inhalation usually involves particles containing inorganic arsenic. Mostof the inhaled and deposited arsenic will probably be absorbed fromeither the respiratory or the gastrointestinal tract. Systemic toxiceffects have resulted from occupational accidents where arsenic acidor arsenic trichloride have been splashed on workers, indicating thatthe skin is a possible route for absorption of arsenic (Ishinishi, et al.,1986).

Due to its accumulation in erythrocytes, the biological half-time ofarsenic In rats is relatively long (60 days). In other animals and inhumans, most inorganic arsenic is eliminated at a much higher ratemainly via the kidneys. Placental transfer of inorganic arsenic has


Arsenic

been demonstrated in both experimental anlnial (rat and hamster) andhuman studies. No data are available which indicate long-termaccumulation of arsenic. Some data on mice and rabbits exposed forup to one year to arsenic demonstrated that levels of arsenic in thebody increased during the first 2 weeks and then decreased.

The in vivo methylation of inorganic arsenic has been demonstrated inboth animals and man. Methylation efficiency decreases withincreasing dose levels. Following ingestion, or inhalation of inorganicarsenic, the major forms of arsenic excreted in human urine aredimethylarslnic add and methylarsonic acid accounting for about 60%and 20% of excreted arsenic, respectively, as well as smaller amountsof inorganic arsenic (about 20%). In other species, methylarsonic acidhas only been observed In minimal amounts. The marmoset monkey isthe only species to date which has been found to be unable tomethylate Inorganic arsenic (Ishinishi, et al.. 1986).

Urine is a suitable indicator medium for assessment of exposure toinorganic arsenic, since most studies show that the elimination ofarsenic, in both animals and man, takes place mainly via the kidneys.Arsenic levels In the hair of unexposed human adults are usually below1 mg/kg, whereas levels of up to about 80 ppm have been recorded insubjects with chronic arsenic poisoning (WHO/IPCS, 1981). However.it Is not possible to distinguish between arsenic adsorbed onto hairfrom external contamination and arsenic incorporated into hair fromthe internal body burden. Unless external contamination cannot beruled out, the use of hair arsenic as an indicator of exposure istherefore not recommended (Ishinishi. et al., 1986).

G. Discussion of Regulatory Standards

According to IARC there is sufficient evidence that arsenic iscarcinogenic to man (Group 1) and EPA has also- classified thesubstance as a human carcinogen (Group A).

The WHO Guidelines for Drinking-Water Quality lists a level of 0.05mg/L for inorganic arsenic (WHO, 1984). In the U.S. a MaximumContaminant Level Goal (MCLGJ of 0.05 mg/L has been set for drinkingwater. The MCLG corresponds to a risk level estimated by EPA that isfar above the incremental increase of cancer risk over a lifetime of onein a million.

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Under CERCLA a Reportable Quantity (RQ) for Release into theEnvironment of 1 pound has been proposed, based on the potentialcarclnogenlcity of arsenic. Further, evidence found in "Water-RelatedEnvironmental Fate of 129 Priority Pollutants" (EPA 440/4-79-029a) isInterpreted to indicate that this material, or a constituent of thismaterial, is bioaccumulated to toxic levels in the tissue of aquatic andmarine organisms, and has the potential to concentrate in the foodchain. To what extent consideration has been given to the fact thatarsenic is converted into the less hazardous organic arseniccompounds in these organisms is not clear.

EL References

Axelson, O, E. Dahlgren, C-D. Jansson. and S. O. Rehnlund (1978)Arsenic exposure and mortality: a case-referent study from a Swedishcopper smelter. Br. J. Ind. Med. 35. 8-15.

Clement Assoc.. (1985) Chemical, Physical, and Biological Propertiesof Compounds Present at Hazardous Waste Sites. Prepared for:USEPA. Prepared by: Clement Associates.

vjEnterline, P.E. and Marsh, G.M. (1982) Mortality studies of smelterworkers. Am. J. Ind. Med. 1. 251-259.

Enterline, P.E. and G.M. Marsh (1982) Cancer among workers exposedto arsenic and other substances in a copper smelter. Am. J. Epidemiol.116, 895-911.

EPA (1978) Metal Bioaccumulation in Fishes and AquaticInvertebrates, A Literature Review. EPA - 600/3-78-103

EPA (1980) Ambient Water Quality Criteria for Arsenic. EPA 440/0-80-00.

EPA (1984) Health Assessment Document for Inorganic Arsenic.Environmental Criteria and Assessment Office. Research TrianglePark. NC. EPA 600/8-83-02IF.

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EPA (1985) Water Quality Criteria; Availability of Documents. FederalRegister 50:30784.

EPA (1986) Quality Criteria for Water 1986. EPA-440/5-86-001.

EPA (1986) Risk Assessment Forum; Special Report on IngestedInorganic Arsenic and Certain Human Health Effects, Washington. D.C..

Goldblatt, E.L., Vandenburgh, A.S., and Marsland. R.A. (1963) Theusual and widespread occurrence of arsenic in well waters of Lanecounty, Oregon, Oregon Department of Health.

Higgins, I. (1982) Arsenic and respiratory cancer among a sample ofAnaconda smelter workers. Report submitted to the OccupationalSafety and Health Administration in the comments of the KennecottMinerals Company on the Inorganic arsenic rulemaking (Exhibit 203-5).

Higgins, I., K. Welch and C. Burchflel (1982) Mortality of Anacondasmelter workers in relation to arsenic and other exposures.University of Michigan. Dept. Epidemiology. Ann Arbor, MI.

IARC (1980) IARC Monographs on the Evaluation of the CarcinogenicRisk of Chemicals to Humans, Vol. 23, International Agency forResearch on Cancer, Lyon. ;

IARC (1987) IARC Monographs on the Evaluation of the CarcinogenicRisks to Humans • Overall Evaluations of Carcinogenicity: An Updatingof IARC Monographs Vol. 1 to 42, Suppl.7. Lyon, France.

IRIS (1988) The Integrated Risk Information System (EPA); Data filefor arsenic.

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Ishinishi. N.. K. Tsuchiya. M. Vahter. and B.A. Fowler (1986) In.Friberg, L. G.F. Norberg and V.B. Vouk (eds) Handbook on theToxicology of Metals 2nd Ed., Elsevier, Amsterdam.

Kroes. R.. M.J. van Logten, J.M. Berkvens. de T. Vries. and G.J. vanEsch (1974) Study of the carcinogenicity of lead arsenate and sodiumarsenate and on the possible synerglstic effect of diethylnitrosamine.Fd. Cosmet. Toodcol. J2, 671-679.

Ledet, A.E., Duncan, J.R., Buck, W.B.. and Ramsey F.K. (1973) Clinical,lexicological and pathological aspects of arsanlllc acid poisoning inswine. Clin. Toxicol. 6, 439.

Lee-Feldstein, A. (1983) Arsenic and respiratory cancer in man:Follow-up of an occupational study. In, Lederer: Arsenic: Industrial.Biomedical, and Environmental Perspectives (W. Lederer and R.Fensterhelm, Edts.) Van Nbstrand Reinhold. New York.

Mabuchi, K., A.M. Ullenfeld, and L.M. Snell (1979) Lung cancer amongpesticide workers exposed to inorganic arsenicals. Arch. Env. Health.34, 312-319.

McCabe, L.J.. Symons, J.M. Lee, R.D.. and Robeck. G.G. (1970) Surveyof community water supply systems, J. Am. Water Works Assoc. 62.670-687.

Moore, J.S. & S. Ramamoorthy. 1984. Heavy Metals in Natural Waters.Applied Monitoring and Impact Assessment. New York: Springer-Verlag.

Morton. W.. G. Starr. D. Pohl. J. Stoner, S. Wagner, and P. Weswig,(1976) Skin cancer and water arsenic in Lane County. Oregon, Cancer31. 2523-2532.

Norin. H.. and Vahter. M. (1984) Organic arsenic compounds in fish.Report to the National Swedish Environment Protection Board, SNVPM.

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Groupit

Arsentc

f Ott, M. G., B.B. Holder, and H.L. Gordon (1974) Respiratory cancer and- occupational exposure to arsenicals. Arch. Environ. Health 29. 250-

255.

Paton. G.R and A.C. Allison (1972) Chromosome damage in human cellcultures induced by metal salts. Mut. Res., 16, 332-336

Pershagen, G., S. Wall, A. Taube, and L. Unnman, (1981) Scand. J.Work Env. Health 7. 302-309.

Rencher. A. C.. M.W, Carter, and D.W. McKee, (1977) A retrospectiveepidemiological study of mortality at a large western copper smelter.J. Occupational Med. 19, 754-778.

Roth, F. (1958) [Bronchial cancer In vineyard markers with arsenicpoisoning], Virchows Arch. 33 J. 119-137 (in German).

Smith, T.J., Crecelius. E.A.. and Reading.J.C. (1977) Airborne arsenicexposure and excretion of methylated arsenic compounds, Env. HealthPersp. 19. 89-93.

Stokinger, H.E. (1981) in Patty's Industrial Hygiene and Toxicology.3rd. Ed.. John Wiley & Sons Inc.. .p. 1521.

Tokudome, S. and M. Kuratsune (1976) A cohort study on mortalityfrom cancer and other causes among workers at a metal refinery, Int.J. Cancer 27. 310-317.

Tseng. W.-P. (1977) Effects and dose-response relationships of skincancer and Blackfoot disease with arsenic. Env. Health Persp. 19, 109-119.

WHO (1984) Guidelines for Drinking-Water Quality. Vol. 1.Recommendations. Geneva.


flR3IH25i*

Arsenic

WHO/IPCS (1981) International Programme on Chemical Safety;Environmental Health Criteria No. 18. Arsenic. WHO, Geneva.

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Q(Q(Jp

BR304256

Bartum

CAS No.: 7440-39-3Synonyms: NA


Chemical Formula: EaForm: yellowish-white, slightly lustrous lumps;

body-centered cubic structure:somewhat malleable; easily oxidized

Chemical Class: metalAtomic Weight: 137.33Boiling Point: approximately 1600°CMelting Point: approximately 710°C

Specific Gravity: 3.6Solubility in Water: decomposes. BaSO4 has a solubility of 1.6

mg/1 at20°CSolubility in Organics: alcohol

Organic CarbonPartition Coefficient: NALog OctanoI/Water

Partition Coefficient: NAVapor Pressure: NAVapor Density: NA

Henry's Law Constant: NABloconcentration Factor; NA


Safe Drinking Water ActMaximum Contaminant Level Goal(MCLG for Drinking Water (mg/L): NA

Maximum Contaminant Level (MCL)for Drinking Water (mg/L): NA

Clean Water ActAmbient Water Quality Criteria (mg/L)Human Health ,

Water and Fish Consumption: NAFish Consumption Only: NA . .

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Bartum

Aquatic Organisms (mg/L)Fresh Water

Acute: NAChronic: NAMarine

Acute: NAChronic: NA

ReferencesSax and Lewis 1989. Verschueren 1983, The Merck Index 1983.SPHEM 1986, EPA 1986NA - Not Available

C Fate and Transport

Barium is a yellowish-white metal of the alkaline earth group whichoccurs in nature chiefly as barite (BaSO4) and witherlte (BaCQs), bothof which are highly insoluble salts. Barium is stable in dry air. butreadily oxidizes In humid air or in water. Industrial applications ofbarium salts include metallurgy, paints, glassmaking. electronics andmedicine. The predominant environmental fate process for barium ishydrolysis, while the major environmental transport process forbarium appears to be volatilization due to fugitive dust emissionsand/or dry fallout. Minor environmental significance is placed uponthe importance of volatilization, biodegradation, hydrolysis, photolysis.oxidation, bioaccumulation, and sorption of barium due to the limitedinformation available. Barium ions in solution are frequentlyprecipitated or removed from solution by absorption andsedimentation (McKee and Wolf, 1963; National Academy of Sciences.1974). Most barium enters human receptors via air or water; littlebarium is found in foodstuffs.

Di Ecotoxlcology

Other than barite and wltherite, many barium salts are water-soluble.Soluble barium salts are reported poisonous (Lange. 1965; NationalAcademy of Sciences, 1974). This problem is exacerbated by acid rainsince lessening of the pH causes further leaching of barium intosurface,waters. Drinking waters normally contain 0.6-10 (ig/1 barium,with extremes in western states at 100-3000 g/1 (Katz. 1970; Little.1971).

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Barium

Experimental data indicate that the soluble barium salt concentration, in fresh water supplies would have to exceed 50 mg/1 before- aquatic\ life Is adversed affected. This is, in part, due to the abundance of

sulfate and carbonate anions in fresh waters, both of which formInsoluble salts of barium, hence, removing this potential toxicant fromsolution. Similar conditions appear to be found in most saline surfacewaters such that no restrictive limits for barium concentrations needto be placed in this medium either. Hence, the ambient water qualitycriterion of 1 mg/1 is strictly for domestic water supplies and basedsolely upon human health.

E. Human Toxicology

The basic mechanisms of barium toxicity appear to involve antagonismto potassium, the latter, of course, being an essential element incellular osmotic balance and therefore central In many homeostaticfunctions, including neurotransmission. Barium poisoning isaccompanied by severe hypokalemia and potassium provides aneffective antidote.The symptoms of clinically overt barium poisoning are muscularstimulation followed, in short order, by paralysis. In severe cases

f respiratory paralysis is sufficient to cause death by asphyxiation. The- acute oral LD50 in humans has been estimated to be 70 mg/kg.

Administration of barium to test animals has been used to study thebasis of human toxicology in experimentally modifiable systems. Ratsgiven 5 ppm barium acetate In drinking water showed no adverseeffects (Schroeder and Mitchener, 1975). As high as 250 ppm barium'chloride in drinking water was tolerated well by rats in experimentsby Tardlff et al (1980). Chickens displayed an even greater bariumtolerance, with 1000 mg/kg showing no adverse effect when mixedinto chicken feed (Johnson et al, 1960).Barium-containing dusts have been associated with a form ofpneumoconiosis termed "barltosis." This has been seen amongworkers chronically exposed to barium sulfate dust and isaccompanied by slight diminution of pulmonary function.Rats given radioactively- tagged barium sulfate particles by intratrachealadministration have been repprted to develop bronchiogeniccarcinoma (Amber and Watson, 1958). However, these experimentsare unconvincing, both on the basis of increases which are not 95percent statistically significant and that there were no controls forradiation carcinogenesis alone in the absence of barium.

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Barium

It should be noted that barium is a prevalent contaminant of theaverage human diet. It is found naturally almost everywhere calcium isfound (ubiquitously) and travels similarly to calcium through thefoodchaln. Some foods (especially brazil nuts) are quite high inbarium, and the average human diet has been reported to contain 1xng barium per day (Schroeder et al, 1972).A further review of barium toxicity is found In Reeves (1986).

F. Phannacokinetlcs

Soluble barium salts are readily absorbed from the alimentary canal aswell as from all segments of the respiratory tract. Barium sulfate.however, is virtually Insoluble and is therefore not readily absorbedfollowing Ingestion or inhalation. The biologic half-life of bariumsulfate in lungs is 8-9 days (Cuddihy and Ozog, 1§73; Morrow et al,1964).As with other alkaline earth metals, barium accumulates in the skeletalsystem, preferentially onto bone surfaces (Elsser et al, 1969). Theavailability of barium for bone uptake is greater than that of eithercalcium or strontium (Domanski et al. 1980).Intravenous injection of barium, low concentrations are found in most ))soft tissues except for the submaxillary gland and pigmented portions -of the eye (especially the choroid). Barium is not bioaccumulated. Ofexcreted barium, 90 percent is found in the feces.

G. References

Amber. H. and Watson, J.A. (1958) Arch. Ind. Hlth. 17. 230-242.

Cuddihy. R.G. and J.A. Ozog (1973) Nasal adsorption of CsCl. SrCl2.BaCl2 and CeCl3 in Syrian hamsters. Health Physics 25, 219-224.

Domanski, T.. D. Witkowska and I. Garlicka (1980) Influence of age onthe discrimination of barium In comparison with strontium.duringtheir incorporation into compact bone. Acta Physiol. Pol. 31, 289-296.

Elsser. J.C, (1969) J. Bone Surgery 51A, 1397-1412. ..V flr

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f , Johnson. D. (1960) Proc. Soc. Exptl. Biol. Med. 104, 436-438.

Katz, M. et al (1970) Effects of pollution on fish life, heavy metals.Ann. Lit Rev. J. Water Poll. Cont. Fed 42. 987.

Lange, N.A. (1961) Handbook of chemistry, 10th ed.. McGraw-HiU. NY.

Little, A.D. (1971) Inorganic chemical pollution of fresh water. Waterquality data book. Vol. 2, U.S. EPA, 18010 DPV, pp. 24-26.

McKee, J.E. and W.W. Wolf (1963) Water quality criteria. Cal. StateWater Res. Cont. Bd. Publ. No. 3-A.

Morrow. P.E. (1964) Health Physics 10. 543-549.

Reeves, A.L. (1986) Ja, Friberg, L., G.F. Nordberg and V.B. Vouk (eds)f Handbook on the Toxicology of Metals, 2d ed., pt. II. pp. 84-94,V_> Elsevier.

Schroeder, H.A., I.H. Tipton and A.P. Nason (1972) Trace metals inman: Strontium and barium. J. Chronic Dis. 25, 491-517.

Schroeder. H.A. and M. Mitchener (1975) Life-term studies in rats:Effects of aluminum, barium, beryllium and tungsten. J. Nutr. 105,421-427.

U.S. EPA (1986) Quality criteria for water 1986, Office of WaterRegulations and Standards, Washington, D.C., EPA 440/5-86-001

U.S. National Academy of Sciences (1974) Water quality criteria, 1972.National Academy of Engineering, Washington. D.C.

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AR30t*26l

flR30l*262

Benzene

Bengene

CASNo.: 71-43-2Synonyms: benzol, benzolene, coal naphtha, carbon

oil, phenyl hydride, cyclohexatriene

A. Physical and Chemical Proerties

Chemical Formula:Fonn: clear colorless liquid

Chemical Class: monocyclic aromaticMolecular Weight: 78. 1 1

Boiling Point: SO.Ol'CMelting Point: 5.5°C

Specific Gravity: 0.8786 at 20°/4°CSolubility In Water: 1.750 mg/L

Solubility in Organics: rniscible with alcohol, ether, acetic acid.acetone, chloroform, glacial acetic acid,oils, and carbon tetrachloride

Organic CarbonPartition Coefficient: 83Log Octanol/Water

Partition Coefficient: 2.13at20°CVapor Pressure: 76 mm at 20°CVapor Density: 2.77

Henry's Law Constant: 5.59E-03Bioconcentration Factor: 5.2



Maximum Contaminant Level (MCL)for Drinking Water (mg/L): 0.005 .


Water and Fish Consumption: 6.60E-04Fish Consumption Only: v. 4.00E-02

Aquatic Organisms (mg/L)Freshwater:Acute: 5.30E+00

Chronic: NA

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flR30t*263 —-«,

Benzene

MarineAcute: 5.10+01

Chronic: NA

ReferencesSax and Lewis 1989, Verschueren 1983. The Merck Index 1983,SPHEM 1986, EPA 1986NA - Not Available


Benzene Is a ubiquitous monocycllc ring of six carbons which share Pielectrons in a resonant structure. It is produced biologically in manyanabolic and catabollc processes and Is amenable to biologicaldegradation when encountering organisms. Indeed, as will be detailedbelow, its metabolites are the toxic intermediaries, rather thanbenzene itself. Hence, benzene is very short lived in any environmentwhich is biologically active. It volatilizes easily from surface waters orsurfkial soils and solubillzes freely in groundwater such that it oftenmoves at the solvent front during soil purging of organics. Along withtoluene and xylenes. benzene is a marker of gasoline spillage.Domestic gasolines may be up to 2 percent benzene-toluene-xylene . j)(BTX), with foreign "benzine" being up to 20 percent BTX. As the only -carcinogen of this series, benzene drives risks where gasoline spillagehas occurred.Benzene occurs naturally in the environment, but anthropogenicinputs/releases have considerably augmented its concentrations invarious media. Predominantly used as a starting material in thesynthesis of organic chemicals, benzene is also used as a commercialsolvent and in the manufacture of pesticides. A moderately volatileorganic chemical with a moderate water solubility, benzene's lowchemical reactivity is related to the stability of the aromatic ring. Thepresence of benzene in excess of its water solubility would rise to thewater's surface.The major environmental fate process is volatilization of benzene fromboth soil and water to the atmosphere. The volatilization half-life ofbenzene in water one meter thick at 25°C has been estimated at 4.8hours. The overall half-life of benzene in water is estimated at 1-6days. Once volatilized, benzene is available for oxidation by hydroxylradicals, yielding phenol and ozone. The atmospheric half-life ofbenzene in rural and urban settings is calculated to b.e 458 and 46hours respectively, with an overall atmospheric half-life exceeding one ^

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Benzene

day. Sorption to soils, sediments, and suspended particles occursunder conditions of constant exposure; however, the limited'datasuggests sorption is a less important fate process. Benzene can beconsidered moderately mobile In soils. Studies indicate thatmicroorganisms in soil and water are capable of biodegrading benzene.However, this process is slow compared to the rate of volatilization.Benzene is resistant to hydrolysis and photolysis. There is a paucity ofdata regarding the bioaccumulation of benzene in aquatic organisms.The limited data indicates bioaccumulation may occur in tissues with ahigh lipid content, however, the octanol/water coefficient suggests theoverall level is low. The major environmental transport process forbenzene is volatilization from soil and water to the atmosphere.

IX Ecotoxicology

Benzene has demonstrated the capacity to cause adverse effects onaquatic life. Benzene has elicited acute toxic responses in freshwateraquatic species at concentrations as low as 5.3 mg/1 (USEPA, 1986).Although benzene is only slightly soluble and highly volatile, there is acycling which occurs between the atmosphere and the water, thereby,providing a means for prolonged bioavailability. Numerous studieshave been performed on single species exposed to benzene inlaboratory media; however, insufficient data exists regarding theeffects of benzene contamination on the higher levels of organization(e.g. ecosystems).Benzene has inhibited cell multiplication In the bacteria (Pseudomonasputida) at 92 mg/1 algae (Mfcrocystfs aeruginosa] at >1400 mg/1, greenalgae (Scenedesmus quadricauda] at >1400 mg/1 and protozoans'(Entosiphon sulcatum) and (Uronema parduczi] at >700 mg/1 and 486mg/1 respectively (Verschueren 1983), EPA: Canada 1984).Benzene exposure caused an inhibition of photosynthesis throughdecreased carbon fixation in the algae (Selenastrum capricojutum}. A48-hour EC50 value of 525 mg/1 was reported for an alga (Chlorellavulgaris). Growth Inhibition was observed In a marine dinoflagellate(Amphidiniwn carferae), diatom (Skeletonema costetum), and alga(Circosphaera carterae] at benzene levels between 10 and 1000 mg/1(EPS: Canada 1984).Benzene is iipophilic and may bioaccumulate in organisms, the targettissues are the brain, liver, and any tissue with high lipid content.Benzene has been reported to accumulate in fish tissues at levels 1000times the concentration in the ambient environment.

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Benzene

In laboratory studies with invertebrates, the cladocerans (Daphntamagna, D. pulexj reached LCso concentrations at 178 and 265 mg/1. >respectively (US EPA 1980). LD50 values of 59 ppm and 210 ppm Jwere reported for mosquito larvae (4th instar) and grain weevils.respectively. Stage 1 crab larvae (Cancer magister] reached an LC50 at108 mg/1 of benzene.In additional invertebrate studies with crustaceans exposed tobenzene, the 96-hr LCSO's for grass shrimp (Palaemonetes pugio) andbay shrimp were 27 mg/L A TLm value of 21 mg/1 and 96 hr-LC50 of66 mg/1 were given for the brine shrimp (EPS: Canada 1984).Fish species appear to be more susceptible to the toxic effects ofbenzene than invertebrates. The early life stages in fish developmentand salmonid species are more sensitive to benzene than adults ornon-game fish (i.e. catfish, suckers, etc.). An LC50 value of 12 mg/1 wasreported for a 1 hour static bioassay with brown trout (Salmo trutta)yearlings. Exposure of herring (Clupea pallasQ and anchovy (Engraulismordex) larvae to benzene caused a delay in larvae developmentdecrease in feeding and growth, and increase respiration rate at 10-35ppm, and delayed egg development and abnormal larvae at 35-45 ppm.Yong coho salmon (Oncorhynchus kisutch] exposed to benzene inartificial seawater. experienced no significant mortalities at 10 ppmafter 96 hours. 60% mortality at 50 mg/1 after 24 up to 96 hours, and100% mortality at 100 mg/1 after 24 hours (Verschueren 1983). . vIn a softwater static bioassay, Plckering (1966) determined the 28. V_x48. and 96 hour Median Tolerance Limit (TLm) for fathead minnowswere 35.5 mg/L, 35 mg/L and 33.5 mg/L. Pickering (1966)conducted the same test in hardwater and reported 24. 48. and 96hour TLm's for bluegills (Lepomis mocrochirus) were all 22.5 mg/L.Additional studies of bluegills exposed to benzene revealed a 24 and48 hour LD50 of 20 mg/L. The 96-hour LCso for the channel catfish(Jctalurus punctatus) and rainbow trout (Salmo gairdneri] werereported as 425 mg/L and 9.2 mg/L, respectively (EPS: Canada 1984).The difference in LCso values for these 2 fish species supports thepostulate that salmonlds are considerably more sensitive to benzenecontamination than rough fish species (e.g., catfish, sucker's).Striped bass (Morone saxattlis), a saltwater fish species, attained LCsolevels of benzene after 96 hours of exposure at 4.1 mg/1 (US EPA1980) and 5.8 - 10.9 mg/I (Verschueren 1983).

E. Human Toxicology

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Benzenei i

Benzene displays a low acute toxicity in mammals. It exerts mainly anarcotic action at high concentration levels.in both animals and man.Chronic intoxication in man may give rise to severe bone marrowtoxicity. eventually resulting in leukemia.

• EpidemiologyEpidemiologic studies have shown that exposure of workers tobenzene is associated with increased risk of aplastic anemia and ofleukemia (IARC, 1982; Infante, 1978; Infante and White, 1983;Grossenbacher and Lob, 1982; Decoufle et al, 1983; Aksoy, 1985;Infante and White, 1985; Rinsky et al. 1987). Benzene-associatedleukopenla has been reported in humans. AKR/S mice, CD mice andWistar rats.

• HeznatologyThe number of blood lymphocytes per cu. mm. in C57BL/6 BNL miceexposed to benzene at 100 or 400 ppm by inhalation for 6 hours perday, 5 days a week for 2 weeks, was 40-50% that of controls. Thenumber of blood lymphocytes was lower than that of the controls after4, 8 or 16 weeks' exposure at 300 ppm, but returned to control levels8-10 weeks after termination of exposure (Cronkite et al, 1985).Benzene affected the hematopoietic system of F344/N rats andB6C3F1 mice (NTP. 1986). Dose-related leukopenia, predominately alymphocytopenia. was observed for rats and mice of each sex. and.compound-related lymphoid depletion and Increased extramedullaryhematopoiesis in the spleen were observed in rats of each sex. Theincidences of malignant lymphomas In all dose groups of mice weregreater than those of controls, however, benzene-associated neoplasticeffects on the hematopoietic system were not observed in male orfemale rats.

• Genetic ToxicologyBenzene is not mutagenic in short-term test systems such as the Amestest, with or without metabolic activation. Although benzenemetabolites, such as catechol and hydroquinone can induce slster-chromatid exchanges (SCEs) in human lymphocytes in vitro, benzeneitself Induces SCEs in vitro only after metabolic activation (Morimotoet al, 1983; Morimoto. 1983). In addition. Tice et al (1982) andErexson et al (1985) have shown that benzene requires metabolictransformation in order to induce SCEs in bone marrow cells of micein vitro.


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Benzene

The acute toxicity of benzene is low (LCso. 7 hrs inhalation, for the rat10.000 ppm; LD50, oral for the rat 6 g/kg). Signs of depression of thecentral nervous system represents main symptoms of exposure to highlevels.Apparently, benzene - or more probably hydroquinone - a metabolite ofbenzene Inhibits maturation of early blood cell precursors In the bonemarrow. It has long been recognized that benzene, upon long-termexposure of man and experimental animals to high concentrations.may elicit signs of severe damage to the haematopoietic systemincluding anemia, reduced number of circulating white blood cells andplatelets. These effects are accompanied by clinical signs like generalweakness, pallor, purpura, and an increased susceptibility to infection.The bone marrow may exhibit hyperplasia as well as aplasia. A numberof fatal cases of aplastic anemia (pancytopenia) due to exposure tobenzene have been reported in the literature.

• Carcinogenic ActivityThe association between chronic occupational exposure to highconcentrations of benzene and the development of leukemias - mainlyacute myelogenous leukemia - has been firmly established. Thecarcinogenic action of this compound has also been corroborated byfindings in experimental animals. In many cases it has been shownthat pancytopenia precedes development of neoplastic disease(average Induction time, about 10 years). However, it is by no meansclear, whether or not significant bone marrow toxicity is aprerequisite for subsequent development of leukemia. Anotherunresolved controversy concerns the reliability of the exposure data insome of the epidemiologlcal investigations linking the appearance ofleukemia to lower exposures (1-50 ppm).Genotoxic effects and adverse effects on reproduction; Negative resultshave been obtained with benzene in the Ames' Salmonella test using anumber of different tester strains. However, this compound seems toinduce chromosome aberrations and sister chromatid exchanges Inmammalian cells in vitro, and a number of positive reports have beenpublished on an Increased incidence of such aberrations In bonemarrow cells of mammals.There are numerous case reports of chromosome aberrations ofperipheral blood lymphocytes in workers with hematological signs ofchronic benzene toxicity, and such findings have also been describedin workers exposed to lower levels of benzene where overt signs ofbone marrow toxicity has been absent. However, due to the fact thatthe incidence of aberrations is influenced by a number of factors (age,smoking, etc.). the significance of these findings have been questionedin view of a questionable choice of control groups.

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Benzene

Evidence from experimental animals indicate that benzene may causetoxic effects to the fetus at 50 ppm and above. However, there seem tobe no evidence that benzene is teratogenic.


Benzene may be absorbed by inhalation, ingestion as well as upon skincontact. However, experimental investigations have shown dermalabsorption to be slow, and in most situations inhalation is by far themost important route of absorption. Benzene is rapidly distributedthroughout the the organism and - as with other lipophUic solvents -preferentially concentrated in fatty tissues. In mammals, includingman, an appreciable fraction of the absorbed dose (10-50%) Isexcreted unchanged In the .expired air. By metabolic oxidation to anunstable epoxide (principally In the liver) benzene is transformed tomore polar products like phenol (main product), and to a lesserextent to other metabolites like catechol and hydroquinone. Themetabolites are excreted in the urine mainly in the conjugated formas sulphates and glucuronides. The elimination of benzene from themammalian organism is relatively rapid and most of the absorbed doseis excreted within 48 hrs following acute exposure. The excretion ofphenol is customarily used for monitoring occupational exposure tobenzene.

G. Discussion of Benzene Leukemogenesis

* Benzene Exposure and Chronic Myelogenous LeukemiaThe prevailing medical literature unambiguously supports theassociation of benzene exposure to induction of acute myelogenousleukemia (AML). In this section epldemioiogic evidence issummarized which demonstrates that chronic myelogenous leukemia(CML) is also vastly increased among workers exposed to benzene, thatAML and CML are probably acute and chronic manifestations of thesame malignancy of the myeloid portion of hematopoietic tissue. Inaddition to AML, many other leukemias, predominantly CML, havebeen epidemiologically linked to benzene exposure. Two summariesof types of leukemia among benzene workers have clearly shown thepredominance of myelogenous leukemia of the chronic type:

• Benzene in Florida Groundwater

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Benzene

In order to address the potential health impacts of benzene incontaminated groundwater. this document summarized the types of \leukemias associated with benzene exposure in numerous published \~S *studies (both U.S. and foreign). All told, of 134 leukemias amongbenzene-exposed workers, 47 were diagnosed as AML and 30diagnosed as CML.

• Browning's Study of Benzene-induced LeukemiasIn her textbook entitled Toxicity and Metabolism of IndustrialSolvents, Ethel Browning found that 21 out of 61 leukemias inbenzene workers were CML.Hence, despite the more frequent occurrence of AML among benzeneworkers, CML is almost as frequently diagnosed and is clearly one ofthe preferential leukemias induced by exposure to benzene.

• Latency for Benzene-induced LeukemogenesisSeveral studies associate the time of benzene exposure withdevelopment of leukemia. The breakdown of AML and CML cases inthe classic NIOSH paper by Infante, Wagoner. Rinsky and Young(1977) Is revealing in regard to the latency question. The followingTable Is excerpted from their Table III:

Temporal Factors in Benzene-induced Leukemia j )Type of Age at Years from Initialleukemia* death exposure to death

AML 60 13AML 65 10AML 62 21AML 57 19CML 29 2**ML 28 3

*AML - acute myelogenous leukemiaCML - chronic myelogenous leukemia

"Acute or chronic not indicated.

Whereas the average age at death from AML for the benzene workersin this study was 61. the age at death for the CML case was 29 and for

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Benzene

the unspecified myelogenous leukemia at 28. Strikingly, both the CMLand unspecified myelogenous leukemia cases reported in the Lancetstudy had received less than five years of exposure to.benzene prior totheir deaths from leukemia.

H. References

Aksoy, M. (1985) Malignancies due to occupational exposure tobenzene. Am. J. Ind. Med.7, 395-402.

Browning, E. (1965) Toxicity and Metabolism of Industrial Solvents.Elsevier, Amsterdam (p. 41).

Cronkite, E., R. Drew, T. Inoue and J. Bullis (1985) Benzenehematotoxicity and leukemogenesis. Am. J. Ind. Med. 7, 447-456.

DeCoufle, P., W. Blattner and A. Blair (1983) Mortality among chemicalworkers exposed to benzene and other agents. Environ. Res, 30. 16-25-

Environment Canada: Environmental and Technical Information forProblem Spills, Benzene. Ottawa, March 1984.

Environmental Protection Service (EPS): Canada. 1984.Environmental and Technical Information for Problem Spills. Benzene.Prepared as part of the series: ENVIRO TIPS.

Erexson, G.. J. Wilmer and A. Kligerman (1985) Sister chromatidexchange induction in human lymphocytes exposed to benzene and itsmetabolites in vitro. Cancer Res. 45, 2471-7.

Florida Petroleum Council (1986) Benzene in Florida Groundwater.An Assessment of the Significance to Human Health. AmericanPetroleum Inst.. Washington, D.C.

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Health and Safety Executive (1982) Toxicity Review 4, Benzene. HerMajesty's Stationary Office, London. v

Infante. P. (1978) Leukemia among workers exposed to benzene.Tex. Rep. Biol. Med. 37. 153-161.

Infante, P.P., J.K. Wagoner. R.A. Rinsky and R.J. Young (1977)Leukemia in benzene workers. Lancet 2: 76-78.

Infante, P. and M. White (1983) Benzene: Epidemlologlc observationsof leukemia by cell type and adverse health effects associated with low-level exposure. Env. Hlth. Persp. 52, 75-82.

Infante, P. and M. White (1985) Projections of leukemia riskassociated with occupational exposure to benzene. Am. J. Ind. Med. 7,403-413.

International Agency for Research on Cancer (IARC) (1977). IARCMonographs on the Evaluation of Carcinogenic Risks of Chemicals toMan, Vol. 15. pp. 255-264. '

International Agency for Research on Cancer (IARC) (1982) IARCMonographs on the Evaluation of Carcinogenic Risks of Chemicals toMan, Vol. 29. pp. 95-148.

Maibach, H.I., and Anjo, D.M. (1981) Percutaneous penetration ofbenzene and benzene contained in solvents used in the rubberindustry. Arch. Env. Health 36, 256-60.

Morimoto, K. (1983) Induction of sister chromatid exchanges and celldivision delays in human lymphocytes by microsomal activation ofbenzene. Cancer Res. 43, 1130-34.

Morimoto, K., S. WolfF and A. Koisumi (1983) Induction of sister-chromatid exchanges in human lymphocytes by microsomal activationof benzene metabolites. Mutat. Res. 119. 355-360.


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OSHA (1985) Occupational Exposure to Benzene. Federal Register 50.Dec. 10, p.50512.

Pickertng, Q.H. and C. Henderson (1966) Acute Toxicity of SomeImportant Petrochemicals to Fish. Journal of the Water PollutionControl Federation 38(9): 1419-1429.

-Rinsky. RA.. A.B. Smith, R. Hornung, T.G. Fiiloon. R.J. Young. A.H.Okun and P.J. Landrigan (1987) Benzene and leukemia: Anepidemiologlc risk assessment. New Engl. J. Med. 316, 1044-50.

Tice, R., T. Fogt and D. Costa (1982) Cytogenetic effects of inhaledbenzene in murine bone marrow. In, Tice, Costa and Schaich (eds)Genotoxic Effects of Airborne Agents. Plenum Press. NY (pp. 257-275).

US EPA (1980) Ambient Water Quality Criteria for Benzene. EPA440/5-80-018.

US EPA (1985) Health advisories for 52 chemicals which have beendetected in drinking water, PB 86-1118338, Washington.

US EPA (1986) Quality Criteria for Water 1986. EPA 440/5-86-001.

U.S. National Toxicology Program (1986) Toxicology andcarcinogenesis studies of benzene. National Inst. Health Report 289.

World Health Organization (1982) IARC Monograph on the Evaluationof the Carcinogenic Risk of Chemicals to Humans, Vol. 29, Lyon.France.

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Beryllium

of the circulating beryllium is excreted in the urine, but an appreciablefraction is gradually transferred to and deposited in the skeleton.

Discussion of Regulatory Standards

According to IARC there is sufficient evidence that beryllium andberyllium compounds Induces neoplasms in experimental animals, andthat there is limited evidence of carcinogenicity in humans (Group2A). EPA has also classified beryllium in class Bl. The current OSHA 8hr TWA has been set at 2 ig/mS. No Maximum Contaminant Level(MCL) for drinking water has established for beryllium.

H. References

ATSDR (1988) Toxicological profile for beryllium. Agency for ToxicSubstances and Disease Registry. ATSDR/TP-88/07.Clement Assoc. (1985) Chemical. Physical, and Biological Propertiesof Compounds Present at Hazardous Waste Sites. Prepared For:USEPA. Prepared By: Clement Assoc., Inc. Arlington, VA.

_/- Reeves, A.L, (1986) "Beryllium" In Handbook on the Toxicology ofMetals. Vol. II, 2nd. Ed. (Friberg, L., et al, eds), Elsevier. Amsterdam,pp. 95-116.Reeves, A.L. and O.P. Preuss (1985) The immunotoxicity of beryllium.In, Dean, J. et al, (eds) Immunotoxicity and ImmunopharmacologyRaven Press, NY, pp. 441-455.Schroeder. H.A. and M. Mitchener (1975) Life-term studies in rats:Effects of aluminum, barium, beryllium and tungsten. J. Nutr. 105,421-427.Sendelbach. L.E., H.P. Mitsch and A.F. Tryka (1986) Acute pulmonarytoxicity of beryllium sulfate Inhalation in rats and mice: Cell kineticsand histopathology. Toxicol. Appl. Pharmacol. 85. 248-256.Stoklnger. H.E. (1981) "Beryllium" In Party's Industrial Hygiene andToxicology (Clayton, G.D.. and Clayton, F.E., Edts.) Vol. 2A, John Wiley.New York. p. 1537.USEPA (1978) Metal Bioaccumulation In Fishes and AquaticInvertebrates, A Literature Review. EPA - 600/3-78-103.USEPA (1979) Reviews of the environmental effects of pollutants: VI.Beryllium. ECAO. Cincinatti, OH (EPA-600/1-79-028).

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ARSONS I

Beryllium

USEPA (1980) Ambient Water Quality Criteria for Beryllium. EPA -440/5-80-024.USEPA (1986) Quality Criteria for Water 1986. EPA - 440/5-85-001.Wagoner. J.R.. P.F. Infante and D.L. Bayiiss (1980) Beryllium: Anetlologic agent in the induction of lung cancer, non-neoplasticrespiratory disease and heart disease among industrially exposedworkers. Environ. Res. 21, 15-34.World Health Organization, International Agency for Research onCancer (1987) IARC Monographs on the Evaluation of theCarcinogenic Risk of Chemicals to Humans, Suppl. 7, Lyon. France,p. 127.

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Beryllium


Like the other metals discussed here, beryllium is carcinogenic forhumans by inhalation. This conclusion comes from epidemiologicstudies of workers exposed to beryllium dust in which the lung cancerincidence is clearly increased. It appears that berylllosis. theautoimmune disease discussed above which results in pulmonarygranule formation, must occur for beryllium induction of lung cancer.

Whether beryllium is carcinogenic by ingestion is considerably lessclear. There are no epidemiologic data which link ingestion ofberyllium to increased cancer risk. Although increased lung tumorshave been seen in experimental animals fed beryllium in their diet.the tumor frequency was not proportional to dose and the results havebeen interpreted as due to aspiration of gastrointestinal reflux.

Due to the poor quality of data concerning the oral carcinogenicity ofberyllium, EPA has recently withdrawn an oral carcinogenic potencyfactor for beryllium from its Integrated Risk Information System(IRIS). A new oral carcinogenic potency factor for beryllium has beenintroduced into IRIS following a re-examination of experimental data.Whether or not this occurs in the near future, this is ERM's positionon the oral carcinogenicity of beryllium as based upon a careful studyof extant data.

ERM maintains that there is no basis for the conclusion that berylliumis carcinogenic by the oral route. In the absence of any such data fromepidemiologic studies in humans, the sole source of data for scrutinyremains studies of experimental animals fed beryllium. If theresponse in animals were linear with dose, or If the response were toorgan systems other than the lungs. ERM might be convinced of thevalidity of these studies. However, neither condition is satisfied andthe studies are essentially worthless in the formation of a decisionregarding the oral carcinogenicity of beryllium.

Until a convincing experimental or epidemiologic study which clearlydemonstrates oral carcinogenicity of beryllium Is available, ERMbelieves it is prudent to treat beryllium like other metals which arecarcinogenic by inhalation and not ingestion. These other metals

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flR30l*279

Beryllium

which are . carcinogenic by inhalation, but not ingestion includecadmium, nickel and hexavalent chromium. ERM maintains that, untilproven otherwise, beryllium ought to be added to this list.

Beryllium metal, beryllium-aluminium alloy, as well as severalberyllium compounds have been shown to induce benign(adenomatous) as well as malign lung tumors (squamous cellcarcinomas) in rats and monkeys after inhalation or intrabronchialimplantation. In addition, beryllium and beryllium compounds havebeen demonstrated to cause osteosarcomas (bone tumors) in rabbitsfollowing Intravenous administration. There exists some indication ofan elevated incidence of lung cancer in occupatlonally exposedworkers.

Genotozlc effects and adverse effects onreproduction:

A positive geno toxic response (chromosome aberrations, sisterchromatid exchanges) has been obtained in several mammalian in vitrosystems. Results from bacterial systems have been equivocal.

Beryllium compounds do not appear to cross the placental barrier Insignificant concentrations, and the administration of these agents hasnot been associated with specific teratological or embryotoxic effects.


Beryllium and beryllium compounds is less readily absorbed from thegastrointestinal tract, and at levels of 0.6-6.6 jig Be/day in thedrinking water, about 80 % remains unabsorbed. Since mostberyllium salts do not remain soluble at physiological pH, there isgenerally little systemic diffusion following skin contact, and ionicberyllium becomes largely bound to epidermal constituents.

Administration by inhalation provides a more effective route ofentry. After acute inhalation exposure, the pulmonary berylliumcontent is Initially halved during the first 14 days, but thereafter theclearance rate decreases rapidly, and residual encapsulated berylliummay be detected in the lungs years after the primary exposure. A part

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flR30l*280

Beryllium

In addition, the early life stages (i.e. Juveniles) demonstrate a greatersensitivity to beryllium than adults.

E. Human Toxicology

Beryllium and compounds of beryllium are not readily absorbed fromthe gastrointestinal tract, and exposures to these substances byinhalation present a much greater health hazard than by ingestion. Inexperimental animals Inhalation of beryllium and/or its compoundshas Induced lung tumors in monkeys and rats, and bone tumors in therabbit by intravenous administration. Other toxic effects associatedwith oral or parenteral administration of beryllium to experimentalanimals include skeletal changes, lever and kidney necrosis, anemiaand adrenal imbalance.

In man chronic exposure by inhalation to beryllium or berylliumcompounds, sometimes at low concentration levels, induces aninsidious and slowly-developing lung disease (chronic pulmonarygranulomatosis; "berylliosis") associated with a high mortality. There isalso limited epidemiological evidence that beryllium causes lungcancer. Dermal contact may give. rise to a serious dermatitis of theallergic type.

Environmental Levels and Exposure

Ordinary agricultural soils contain beryllium in the range of severalHg/kg, and several common plants (aspen, willow) are accumulators ofsoil beryllium, with levels sometimes reaching 3 ppm. Potatoes andlettuce have been reported to contain 200 - 300 g Be/g drysubstance.


Beryllium exhibits a wide variety of toxic potentialities, especially uponinhalation. Administration by this route of aerosols of beryllium orberyllium compounds produce an acute chemical pneumonitis in manand experimental animals. The LCSO for the sulphate In severalmammalian species are in the range of 0.5-2.0 mg Be/m3. In addition


AR30l»277

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to the acute pneumonitis, five chronic disease entitles caused byexposure to beryllium have been identified in experimental animals:

• chronic pneumonitis• benign and malignant lung tumors• bone sarcoma* rickets and osteosclerosis• granulomatous leisons of the skin

Focal lesions may also appear in the spleen, liver, lymph nodes, kidneyand bone marrow indicating an extensive systemic involvement.Biological activity is correlated with the physico-chemical propertiesof the inhaled aerosol, as demonstrated by the relative inertness of theoxide fired at 1600C as compared to the oxides calcined at e.g. 500C.

In man acute pulmonary disease may be induced by low-fired oxide at aconcentration level of 1-3 mg Be/m3. and possibly as low as 0.1-0.5mg/m3 for the sulphate. In contrast to what is the case for thechronic disease, recovery from acute disease Is here usually complete.The onset of chronic beryllium pulmonary granulomatosis (beryiliosis)may be Insidious, with only slight initial respiratory symptoms andfatigue, and which can occur as early as 1 year or as late as 25 yearsafter exposure. Progressive pulmonary insufficiency, anorexia, weightloss and varying degrees of cyanosis characterize the advanced diseasewhich has been associated with a high mortality (up to 30%). Belowan occupational exposure level of 1-2 jig/m3 the risk for berylliosisseems very low.

The "tissue reactions associated with both dermatitis as well as withchronic beryllium granulomatosis have been characterized asimmunological reactions of the delayed or tuberculin type, ascribed tothe action a cell damaging beryllium-antigen-antibody reaction. Skincontact to beryllium may result In a dermatitis of the allergic-eczematous type, and if Insoluble beryllium compounds becomeembedded in die skin - e.g. following injury - necrotizing ulcerationsappear which do not heal readily. As to the cause of the sudden onsetof the chronic disease long after exposure has ceased, this has notbeen clarified, but has been ascribed to adrenal stress caused by acuteinfections, pregnancy, surgery, etc.

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flR30l*278

Beryllium

Beryllium'

GAS No.: 7440-41-7Synonyms: glucinium


Chemical Formula: BeForm: gray metal: close-packed hexagonal

structure; anisotrophic; highpermeability to x-rays

Chemical Class: metalAtomic Weight: 9.01Boiling Point: 2500°CMelting Point: 1287°C

Specific Gravity: 1.8477Solubility in Water: insoluble; most salts are soluble

Solubility in Organics: soluble in dilute acid and alkaliOrganic Carbon

Partition Coefficient: NALog Octanol/Water

Partition Coefficient: NAVapor Pressure: 0• Vapor Density: NA

Henry's Law Constant: NABioconcentration Factor: 100



Maximum Contaminant Level {MCL)for Drinking Water (mg/L): NA

Clean Water ActAmbient Water Quality Criteria (mg/L)Human Health ?

Water and Fish Consumption: 6.80E-06Fish Consumption Only: - 1.20E-04

" " ' . * , ' .Aquatic Organisms (mg/L)

Freshwater:Acute: l.OOE-01

Chronic: 5.30E-03

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AR3Ql*275

Beryllium

MarineAcute: NA \

Chronic: NA /t

* ReferencesSax and Lewis 1989. Verschueren 1983. The Merck Index 1983.SPHEM 1986. EPA 1986NA - Not Available


The low solubility of beryllium under normal pH conditions causes theelement to be precipitated or adsorbed on to solids in natural watersystems. Solubilization by completing agents may be possible, butmost studies have shown beryllium to be strongly associated with theparticulate phase. Therefore, beryllium will tend to remain ImmobileIn soil systems. No evidence of volatilization from soils or aquaticsystems has been discovered, although the inhalation of airborne dustis a hazard associated with beryllium (EPA, 1979).

D. .Ecotoxlcology \

There Is a paucity of data concerning the ecotoxlc properties ofberyllium. Only limited single species bioassays have been conductedfor freshwater fish and invertebrates.Similar to other metals, beryllium toxicity is inversely related to waterhardness levels. The only plant study identified tested a green algae(Chlorella vannieili) and reported growth inhibition at 100.000 ig/1(USEPA 1980, Clement Assoc. 1985). The only invertebrate speciestested was a cladoceran (Daphia magna). An acute value of 2,500 g/1(hardness 220 mg/1) was reported along with a chronic value of 7.3jig/1 which inhibited reproduction.Only acute studies using freshwater fish were identified in theliterature. According to studies using bluegills (Lepomis macrochirus),beryllium does not appear to bioconcentrate In fish and possesses ashort half-life in tissue (USEPA 1980. Clement Assoc. 1985). In acutetests with fathead minnows (Pimephales promelas], LCSO values of150 and 20,000 jig/1 were reported at hardness (as CaCOs) levels of20 and 400 mg/1, respectively. A similar trend in LCSO's withincreasing hardness was reported for bluegills (Lepomis macrochirus) .

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flR30l*283

BCEE

2f2-Chloroethv»ether

CASNo.: 111-44-4Synonyms: bis(2-chloroethyl)ether. BCEE. 2,2'-

Dichloroethyl ether, l-chloro-2-(beta-chloroethyl) ether, DCEE, l,l1-oxybis-(2-chloroethane) bis-(beta-chloroethyl)ether, dichlorodiethyl ether


Chemical Formula:Form: liquid

Chemical Class: halogenated etherMolecular Weight: 143.02

Boiling Point: 178°CMelting Point: -24.5°C

Specific Gravity: 1.22 at 20°CSolubility in Water: 10,200 mg/1

Solubility in Organics: miscible with most organic solventsOrganic Carbon

Partition Coefficient: 13.9Log Octanol/Water

Partition Coefficient: 4.93Vapor Pressure: 0.71 mm at 20°CVapor Density: NA

Henry's Law Constant: 1.3E-05Bioconcentration Factor: 9.2 (microbial)





Water and Fish Consumption: NAFish Consumption Only: NA

Aquatic Organisms (mg/L) :Fresh Water • ;

Acute: NA

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fiR30t*28l* —-«,

BCEE

Chronic: NAMarine


ReferencesSax and Lewis 1989, Verschueren 1983, The Merck Index 1983,SPHEM 1986, EPA 1986NA - Not Available


Based on the limited information available, the primary fate processesfor bis(2-chloroethyl)ether (BCEE) appear to be volatilization.oxidation and hydrolysis. Volatilization from aquatic and terrestrialsystems is thought to occur but its relative Importance to other fateprocesses is not clear. The compound is somewhat soluble in waterand can therefore migrate through soils since sorption processes donot appear to be significant.Ethers are resistant to hydrolysis and also the C-C1 bond is quitestable. Hence, the half-life of BCEE in various media is significantlylong, in the order of years (Callahan et al, 1979). BCEE is amenable tobiodegradation, as shown by Tabak et al (1981). When reacted withactive sewage sludge, 100 percent of added BCEE disappeared within7 days. Ludzack and Ettlnger (1963) reported similar biodegradation.but only after their microbes had adapted for 25 days (this probablyreflects the presence of different microbes in the original inocula).When a second dose of BCEE was added in the latter experiment afteradaptation had occurred, biodegradation was 80 percent complete in15 days. However. Dojiido (1979) was unable to biodegrade BCEE in anumber of different biodegradative schemes, although only 2 weekswere allowed which may have been insufficient for adaptation.Obviously, biodegradation in nature may be slower than in thelaboratory, but, nonetheless, is probably a major consideration for thefate of BCEE in the environment.

D. Ecotoxicology

Virtually nothing is known about BCEE in terms of its toxicity inecosystems. The highly irritating effect in man and test animals surelyare applicable to environmental biota. However. It does not


flR30lf285

BCEE

appreciably bloaccumulate and , therefore, does not present a moreprofound risk to predators. Including man.

E. Human Toxicology

There is no question as to the irritating effect of BCEE on mucousmembranes. Whether or not this irritation and the compound's closeresemblance to the related bls(2-chloromethyl)ether (BCME), a potenthuman lung carcinogen have bearing on the potential carcinogenicityof BCEE remains conjectural.

• Acute and Chronic ToxicityThe respiratory epithelium is highly sensitive to BCEE exposure.Schrenk et al (1933) found that 550 ppm in air can only be toleratedfor a few minutes, with exposure at 260 ppm tolerated slightly longer.but still accompanied by severe irritation. At 100 ppm. irritation ismild, and at 35 ppm it is absent (Schrenk et al, 1933).Similar findings have been reported in experimental animals.Schrenk et al (1933) exposed guinea pigs to 35 ppm with only mildirritation, whereas progressively worse symptoms were encounteredas the BCEE concentration was Increased. At levels of 100 ppm orgreater there was histological confirmation of lung damage. Edema,hemorrhage and marked congestion were noted. In otherexperiments with rats and guinea pigs Dow Chemical (1958) found nomacroscopic or histopathologic effects of 69 ppm BCEE In air for 130'days of exposure, however, the treated animals did not gain weight atthe same rate as controls. :

* Carcinogenic ActivityEpidemiologic studies are inadequate to judge human carcinogenicityby BCEE. In animal tests, BCEE has been found carcinogenic byingestion, however, inadequate data has been accumulated to adjudgeits carcinogenicity by inhalation.Innes et al (1969) found statistically increased hepatomas in twomouse strains exposed to 41 mg/kg/day for 80 weeks. Male miceshowed a higher carcinogenic frequency than females, with up to 88percent of the treated males contracting hepatoma. (It is not clearfrom these studies if "hepatoma" refers to neopl-astic nodules.adenomas or hepatocellular carcinomas.) Weisburger et al (1981)found no increased carcinogenesis In male and female rats exposed atup to 100 mg/kg/week.


AR30I}286

BCEE:

EPA considers BCEE to be a class B2 (probable human) carcinogen asbased upon the positive carcinogenesls experiments in two mousestrains and corroborated by some positive mutagenicities in bacteria(see below). The Agency has assigned a carcinogenic potency factor of1.1 (mg/kg/day)'1 to BCEE.

• Mutagenicity 'BCEE has been tested for bacterial mutagenesis (Ames test) in S.typhimuriwn, E. coli and B. subtllis. Whereas Simmon (1977) andShirasu et al (1975) found BCEE to be mutagenic for S. typhimurium,Norpoth et al (1986) did not Shirasu et al (1975) also found BCEE tobe mutagenic for E. coli and B. subtiUs, but Qulnto and Radman (1987)did not find the same for three different E. coli strains. Unfortunately,there have been no mutagenic or genotoxic studies reported forhuman cells in culture or in lymphocytes derived from exposedworkers.

P. Phannacokinetlcs

Limited data are available concerning absorption of BCEE from variousexposure routes. Gwinner et al (1983) found that 95 percent of the JBCEE was absorbed in 18 hours by rats In an enclosed exposure _xchamber. When given a single dose orally, rats only excrete 2 percentof administered BCEE in their feces, indicating that gastrointestinalabsorption is also essentially complete (Lingg et al, 1982). Similarly,Smyth and Carpenter (1948) indicate that dermal absorption is high.although these data are not as complete as those for inhalation oringestion.The primary catabolic product of BCEE is thiodlglycolic acid (TOGA),which is formed by a conjugation of chloroacetate with glutathione(Ungg et al. 1979; Norpoth et al, 1986). Thiodlglycolic acid is readilysoluble and its excretion in urine accounts for 50-80 percent ofadministered BCEE (Lingg et al, 1979; 1982). Lingg et al (1982)conclude that 12 percent of administered BCEE is completelydegraded to COa- Only 2 percent of administered BCEE by inhalationis exhaled unchanged (Ungg et al, 1979).Gwinner-et al (1983) exposed rats to 14C-Iabelled BCEE in air andlooked for macromolecular conjugation. Most labelled protein wasfound In liver, kidney and small intestine, suggesting adductformation. However, no radiolabel was found in DNA.

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GBCEE

G. References

ATSDR (1989) Toxicological profile for bis(2-chloroethyl)ether.Agency for Toxic Substances and Disease Registry, Atlanta.Caliahan. M.A., M.W. Slimak. N.W. Gabriel et al (1979) Halogenatedaliphatic hydrocarbons, halogenated ethers, monocyclic aromatics.phthalate esters, polycyclic aromatic hydrocarbons, nitrosamines andmiscellaneous compounds. Office of Water Planning and Standards.EPA, Washington, D.C.. PB80-204381, pp. 65; 1-7.Dojlido. J.R. (1979) Investigations of biodegradability and toxicity oforganic compounds. Office of Research and Development, EPA.Cincinnati, EPA-600/2-79-163,Dow Chemical (1958) Results of repeated exposures of laboratoryanimals to the vapor of dichlorodiethyl ether at a concentration of 69ppm.Gwinner. L.M., R.J. Laib, J.G. Filser et al (1983) Evidence ofchloroethylene oxide being the reactive metabolite of vinyl chloridetoward DNA: Comparative studies with 2.2-dichlorodiethyl ether.Carcinogenesis 4, 1483-1486.Innes, J.R.M., B.M. Ulland, M.G. Valeric et al (1969) Bioassay ofpesticides and industrial chemicals for tumorigenicity in mice. J. Nat.Cancer Inst. 42. 1101-1114.Ungg, R.D.. W.H. Kaylor, S.M. Pyle et al (1979) Thiodiglycolic acid: Amajor metabolite of bis(2-chloroethyl)ether. Toxicol. Appl. Pharmacol.47. 23-34.Ungg. R.D., W.H. Kaylor. S.M. Pyle et al (1982) Metabolism of bis(2-chloroethyljether and bis(chloroisopropyl)ether in the rat. Arch.Environ. Contam. Toxicol. 11. 173-183.Ludzack. F.J. and M.B. Ettinger (1963) Biodegradability of organicchemicals isolated from rivers. Eng. Bull. Ext. Serv. (Purdue Univ.)115. 278-282.Norpoth, K., M. Heger. G. Muller. E. Mohtashamlpur. A. Kemena and C.Witting (1986) Investigations of metabolism, genotoxic effects andcarcinogenicity of 2,2-dichlorodiethyl ether. J. Cancer Res. Clin.Oncol. 112, 125-130.Qutnto, I. and M. Radman (1987) Carcinogenic potency in rodentsversus genotoxic potency In E. coll: A correlation analysis forbifunctional alkylating agents. Mutat Res. 181, 235-242.

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ABSORBS

BCEE

Schrenk, H.H., FA. Patty and W.P Yant (1933) Acute response of guineapigs to vapors of some new commercial organic compounds. Publ.Hlth. Rpts. 48, 1389-1398. .Shirasu, Y., M. Moriya, K. Kato et al (1975) Mutagenicity screening ofpesticides in mlcrobial systems. Mutat. Res. 31, 268-269 (abstract).Simmon. V.F.. K. Kauhanen and R.G. TardiflF (1977) Mutagenic activityof chemicals identified in drinking water. In, Scott, D.! B.A. Bridgesand F.H. Sobels (eds) Progress In Generic Toxicology, pp. 249-258.Smyth, H.F. and C.P. Carpenter (1948) Further experience with therange finding test in the industrial toxicology laboratory. J. Ind. Hyg.Toxicol. 30. 63-68.Tabak, H.H., S.A. Quave, C.I. Mashni et al (1981) Biodegradabilitystudies with organic priority pollutant compounds. J. WPCF 53, 1503-1518.Weisburger, E.K., B.M. Ulland, J. Nam. J.J. Gart and J.H. Weisburger(1981) Carcinogenicity tests of certain environmental and industrialchemicals. J. Nat. Cancer Inst. 67, 75-88.


L ,QtoupflR30U289

CChloroform

Chloroform

CASNo.: 67-66-3Synonyms: formyl trichloride. Freon-20, methane

trichloride, trichloroform, trichloromethane


Chemical Formula:Form: colorless liquid, heavy, ethereal odor

Chemical Class: halogenated aliphatic hydrocarbonMolecular Weight: 119.38

Boiling Point: +620CMelting Point: -64°C

Specific Gravity: 1,489 at 20°CSolubility in Water: 8,000 mg/L at 20°C

Solubility in Organics: acetone; miscible with alcohol, benzene.ether and ligroin

Organic CarbonPartition Coefficient: 3 1Log Octanol/Water

Partition Coefficient: 1.97 at 20°CVapor Pressure: 160 mm at 20°'CVapor Density: 4.12






Water and Fish Consumption: 1.90E-04Fish Consumption Only; 1.57E-02


Acute: 2.89E+01Chronic: 1.24E+00

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AR30lt290

Chloroform

MarineAcute: NA -|

Chronic: NA J

ReferencesSax and Lewis 1989, Verschueren 1983, The Merck Index 1983:SPHEM 1986, EPA 1986NA - Not AvailableC Fate and TransportThe major environmental fate process is volatilization of chloroformfrom both soil and water to the atmosphere. The overall half-life ofchloroform in water is estimated at 0.3 to 30 days. Because of thehigh vapor pressure of chloroform, volatilization Into the atmosphereis quite rapid. The log octanol/water partition coefficient (Kow) ofchloroform indicates a possible tendency of this compound tobloaccumulate under conditions of constant exposure. However, thereis no evidence for biomagnification of chloroform In the aquatic foodchain. Sorption and biodegradation are considered minorenvironmental fate processes.IX EcotoxicologyChloroform's ubiquitous presence In the environment results largelyfrom the chlorination of water and wastewater. Except in areas of )spills or persistent releases, chloroform should not pose a significant '"—'hazard to terrestrial or aquatic systems, since it readily volatiles andhas not demonstrated the propensity to accumulate.Early acute toxicity studies with goldfish (Carossfus aculeatus} andthree-spine sticklebacks (Gosterosteus aculeatus) suggest anestheticeffects occur at 97 and 207 mg/1, respectively (USEPA 1981, 1985).Additional studies suggest an avoidance response in fish exposed tosimilar levels.A fresh water invertebrate (Daphnia magna) reached LC50 levels in a48 hour test at 28.9 mg/1 (USEPA 1980. 1981. 1985. Moore andRamamoorthy 1985), A 96-hour LCso of 81.5 mg/1 was reported forthe pink shrimp (Penaeus duorarum) (USEPA 1981, 1985).Chloroform levels of 43.8 mg/1 and 100 mg/1 were reported as 96-hrLCso values for rainbow trout (Salmo gairdnerft and bluegills (Lepomismacrochirus). In a 1-hr test, chloroform levels of 107 to 152 mg/1were lethal to orange spot sunfish (L. humilis) (USEPA 1980, 1981,1985).The most representative tests for chronic effects were 27-day embryo-larval tests with rainbow trout (S. gairdneri) in which a LC50 of 1.24

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Chloroform

mg/1 was reported along with a 40% teratogenesis response inf embryos at hatching (USEPA 1985);—' E- Human Toxicology

• Overview .Chloroform has a low acute toxicity in mammals. However,overexposure may result in serious and irreversible damage to liverand kidneys. As for a number of other chlorinated solvents, chloroformmainly exerts a depressing action on the central nervous system.Chloroform has been shown to increase the incidence of spontaneousliver tumors in mice and induces kidney tumors in male rats and miceat toxic dose levels. It does not seem to possess any significantmutagenic or teratogenic activity. However, in animal experimentschloroform has demonstrated a fetotoxicity - at maternally toxicconcentrations.

• Acute and Chronic ToxicityChloroform has a low acute toxicity. A probable oral lethal dose forhumans is 0.5 to 5 g/kg 70 kg person. It mainly acts as a centralnervous system depressant inducing dizziness, salivation, nausea,fatigue, and headache. At high exposure levels respiratory depressionand unconsciousness may be induced. Overexposure has, in addition,frequently also caused liver as well as kidney damage.in man signs of chronic intoxications are loss of appetite, moodiness,physical and mental sluggishness. Enlargement of liver and toxichepatitis has also been described in workers regularly exposed tochloroform for an extended period of time.Upon long-term exposure chloroform has induced pathologicalchanges in liver and kidneys of experimental animals. Liver damage inthe form of lobular granular degeneration and focal necrosis, as well ascloudy swelling of the kidneys has been observed in both sexes of ratsafter inhalation exposure at 50-85 ppm 7 hrs/day for 6 months. Astudy In rats, using only one treatment dose (Palmer et al., 1979),identified 60 nig/kg/day by gavage as a LOAEL for decreased weightgain and relative liver weight.In a long-term study, rated by USEPA as being of acceptable quality,beagle dogs were administered chloroform in a toothpaste base ingelatin capsules (Heywood et al., 1979). Experimental groups of eightmale and'eight female dogs received 15 or 30 mg chloroform/kg/dayfor 6 days/week. Treatment was continued for 7.5 years. Fatty cysts.considered to be treatment-related, were observed in livers of somedogs In both treatment groups. A dose-related increase in SGPT levelsand a less marked increase in SGOT was noted in the high-dose

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Chloroform

animals. The LOAEL was determined to be 12.9 mg/kg/day. and anRfD has been set by the USEPA at 0.01 mg/kg/day. Here uncertaintyfactors of 10 each were applied to the LOAEL of 12.9 mg/kg/day toaccount for the interspecies conversion, protection of sensitive humansubpopulations, and concern that the effect seen was a LOAEL and nota NOEL.

* Carcinogenic ActivityThe long-term effects of chloroform has been evaluated in mice, rats.and dogs. The main supporting evidence of carcinogenicity bychloroform derives from the rodent studies involving oraladministration (gavage) of chloroform in corn oil conducted by NCI. Inthese investigations induction of renal epithelial tumors - mainlymalignant - was found In male Osborne-Mendel rats, hepatocellularcarcinomas in male and female 36C3F1 mice (NCI, 1976). Doses.expressed as time-weighted averages for the entire study, amountedto 90 and 180 mg/kg/day for male, 100 and 200 mg/kg/day for femalerats. Male mice received 138 and 277 mg/kg/day and females 238 and477 mg/kg/day. To validate these results, the study was repeatedusing the same strains and sexes of rodents as was used in the NCIstudy, but administering chloroform (without diethylcarbonateImpurities present in the previous study) In the drinking water atconcentrations of 200. 400, 900, and 1800 mg/L. In this bioassay astatistically increased incidence of renal tumors in male rats could besubstantiated, but no significant elevation of liver tumors was noted.The basis for this discrepancy is not clear, but differences inabsorption pattern depending on the carrier vehicle, the dosingregimen, and the resulting peak blood and tissue levels have beencited (EPA, 1985). An increased Incidence of renal tumors was alsoseen in male mice at the highest dose in the investigation conductedby Palmer et al. (1979). No treatment related increase in the tumorincidence was found in the long-term study in dogs discussed above(Heywood et al., 1979).It should be pointed out, that the high incidence of liver tumors in theB6C3F1 mouse, and which is normally present, may be Increased (anddecreased)' to an appreciable extent by a number of unspecific factorslike changes in the composition of the diet, etc. Further, the inductionof renal tumors in the male rodents is similar to the effects ofunleaded gasoline in the rat. In view of the apparent lack of genotoxicactivity, as well as the necrotizirig action exerted by chloroform Inliver and kidney, the significance of the results from the bioassays inrodents has been the subject of some controversy.No adequate epidemiologlcal data exist on which to base an evaluationof the carcinogenic activity in man.

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• Genotoxic effects and adverse effects onreproduction

The mutagenic potential has been investigated in assays withSalmonella typhimurium TA1535 and TA1538, yeast, in the host-mediated assay, the Drosophila sex-linked recessive lethal test.mammalian cell culture mutagenicity assay, as well as with SCE. UDSand in various cytogenetic studies. Although increases in mitotic geneconversion and mitotic crossing over in yeast was found in oneInvestigation, there is no convincing evidence of a genotoxic action ofchloroform.Investigations in rats indicate that chloroform exerts an embryotoxicaction (retarded development Increased fetal mortality) at maternallytoxic levels, with no clear indication of teratogenlcity.F. Phannacokinetics and MetabolismChloroform is extensively absorbed from the lungs as well as from thegastro-intestinal tract and is subsequently rapidly distributed to allorgans with a relatively high concentration in the nervous as well as inother adipose tissue. The compound also crosses the placenta! barrier.Dermal absorption through Intact skin is slow.Elimination of chloroform occurs via the lungs (unchanged) as well asby metabolic transformation in the liver, and to a lesser extent in thekidneys. Elimination is Initially rapid, but then slows down due toretention in the fat depots. However, after a single acute exposure,little remain in the human organism after 48 hrs. Metabolism is dose*dependent and saturable. Appreciable quantitative species differencesexist with respect to rate of elimination, extent of biotransformation aswell as degree of tissue binding of metabolites. Thus, whereas the.mouse metabolizes more than 85% of the steady-state body burden athigh exposures, man is only able to convert 30-40% of the compoundunder similar conditions. Upon metabolism phosgene as well as otherputative reactive metabolites are formed that coyalently bind tomacromolecules (mainly proteins and lipids and only to a limitedextent to nucleic acids). The tissue levels of glutathlone here play animportant role in modifying the extent of final tissue damage.Using pharmacoklnetic data relating to the amount of chloroformmetabolized (oral'dose-minus. Tthe • fraction of dose excreted) in mice,the upper bound unit risk has been estimated by EPA be be 8. IE-02(geometric mean for male and females).G. Discussion of Regulatory StandardsAccording to IARC there is sufficient evidence that chloroform iscarcinogenic in mice and rats. (Group 2B) and EPA has also classified

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Chloroform

the substance as a probable human carcinogen (Group B2). Thecurrent ACGIH 8 hr TLV Is 10 ppm.An interim MCL of 0.10 mg/L for total trihalomethanes has beenestablished by the USEPA based on chronic toxicity data forchloroform, taking into consideration existing technology andtreatment methods. This "MCL (equivalent to 100 ppb) is not risk-based, but rather a concession to the production of trihalomethanes asa by-product of disinfection by chlorination.The ambient water quality criterion (WQC) of 0.19 ng/L represents acancer risk level of l.OE-06, based on consumption of contaminatedorganisms and water. A WQC of 15.7 tig/L (cancer risk level of IE-6)has also been established based on consumption of contaminatedorganisms alone.H. ReferencesHeywood, R., R.J. Sortwell, P.R.B. Noel, Street, A.E.. Prentice. D.E.,Roe, F.J.C.. Wardsworth, P.P.. Worden, A.N., and Van Abb, N.J. (1979);Safety evaluation of toothpaste containing chloroform. III. Long-termstudy in beagle dogs. J. Environ. Pathol. Toxicol. 2.835-851.Moore, J.W. and S. Ramamoorthy (1984). Organic Chemicals inNatural Waters, Applied Monitoring and Impact Assessment.Springer-Verlag. New York.National Cancer Institute Carcinogenesis Program (1976); Report onCarcinogenesis Bioassay of Chloroform, NTIS PB-264 018. March 1.1976.Palmer, A.K.. Street, A.E., Roe. F.J.C.. Worden, A.N., Van Abb. N.J.(1979); Safety evaluation of toothpaste containing chloroform. II.Long-term study in beagle dogs. J. Environ. Pathol. Toxicol. 2, 821-833.Rehm, R.M.. Anderson, M.E., Duletsky. S.A., Misenheimer. D.C., andRollius. H.F. (1982); Chloroform materials balance. Draft Report, EPAContract 68-02-3168. Task 69, USEPA, Washington D.C.Symons, J.M., Bellar. T.A., Carswell, J.K.. DeMarco. J.. Kropp, K.L.,Robeck, G.G.. Seeger, D.R., Slocum, C.J., Smith. B.L., and Stevens. A.A.(1975); National organics reconnaissance survey for halogenatedorganics, J. Am. Water Works Assoc. (Nov. 1975). pp. 634-647.USEPA. (1980) Ambient Water Quality Criteria for Chloroform. EPA-440/5-80-033.USEPA. (1981) Exposure and Risk Assessment for Trihalomethanes.EPA- 440/4-81018.

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Chloroform

USEPA. (1985) Health Assessment Document for Chloroform. EPA -600/8-84-004F.USEPA. (1986) Quality Criteria for Water 1986. EPA - 440/5-86-001.World Health Organization (1979): IARC Monograph on the Evaluationof the Carcinogenic Risk of Chemicals to Humans. Vol. 20. Lyon,France.

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flR30i*296

Chromium

Chromium

CASNo.: 7440-47-3Synonyms: NA


Chemical Formula: CrForm: steel-gray, lustrous metal; body-centered

cubic structure

Chemical Class: metalAtomic Weight: 52Boiling Point: 2642°CMelting Point: 1900°C

Specific Gravity: 7.14Solubility in Water: Insoluble; some compounds are soluble

Solubility In Organics: 0Organic Carbon



/ . Henry's Law Constant: NABloconcentration Factor: NA



Maximum Contaminant Level (MCL)for Drinking Water (mg/L): . 0.05



Aquatic Organisms (mg/L) *Freshwater - ;Acute: 1.60E-02

Chronic: 1.10E-02Marine r

Acute: 1.10E+00;


RR30U298

Chromium

Chronic: 5.00E-02

ReferencesSax and Lewis 1989. Verschueren 1983. The Merck Index 1983,SPHEM 1986, EPA 1986NA - Not Available


The major environmental fate processes of chromium are sorption andbioaccumulation. Most of the trivalent chromium In the aquaticenvironment is hydrolyzed and precipitates as Cr(OH)3. Sorptionprocesses and bioaccumulation will remove the remaining Cr(III) fromsolution. Under certain natural water conditions, chromium can existin hexavalent form. Chromium (IV) exists as an oxyanion in aqueoussolution and is quite soluble. Chromium Is an essential nutrient, and itIs accumulated in aquatic and marine biota to levels much higher thanIn ambient water. Bloconcentration factors for chromium range from70 in fish muscle to 4.000 In freshwater plants. Photolysis, oxidation,volatilization, and hydrolysis are considered to be environmentallyinsignificant processes based upon the limited quantitative dataavailable for chromium.

Chromium occurs ubiquitously in nature. In various types of rocks theconcentration varies from an average of 5 ppm in granitic rocks to anaverage of 1.800 ppm in ultrabasic and serpentine rocks. It is alsofound in coal (5-10 ppm). The commercially most important mineralis chromite (FeO.C Os"). In most soils, chromium occurs in lowconcentrations; an average of 863 U.S. soil samples contained 53mg/kg (Shacklette et al., 1970). Many fertilizers incorporateappreciable levels of chromium.

In natural waters the positively charged Cr3* has a strong tendency toform very stable complexes with negatively charged organic orinorganic ionic species. Under most conditions It is therefore unlikelythat appreciable quantities of uncomplexed Cr3+ will persist in thepresence of any suspended anionic. dissolved or particulate matter(e.g. decaying plant or animal tissue, silt or clay particles). In theabsence of anionic species. Cr3* may form colloidal hydrous oxides inneutral solutions. Below pH 5. the Cr3+ hexaquo complex is stable.Above pH 9 soluble, negatively charged hydroxides are formed. Cr3* \

X _ X

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flR30l4299

Chromium

has Its minimum solubility in the pH range covered by natural waters.Trivalent chromium is for this reason mostly associated 'with

- partlculate matter and subject to sedimentation or filtration. Inaqueous solution Cr6* exists almost exclusively in the form of oxoanions (CrO42-. CraOy2-), the chemistry of which are very differentfrom that of Cr3*. CrO42' Is the predominant form In dilute solutions(< Img/L) and does not complex with anionic paniculate matter.Hence, the higher mobility in soils and ground water of CrO42- ascompared with Cr3+. Hexavalent chromium compounds are. on theother hand, strong oxidizing agents, and have a strong tendency to"react with oxldizable substances to form Cr3*. In well-oxygenatedwater, free of oxidizible material. Cr3+ is slowly converted tohexavalent ionic species, and in oxygenated sea water with a lowcontent of organic matter and a relatively high pH, Cr6* predominates.In freshwater, as well as in anoxlc marine bottom layers, Cr3* is morelikely to be formed (NRCC. 1976. 1984).

The general population Is mainly exposed to chromium via itspresence In food. The daily intake has been estimated to be 50-200Hg/day (IPCS, 1988).

f : D. Ecotoxicology

Most microorganisms (protozoa, protophyta, fungi, algae, bacteria) areable to absorb chromium, and this element has been shown to beessential in fungi. The active uptake of chromium salts by the sulfatetransport system has been demonstrated In Neurospora crassa.. Ingeneral, toxicity for .most microorganisms occurs in the range of 0.05-5 mg chromium/kg of medium. Trivalent chromium Is less toxic thanhexavalent. Biological oxidation by microorganisms in sewage sludgeshas been reported to be adversely affected by as little as 50 ppm Cr3*.or by 5 ppm Cr6* (NRCC, 1976). In general, invertebrate species suchas polychaete worms, insects, and crustaceans are more sensitive tothe toxic effects of chromium than vertebrates such as fish.Reproduction of Daphnia was found to be adversely affected by Cr3*down to 0.33 ppm and by Cr6* at 0.01 ppm. Aquatic toxicity Isstrongly dependent on water hardness. Representative acute toxicitydata for some freshwater organisms are given in Table 1.

Exposure of salmon fingerUngs to 0.2 ppm Cr6+ for 12-weeks instream water resulted in a 53% lethality, while the same

(; : . concentration of the trivalent chromium was below the mortality

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HR30U300

Chromium

threshold. According to the European Inland Fisheries AdvisoryCommission (EIFAC, 1983), the mean aqueous concentration of"soluble" chromium should not exceed 0.025 mg/L, and the 95percentile should not exceed 0.1 mg/L in order to protect sensitiveSoimonid species. However, more stringent values may be necessaryin very soft, addle waters (NRCC, 1978; IPCS 1988).

Table 1 The toxicity of chromium for freshwater organisms(expressed as 50 per cent mortality; EPA, 1980)

Cr Category Exposure Toxic Range Most sensitive species

6+ inverte- - acute 0.07 - 60,0 scudbrates

verte- acute 17.6 - 249 fathead minnowbrates chronic 0.27 - 2.0 rainbow trout

3+ Inverte- acute 2.0 - 64.0 cladoceranbrates chronic 0.07 cladoceran

verte- acute 3.3 - 71.9brates chronic 1.0 fathead minnow

E. Human Toxicology

OVERVIEW: The biological action of chromium is, clearly, dependentupon its valence. However, since hexavalent chromium is reduced tothe trivalent state upon contact with biological material during itspassage through membranes and cells - and also to some extent in thegastro-intestlnal-tract - it may be difficult to lexicologically distinguish \

Vk_


Chromium

between the effects of these two oxidation states. The claim thatis converted into Cr6* in organisms (IRIS. 1988) lacks adequatescientific support. For many systemic effects, at least those inducedafter oral administration, it may be assumed that trivalent chromiumwill be the major causative agent reaching the target, even when Cr6*had been administered. However, the oxidizing and corrosiveproperties of Cr6*. causing cell necrosis, are certainly of importancefor the induction of local toxic effects and promoting absorption, e.g.in the lungs. Direct uptake of hexavalent chromium by cellularsystems is often rapid enough for expression of the higher cytotoxlcityof this Ionic species. The contamination of Cr3* compounds with Cr6*constitutes another complicating factor, especially when assessing theresults from in vitro cellular systems.

SUMMARY OF Toxicrrv: Chromium compounds are poorly absorbed fromthe human gastro-intestinal tract but appreciable intake may occur viaInhalation. Hexavalent chromium is. in general, considerably moretoxic than the metal in its trivalent state. Due to its corrosiveproperties, concentrated solutions of hexavalent - chromiumcompounds may induce local as well as systemic toxic effects upondirect contact with skin and mucous membranes. Occupationalinhalation exposure to slightly soluble, hexavalent chromiumcompounds has been associated with an Increased incidence of lungcancer. However, studies in animals as well as human experienceindicate that chromium compounds have a relatively low toxicity uponchronic oral exposure, and no carcinogenic effects have beendemonstrated via this route of administration. Chromium salts act assensitizers, causing contact dermatitis upon prolonged or repeatedskin exposure. Chromium is an essential element for the normalfunctioning of the organism.


The toxicity of chromium compounds to mammals is moderate uponoral administration. In one investigation the LD50 for potassiumdichromate was found to be. In .-the range 140-180 mg/kg for rats(Hertel, 1982). Oral intake for 29-685 days of 1.9-5.5 mg Cr/kg /dayas dichromate did not produce any observable, harmful effects In dogs.cats, or in rabbits (IPCS. 1988).

In a subchronic feeding study (Ivankovic and Preussmann. 1975) ratswere given Cr2O3 in bread at dietary levels of 0. 2. or 5%, 5

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Chromium

days/week .for 90 days. Toxlcologic parameters Included serumprotein, bilirubin, hematology. urinalysis. organ weights, andhlstopathology. The only effects observed were reductions (-12-37%)in the absolute weights of the livers and spleens of animals in thehigh-dose group. The high dose is equivalent to 1400 mg/kg/day. Inanother experiment the same investigators administered chromicoxide in bread to groups of* 60 male and female rats at dietary levels of0. 1. 2. or 5%. 5 days/week for 600 feedings (840 days). The averagetotal amounts of ingested Cr2©3 were given as 360, 720, and 1800g/kg for the 1, 2, and 5% treatment groups, respectively. The animalswere maintained on control diets following termination of exposureuntil they became moribund or died. All major organs were examinedhistologically. No effects due to the treatment were observed at anydose level.

In a long-term oral study, Sprague-Dawley rats were given drinkingwater containing up to 25 ppm chromium as K2CrO4. or 25 ppmchromium as chromic chloride for 1 year.* No significant clinical orpathological adverse effects were seen. However, the rats receiving25 ppm of chromium (as K2CrO4) showed an approximate. 20%reduction In water consumption (2.4 mg Cr/kg/day). Further, in the25 ppm treatment groups, tissue concentrations of chromium wereapproximately 9 times higher for those treated with hexavalent }chromium than for the trivalent group (MacKenzie, et al., 1958). —

Similar no-effect levels have been observed in dogs and humans.Anwar et al. (1961) observed no significant effects in female dogs(2/dose group) given up to 11.2 ppm chromlum(VI) (as K2CrO4) indrinking water for 4 years. The calculated doses were 0.012-0.30mg/kg of chromiumfVI).

Hexavalent chromium is considerably more toxic when administeredintravenously, or by inhalation. Following parenteral administration ofCr6+, the most common lesions consist of selective damage in theproximal convoluted tubules of the kidney as well as liver damage. Ina long-term inhalation study in the rat. an LC50 of 28 mg/m3 wasfound for sodium dichromate (Glaser. et al. 1984). Typical lesionsfound in experimental animals after long-term inhalation of hexavalentchromium compounds are bronchitis and pneumonia (IPCS. 1988).


flR3Ql*303

Chromium

Guinea pigs may be sensitized to hexavalent as well as to trivalentchromium (IPCS. 1988).

The acute oral toxicity of chromium compounds to humans is notaccurately known. A dose of 50-70 mg/kg of soluble chromates hasbeen judged to be lethal for an adult (IPCS, 1988). There are someindications, however, that children may be more sensitive (Kauftnan etal., 1970). Corrosive ulceration in the gas tro- intestinal tract afteringestion of concentrated solutions may considerably increase-absorption, and enhance the toxic action of hexavalent chromium. Noadverse health effects were, on the other hand, detected (by physicalexamination) in a family of four persons who drank for 3 years from aprivate well containing chromiumfVT) at approximately 1 mg/L (0.03mg/kg/day for a 70-kg human; Davids and Ueber, 1951)

When inhaled in significant concentrations, hexavalent chromiumcompounds cause severe irritation of the respiratory tract. Ulcerationand perforation of the nasal septum have occurred frequently inworkers chronically exposed to chromates and similar compounds.Rhinitis, bronchospasm. pneumonia, and emphysema accompanied byimpairment of pulmonary function may result from chronic exposureto hexavalent chromium. In addition, there is clear evidence fromepidemiological investigations that long-term inhalation exposure to:hexavalent chromium is associated with an increased incidence ofbronchiogenic carcinoma (see below).

In the beginning of this century, chromates and chromic acid wereoccasionally used as therapeutic chemicals in high concentrations forvarious skin ailments. Acute nephritis, some fatal, due to tubularnecrosis were reported (Kaufman. et al.. 1970). However, thereseems to be no clear evidence of increased kidney disease in workersoccupationally exposed to chromium compounds (IPCS, 1988).

Hexavalent. and possibly to a lesser degree trivalent chromium, induceirritant as well as allergic dermatitis In man. A number of reports onoccupational dermatitis has been published where sensitization to Cr6*has occurred as a result of long-term exposure to products (e.g.,cement) contaminated only with low concentrations of the metal.


Chromium

• Carcinogenic Activity

The carcinogenic properties of chromium compounds have beenextensively investigated in mice, rats and rabbits. In rodents, calciumchromate induced bronchial carcinomas upon intrabronchialimplantation and sarcomas at the injection site after intramuscularimplantation or after intrapleural injection. Similarly, the chromatesof strontium and zinc have been demonstrated to induce bronchialcarcinomas in rats after intrabronchial implantation. Injection sitesarcomas were produced in rats and mice after intramuscular,intrapleural or subcutaneous injections of chromite ore, strontiumchromate, chromium trioxide, lead chromate and zinc chromate. Fewor no sarcomas were induced by barium chromate, sodium chromateor dichromate. No adequate support for carcinogenic activity has beenobtained in experimental animals for trivalent chromium. In addition,evidence of carcinogenicity is lacking for chromium compounds (tri-as well as hexavalent) administered by the oral route (IARC. 1980,1987).

The induction in experimental animals of local sarcomas, or lungtumors after implantation, may be caused by a number of unspecificagents, and cannot per se be taken as sufficient evidence ofcarcinogenicity. However, a number of epidemiological studies in theU.S., Great Britain, Japan, and West Germany have demonstrated anincreased risk of lung cancer among workers engaged in thebichromate-producing industry as well as in the manufacture ofchromate pigments. There is also evidence of a similar risk amongchromium platers and chromium alloy workers. The latent periodshave been estimated to vary from 10 to 20 years (IARC. 1980. 1987;IRIS. 1988).

An increased incidence of tumors at pther sites have occasionally beenreported for chromate paint workers (gastrointestinal tract),chromate-pigment users (stomach and pancreas), as well as chromeplaters (gastrointestinal tract). Since the observed incidences aresmall, the significance of these findings need further verification(IARC. 1987).

Although a clear distinction between the relative carcinogenicity ofchromium compounds of different oxidation states or solubilities hasbeen difficult to achieve, it is commonly believed that trivalentchromium lacks significant carcinogenic activity in humans (IPCS.

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Group

Chromium

1988; NRCC 1984). Further, available evidence seems to indicate thatf hexavalent chromates of intermediate solubility, like zinc chromate.V_> have the highest carcinogenic -potency (NRCC, 1984).

• Genotoxic Effects and Adverse Effects on Reproduction

Because Cr6+ can 'cross both the outer plasma membrane and thenuclear membrane of the cell before being reduced, it may readilycause DNA-damage intracellularly. A large number of chromiumcompounds have been assayed in in vitro genetic toxicology assays. Ingeneral, hexavalent chromium has been ound mutagenic in bacterialassays, whereas trivalent chromium has not. Likewise Cr6*. but notCr3+, was found to be mutagenic In yeast and in V79 cells. Cr6*compounds inhibit replicative DNA synthesis in mammalian cells andinduce unscheduled DNA synthesis, presumably repair synthesis, as aconsequence of DNA damage. Chromate has been shown to transformboth primary cells and cell lines. Chromosomal effects produced byboth trivalent- and hexavalent chromium compounds have beenreported (IRIS, 1988). Cr6* .induced a significant and "dose-relatedincrease in micronuclei in the bone marrow of mice following 2Intraperitoneal injections of doses ranging from 12 to 14 mg/kg. andcaused a significant increase in chromosomal aberrations in the bonemarrow of rats given repeated intraperitoneal injections of 1 mg/kg(IARC, 1980).

Teratogenlc Activity

Upon single intravenous injections of 5-15 mg/kg chromium trioxideto Syrian golden hamsters, 15 mg/kg proved to be lethal to 3/4mother animals; with 5 mg/kg an increased incidence of cleft palatewas induced. In mice subcutaneously injected Cr3+ failed to induceincreased resorption. but an increase in malformations was seen*There seems to be no evidence of teratogenic effects from chromiumcompounds administered by the oral route.

Chromium Deficiency

Studies in man and experimental animals have established theessential role of chromium for the maintenance of a normal glucosemetabolism. Chromium deficiency has been demonstrated in

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AR30l»306

Chromium

malnourished children as well as in middle-aged subjects, and maybe induced by prolonged use of a synthetic diet without chrdmium. JThere is some epidemiological evidence suggesting a link between ^chromium deficiency and risk factors for cardiovascular diseases.

F. Phannacokinetlcs

Only about 0.5-3% of the total intake of trivalent chromium is absorbedfrom the gastro-intestinal tract. Oral absorption of hexavalentchromium seems to be somewhat greater. In the form of respirableparticles, inhaled chromium compounds are trapped in the lungtissues, and the concentration of this metal Increases with age in thelungs. Larger particles (greater than 5 n), are moved to the larynx byciliary action and will be ingested. Soluble chromates are more rapidlycleared from the lungs to other tissues than trivalent chromicchloride. Chromium absorbed from the gastro-lntestinal tract istransported by plasma proteins, and is subsequently accumulated inbone, spleen, testes, and epidldymis of experimental animals; muchless is retained in liver, lungs, brain, heart, and pancreas. Absorbedchromium is mainly excreted with the urine. In rats the three-compartment model half-lives for elimination have been estimated as0.5, 5.9, and 83.4 days, respectively (Mertz, 1969). J

G. Discussion - Quantification of risk

Based on a NOEL of 1.468 mg/kg/day derived from the study ofIvankovic and Preussmann (1975). EPA has derived a reference dose(RfD) for trivalent chromium of 1 mg/kg/day. An uncertainty factor of100 was used In combination with an additional safety factor of 10(modifying factor; MF). The additional modifying factor of 10 wasadopted to reflect the following uncertainties in the NOEL:

• The effects observed in the 90-day study were notexplicitly addressed in the 2-year study and, thus, the highestNOAEL in the 2-year study may be a LOAEL. The study lackedhigh-dose supporting data.• The absorption of chromium is low, and is influenced by anumber of factors; thus, a considerable potential variation inabsorption exists.• Animals were allowed to die naturally after feedingstopped (2 years) and only then was histology performed. ^

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flR3Ql*307

Chromium

* There was a lack of explicit detail on study protocol andresults.

The confidence given to the derived RfD value is. therefore,considered as low.

For hexavalent chromium administered by the oral route, the NOAELof 2.4 mg Cr/kg from the study by McKenzie et al. (1958) was used byEPA to estimate an RID of 0.005 mg/kg/day. A total safety factor of500 was here employed for very much the same reasons as fortrivalent chromium.

Using the linearized multistage model (extra risk), an inhalationslope factor of 41 (mg/kg/day)"1 (corresponding to a unit risk of 0.012/Hg/m3) was derived on the basis of the epidemiological study ofcancer mortality data presented by Mancuso (1975). The EPA riskfactors probably overestimate the real risk involved, due to theImplicit assumption that the smoking habits of chromate workerswere similar to those of the general white male population. However.it is generally accepted that the proportion of smokers is higher forindustrial workers than for the general population. Strong synerglsticeffects between smoking and other agents causing lung cancer (radon,asbestos, arsenic) have been well documented, and there is no reasonto believe that chromium is an exception.

H. References

Anwar. R.A.. Langham, R.F.. Hoppert. C.A., Alfredson. B.V.. andByerrum. R.U. (1961) Chronic toxicity studies. Ill, Chronic toxicityof Cd and Cr in dogs. Arch. Environ. Health 3. 456-460.

•Davids, H.W. and Ueber, M. (1951) Underground water contaminationby chromium wastes. Water Sewage Works 98, 528-534.

EIFAC (1983). the European Inland Fisheries Advisory Commission,Working Party on Water Quality, Criteria" for European Freshwater Fish.EIFAC Technical Paper No. 43, FAO. Rome.


Chromium

Glaser, U.. Hochralner, D., Kloppel, H., Kordel, W., and Kuhnen, H.(1985): [ Inhalation studies with Wistar rats and patho-physiologicaleffects of chromium]. Report to the Bundesumweltsamt, Berlin, D-1UFOPLAN F+E 10606007/2) (in German).

Hertel, R.F. (1982): [Chromium as a problem in physiology,epidemiology and biological monitoring]. Staub-Reinhalt. Luft, 42:135-137 (In German).

IARC (WHO) (1980) IARC Monographs on the Evaluation of theCarcinogenic Risk of Chemicals to Humans, Vol. 23, Lyon, France.

IARC (WHO) (1987) IARC Monographs on the Evaluation of theCarcinogenic Risks to Humans - Overall Evaluations of Carcinogenicity:An Updating of IARC Monographs Vol. 1 to 42, Suppl.7. Lyon. France,pp. 165-168.

IRIS (1988) The EPA Integrated Risk Information System.

Ivankovic, S. and Preussmann. R. (1975) Absence of toxic and V-xcarcinogenic effects after administration of high doses of chromicoxide pigment in subacute and long-term feeding experiments In rats.Food Cosmet Toxicol. 13, 347-351.

Kaufhian, D.B.. DiNicola, W. and Mclntosh, R. (1970) Acute potassiumdichromate poisoning. Am. J. Dis. Child. 119, 374-376.

MacKenzie. R.D., Byerrum, R.U.. Decker,- C.F., Hoppert, C.A.. andLangham. R.F. (1958) Chronic toxicity studies. II. Hexavalent andtrivalent chromium administered in drinking water to rats. Am. Med.Assoc. Arch. Ind. Health. 18. 232-234.

Mancuso, T.F. (1975) Consideration of chromium as an industrialcarcinogen, in Proceedings of the International Conference on HeavyMetals in the Environment (Hutchinson T.C.. Ed.). Institute forEnvironmental Studies, Toronto. Ontario, Canada.


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Chromium

Mertz. W (1969) Chromium occurrence and function in biologicalsystems, Physiol. Rev. 49. 163-239.

NRCC (1976, 1984) National Research Council of Canada, AssociateCommittee on Scientific Criteria for Environmental Quality.Subcommittee on Heavy Metals and Certain Other Compounds: Effectsof Chromium in the Canadian Environment, NRCC No. 15017; ibid.Chromium Update 1984t Environmental and Nutritional Effects ofChromium, NRCC No. 23917.

Shacklette, H.T., Sauer, H.I., Miesch. A.T. (1970) Geochemicalenvironments and cardiovascular mortality rates in Georgia, USGeological Survey Professional Paper No.574- C, Washington D.C.

U.S.EPA (1986). Ambient water quality criteria for chromium. Qualitycriteria for water Washington, D.C,

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Or Sup

HR30143M

7,4-Dtchloroberaene

1.4-Pichlorobenzene

CASNo.: 106-46-7Synonyms; p-dichlorobenzene

• •A. Physical and Chemical Properties

Chemical Formula: C6H4C12Form: colorless or white crystals, penetrating

odor

Chemical Class: halogenated monocyclic aromaticMolecular Weight: 147.01

Boiling Point: 173.4°CMelting Point: 53°C

Specific Gravity: 1.458 at 20/4°CSolubility in Water: 49 mg/L at 22°C, 79 mg/L at 25°C

Solubility In Organics: alcohol, ether acetone, benzene, carbontetrachloride and ligroin

Organic CarbonPartition Coefficient: 1700Log Octanbl/Water

Partition Coefficient: 3.39 at 20°CVapor Pressure: 0.6 mm at 20°C. 1.8 mm at 30°CVapor Density: 5.07

Henry's Law Constant: 2.89E-03Bioconcentration Factor: 56






Aquatic Organisms (mg/L)Fresh Water: . • , • : - .



1 ,4'Dlchtorobenzene

MarineAcute: NA »

Chronic: NA J

ReferencesSax and Lewis 1989. Verschueren 1983, The Merck Index 1983,SPHEM 1986. EPA 1986NA - Not Available


The competing fate processes for 1.4-dlchlorobenzene are sorption,bioaccumulation, and volatilization, with the dominant process beingdetermined by the specific environmental conditions. In theatmosphere, 1-4 dlchlorobenzene may be degraded through oxidationor absorption on to partlculates and returned to terrestrial systems.Degradation In aquatic and soil systems may be accomplished byspecific acclimatized microorganisms, however, the compound isquite resistant in most natural environments. Volatilization . fromsurface waters is rapid with a half-life of less than 30 minutes.Adsorption of 1.4-dichlorobenzene to organic matter probablycompetes with volatilization processed in aquatic systems. JBioaccumulation in aquatic organisms is likely based on the V_Xoctanol/water partition coefficient and chlorine content.

D. Human Toxicology

Isolated cases of human exposure to 1,4-dichlorobenzene (1,4-DCB)show that its exerts toxic effects on the liver (enlargement, jaundice,porphytia), blood and. blood forming system (anemia), the centralnervous system (headache, dizziness), and the respiratory tract(irritation). Animal studies also show growth depression and increasesin liver and kidney weights, as well as evidence of carcinogenicity inmale rats (kidney tumors), and in male and female mice (liver tumors)(NTP 1987). The calculated cancer potency factor (CPF). based inliver tumors in mice, is 1.0 x 10"2 {mg/kg/day)' * .

• Acute and Chronic ToxicologyDespite the broad spectrum of use of 1,4-DCB there are few reports ofhuman oral or inhalation toxicity of this compound, and no data areavailable for skin exposure (Loeser 1983).

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flR30i*3!3

(

• lA-Dichlorobenzene

A six-month inhalation experiment on the toxicity of 1,4-DCB wascarried out on rats, guinea pigs, rabbits, mice, and monkeys byHollingsworth et al. (1956). Animals were exposed for seven hours aday, five days a week to levels of 1.4-DCB ranging from 580 mg/m3 to4,800 mg/m3 for various periods up to 219 days (not all species wereexposed to all levels). The higher doses induced weight loss, liverdegeneration and necrosis, and kidney changes in rats. Other effectsseen were increased liver, spleen, and kidney weights in guinea pigs,and lung congestion in rabbits. There were no adverse effects seen inthe 5 species after a 6 month exposure to 580 mg/m3 (a doseapproximately equal to 69 mg/kg/day averaged over 7 days). The

' NOEL from this study is 69/mg/kg/day. (Dose conversions were basedon inhalation of 6 L air during a 7 hour day and rat body weight of 250g.)In a more recent inhalation study of longer duration. Loesar andUtchfield (1983) exposed mice and rats to 1,4-DCB at 75 or 500 ppmfor 57 or 76 weeks respectively, followed by a recovery period of 19-20 weeks (female mice) or 36 weeks (rats) (male mice wereterminated at the end of the exposure due to high mortality attributedto fighting and respiratory infections). No treatment related changeswere seen in body weight* food consumption, mortality, or tumorincidence. There were slight, but apparently nonsignificant, increasein liver and kidney weights at the 500 ppm dose (this dosecorresponds to approximately 285 mg/kg/day in rats).Adverse effects of the Uver and kidney were observed in rats dosedorally at 376 mg/kg/day over a 6 month period (Hollingsworth 1956),but no effects were observed at 19 mg/kg/day (there were nointermediate doses).There are no peer-reviewed studies on the reproductive toxicity of1,4-DCB; however, a series of inhalation studies by Imperial ChemicalIndustries (ICI) concluded that there was no evidence ofembryotoxicity or teratogenicity in mice and rats. (Riley et al. 1980 aand b. Hodge et al. 1977). This ICI study involved exposure ofpregnant rats on gestation days 6-15 to 75. 200. or 500 ppm of 1,4-DCB. Some fetal effects were noted but in the authors' opinion, theywere not significantly dose-related.NTP (1987) recently performed a two-year gavage study to assess thecarcinogenicity of 1.4-dichlorobenzene. Female rats and male andfemale B6C3F mice were dosed at 300 and 600 mg/kg. Male F344/Nrats were dosed at 150 and 300 mg/kg because subchronic studiesshowed them to be more sensitive to the effects of 1,4-dichlorobenzene than female rats. Under the conditions of thebioassay NTP concluded that 1.4-dichlorobenzene produced clear

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1 ,4-Dtchlorobenzene

evidence of carcinogenicity in male rats (kidney tumors), and bothmale and female mice (liver tumors).

E. Pharmacokinetics

The dichlorobenzenes, in general, have low water solubility and highlipid solubility. Therefore, 1,4-DCB is likely to diffuse through mostbiological membranes, including the surface of the lungs.gastrointestinal tract and skin. Absorption of 1.4-dichlorobenzene byhumans is indicated by poisonings resulting from inhalation andingestion exposures, but quantitative studies in humans and animalsare lacking (USEPA 1985). One study in rats (Hawklns et al. 1980)observed greater than 90% absorption of a single dose (250 mg/kg) of1,4-DCB. Hawkins also noted that radiolabelled 1,4-DCB was rapidlydistributed, with the highest concentrations occurring In fat, liver.and lungs. Elimination of 1,4-DCB occurs within 5-6 days of exposure.although elimination from adipose tissue is slowest.

P. Discussion • Derivation of Target Concentrations

Based on the data from the NTP (1987) bioassay. ENVIRON hascalculated a cancer potency factor of 1.0 x 10' 2 (mg/kg/day)' 1 basedon male and female mouse lover tumors using GLOBAL 82 (Crump1985).

References

Crump, K.S. 1985. Global 82. A computer program to extrapolatequanta! animal toxicity data for low doses. Version 3.3. October.

Hawklns, D.R.. L.F. Chasseand, R.N. Woodhouse. and D.G. Cresswell.1980. The distribution, excretion, and biotransformation of p-dichloro (l C) benzene in rats after repeated inhalation oral, andsubcutaneous doses. Xenobiotica 10(s): 81195. (Reported inUSEPA 1985).

Hodge, M.C., S. Palmer, J. Wilson, and I.P. Bennett. (1977). Para-dichlorobenzene: Teratogenicity study in rats. Unpublishedreport: Imperail Chemical Industries Ltd. Central ToxicologyLaboratory. Alderley Park. Macclesfield, Chesshire, UK. (Reportedin Loeser and Litch field 1983).

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1,4-Dichlorobenzene

Hollingsworth, R.L.. V.K. Rowe, F. Oyen, H.R Hoyle, and H.C. Spencer.1956. Toxicity of paradlchlorobenzenes. Determinations ofexperimental animals and human subjects. Am. Med. Assoc. Arch.Ind. health. 14:138-147.

Loeser, E. and M.H. Utchfield, 1983. Review of recent toxicologystudies on p-dichlorobenzene. Food Chem. Toxicol. 21:825-832.

National Toxicology Program (NTP). 1987. Toxicology andCarcinogenesis studies of 1.4-dichlorobenzene in F344/N rats andB6C3Fi, mice. U.S. Department of Health and Humas Services,Public Health Service, National Institutes of Health. TechnicalReport Series No. 319.

Riley RA., I.S. Chart A. Doss, C.W. Gore, D. Patton, and T.M. Weight.(1980a). Para-dichlorobenzene: long term inhalation study in rat.Unpublished report: Imperial Chemical Industries Ltd. CentralToxicology Laboratory Alderly Park, Macclesfield, Cheshire. UK.(Reported in Loeser and Utchfield 1983).

Riley RA.. I.S. Chart, B. Gaskell, and C.W. Gore. (1980b). Para-dlchlorobenzene: long term inhalation study In mouse.Unpublished report: Imperial Chemical Industries Ltd, CentralToxicology laboratory, Alderly Park, Macclesfleld, Cheshire, UK.(Reported in Loeser and Utchfield 1983).

/ , U.S. Environmental Protection Agency (USEPA). 1985. HealthAssessment Document for Chlorinated Benzenes. Office of Healthand Environmental Assessment, Washington. D.C. EPA/600/8-84/015F.

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AR30l»3l7

1,1 'Dichlaroethane

1.1-Dichloroetharie

CASNo.: 75-34-3Synonyms: Ethylidene chloride. ethylidene

dichloride

A Physical and Chemical Properties

Chemical Formula: C2H4C12Form: Colorless aromatic liquid

Chemical Class: Chlorinated aliphatic volatilehydrocarbon

Molecular Weight: 98.96Boiling Point: 57.3CMelting Point: -97C

Specific Gravity: 1.174 O 20CSolubility in Water: 5500 mg/1 @ 20C

. Solubility in Organics: alcohol, ether, acetone, benzeneOrganic Carbon

Partition Coefficient: 30Log Octanol/Water

Partition Coefficient: 1.79Vapor Pressure: 234 mm Hg @ 25CVapor Density: 3.42

Henry's Law Constant: 4.3 IE-03Bioconcentration Factor: 6.6

B. Regulations and Standards '







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flR30l*3!8

1,1 -Dichlaroethane

Acute: NAChronic: NA *

ReferencesSax and Lewis 1989, Verschueren 1983, The Merck Index 1983.SPHEM 1986, EPA 1986NA - Not Available


1.1-dichloroethane is highly volatile, and can be expected to bereleased quickly into the atmosphere from an aquatic environment.Once in the atmosphere It is transformed by hydroxylation. Thecompound has a moderate level of aqueous solubility, a low HOC arid alow KOW and therefore would be expected to leach out fairly easily fromaffected soil into water. (Clement Assoc., 1985)

D. Ecotoxicology

There are no data in the literature toxic effect to aquatic organismsspecific to 1.1-dichloroethane. If the data or aquatic toxicity from 1.2-dichloroethane can be extrapolated to 1.1-dichloroethane. it can bereasonably assumed that the latter compound has a low degree ofaquatic toxicity. In general, the toxicity of the chlorinated aliphaticsincreases with increasing chlorination. 1.2-dichloroethane is amongthe least toxic of the organic volatiles within an aquatic system. LCSOvalues for this compound to the fathead minnow. Daphnia magna andthe bluegill are 118. 218. and 550 mg/L, respectively (USEPA. 1984.p. B-l toB-7).

E. Human Toxicology

• Acute and Chronic Toxicology1.1-dichloroethane was once used as a human anesthetic, but itstendency to induce cardiac arhythmias led to its discontinuation forthat usage.

The experimental data on the toxicity of the compound are scarce. \

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1,2 -Dtchloroethane

An inhalation study on four species of laboratory animals was carriedout using 500-1000 ppm for six months. The most sensitive animalappeared to be the cat, in which renal tubular damage wasdemonstrated. Another inhalation study under similar conditionsrevealed no gross or histopathologtcal changes due to exposure.

A 78 week oral study at doses ranging from 382 mg/kg/day to 950mg/kg/day in rats and mice led to increased mortality due to murinepneumonia and nephritis (USEPA, 1984, p. 4-7).

No data on the reproductive or teratogenlc effects of oral exposure to1.1-dichloroethane are available. One inhalation study indicated thatat high doses cause delayed ossification of sternebrae in rats; theNOAEL derived from there study is approximately 3333 mg/kg/day(USEPA, 1984, p. 7).

In accordance with the effect of other chlorinated allphatics onhumans, it can be expected that the primary effects of acute exposureto high doses of the compounds would be manifested by alterations inthe central nervous system: dizziness, incoordination, drowsiness andloss of consciousness.


Bioassays on carcinogenicity or mutagenicity have been eitherinconclusive or equivocal. -There is marginal evidence that 1.1-dicloroethane produces hepatocellular carcinomas in laboratoryrodent, a finding that has been statically demonstrated with otherchlorinated aliphatics. It is possible, therefore, that the finding with1.1-dichloroethane is biologically, if not statistically, significant. Atpresent however, neither IARC nor the Carcinogen Assessment Groupof the USEPA regard the compound as a carcinogen. Its currentweight-of-evidence classification Is D: Not Classified.

Compared to the other members of halogenated volatile organics. 1,1-dichloroethane is among the least toxic (USEPA, 1984, p. 4-7).

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1.1 -Dtchloroethane

F. References

IARC (1986) Monographs on the Evaluation of the Carcinogenic Risk ofChemicals to Humans - Overall Evaluations of Carcinogenicity: AnUpdating of Vol. 1 to 42, Supp. 7. International Agency for Researchon Cancer, Lyon. France.USEPA (1984) Health Effects Document on 1,1-Dichloroethane.Environmental Criteria and Assessments Office. Cincinattl, OH.

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AR30l*32l

flR3(H322

1,2'Dtchloroethane

f 1.2-Dichloroethane

CASNo.: 107-06-2 •Synonyms: ethylene dichloride, EDC


Chemical Formula: C2H4C12Form: Colorless liquid with chloroform odor

Chemical Class: Chlorinated aliphatic volatile• hydrocarbon

Molecular Weight: 98.96Boiling Point: 83.5CMelting Point: -35.3C

Specific Gravity: 1,25 © 20CSolubility in Organics: alcohol, ether, acetone, benzene

Organic CarbonPartition Coefficient: M 43Log Octanol/Water

Partition Coefficient: 1.483Vapor Pressure: 105 mm Hg @ 30CVapor Density: NA

, Henry's Law Constant: 9.78E-04I Bioconcentration Factor: 1.2 (lepomte mocrochfrus, bluegill)

B, Regulations and Standards

Safe Drinking Water ActMaximum Contaminant Level Goal(MCLG for Drinking Water (mg/L): 0

Maximum Contaminant Level (MCL)for Drinking Water (mg/L): ' 0.005

Clean Water ActAmbient Water Quality Criteria (mg/L)Human Health ;

Water and Fish Consumption: 0.00094Fish Consumption Only: 0.24

Aquatic Organisms (mg/L)Freshwater - , - - . - - -Acute: 18

Chronic: 9 . 4 ' . , - , . -Marine

Acute: 31.2Chronic: NA

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flR30l*323

1,2-Dtchlaroethane

References )v J'Sax and Lewis 1989. Verschueren 1983, The Merck Index 1983. ^

SPHEM 1986. EPA 1986NA - Not Available


Two primary means of environmental transport and fate are expectedfor 1,2-dichlorbethane: 1) Volatilization from surface and 2) leachinginto ground water from a source area in the soil.

Upon entering the atmosphere, the compound is degraded byhydroxylation. In soil, the compound would be expected to leach intoground water because of its very low organic carbon partitioncoefficient and moderate solubility. Its vapor pressure and Henry'sLaw Constant are high, indicating the compound's strong tendency toescape from surface water (Clements Assoc.. 1985).

1IX Ecotoxicology \ _ '

1,2-Dichloroethane exhibits the lowest order of toxicity of all thechlorinated ethanes. A 48-hour LCSO value for Daphnia magna hasbeen determined to be 218 mg/ L. Based on a flow-throughexperiment with the fathead minnow, a 96-hour LCSO value of 118mg/L has been estimated; the bluegill shows a 96-hour LCSO value of550 mg/L for 1.2-Dichloroethane with static toxicity tests.

Data on effects from chronic exposure are scant; one embryo- larvaestudy on the fathead yielded a chronic value of 20 mg/L for 1,2-dichloroethane. This species also shows an acute- chronic ratio of 5.9,indicating a fairly low order of chronic toxicity.

Data on toxicity of the compound to freshwater plants Is lacking, but astudy on the saltwater algae Skeletonema castatum showed a 96-hourEC50 value (effect was removal of chlorophyll a) of greater than 433mg/L. The sheepshead minnow, a saltwater vertebrate, has a 96-hourLCSO of 126-226 mg/L for the compound (USEPA, 1980, p. B1-B7). A

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1 ,2-Dichloroethane

E. Human Toxicology

• Summary of Toxicity

1,2-Dichloroe thane is moderately toxic upon acute exposure by theoral or Inhalation routes, having a depressing action on the centralnervous system. Higher concentrations may also elicit toxic responsesin other organs including liver, kidney, lungs, and heart muscle. Uponrepeated exposures the liver constitutes the main target organ.


1,2-Dlchloroethane is moderately toxic to mammals upon short termexposure. The oral LDso- values in rodents lie in the range 400-700mg/kg. In addition to the depression of the central nervous systemcharacteristic of this group of compounds at high dose levels,exposure of rats to single high doses elicits damage to liver, kidneys,adrenals, lungs, and myocardium.

, . .The liver appears to be the main target organ of 1 ,2-dichloroethanetoxicity upon repeated exposure, but at higher dosage levels adrenalsas well as myocardium may be adversely affected in several species.The NOEL for subchronic inhalation exposure (4-9 months) seem tolie around 400 mg/m3. Mice and rats appear to be more sensitive tothe toxic action of this compound than guinea-pigs, rabbits, monkeys,dogs, and cats.

Acute effects on human health from inhalation to 1,2-dichloroethaneinclude headache, dizziness, nausea, vomiting, irritation of mucousmembranes, and liver and kidney disfunction. Direct skin contactwith concentrated solutions may produce dermatitis.

For subchronic Inhalation exposure in experimental animals, severalstudies suggest a No Observed Effect Level (NOEL) of 100 ppm inambient air. Subchronic oral effects In experimental animals Includedecreased growth rates and leucocytosls (USEPA, 1984, p. 5-9).

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flR30ti325

1,2'Dtchloroethane

• Carcinogenic Activity

O1,2-Dichloroethane, administered by gavage, has been found to becarcinogenic in rats and mice. In the former species tumors wereinduced at multiple sites at a dose level of 47 or 95 mg/kg bodyweight for 78 weeks. Statistically significant increases of squamouscell carcinoma of the forestomach, hemangiosarcomas of thecirculatory system, subcutaneous fibromas as well as of mammarycarcinomas in females were found. In mice dosed at 97 to 299 mg/kgstatistically significant Increases in the Incidence of mammaryadenocarcinomas in female mice and of alveolar/bronchiolar adenomasin both sexes was detected.In corroboration of its carcinogenicity, 1,2-Dichloroethane is weakly -but consistently - mutagenic in Salmonella typhtmuriwn TA 1535 withor without metabolic activation system. Positive responses have beenobtained in a number of other short-term assays including Chinesehamster ovary cells, sex-linked recessive lethals in Drosophila, andunscheduled DNA synthesis in human lymphocytes. It has beenpossible to correlate the induced mutation frequency of two humancell lines with the difference in levels of glutathlone-S-transferaseactivities. An episulfonium ion derived from non-enzymlc conversionof the metabolite S-(2-chloroethyl)glutathione seems to constitute the .proximate alkylatlng agent in the formation of DNA-adducts in vivo jfrom exposure to 1,2-dichloroethane. The formation of apurinic sites Xs-'from the adduct S-{2-(N7-guanyl)ethyI]glutathione) may be linked tothe mutagenic as well as carcinogenic action of this compound.

In one study 1,2-dichloroethane was found to induce resorptions inpregnant rats at toxic exposure levels, but no clear-cut teratogenicaction have been demonstrated in experiments involving rodents.

1,2-dichloroethane Is classified by the USEPA as a probable humancarcinogen, with a weight-of-evldence ranking of B2. This ranking isbased on the induction of several tumor types in rats and mice by oralexposure and of lung papillomas after dermal application. Tumorsresulting from oral exposure included squamous cell carcinomas of thefore stomach and hemangio sarcomas of the circulatory system.

Carcinogenic responses from inhalation exposure were not observed Inseveral studies. 1,2-dichloroethane has shown positive results inSalmonella mutagenicity assays (IRIS. II.3.A.).


AR30l»326

1,2-Dichloroethane

Chronic occupational exposure to 1,2-dichloroethane vapor has beenshown to cause anorexia, nausea, vomiting, weakness and fatigue. Noevidence of teratogenicity in humans or animals has been produced todate (USEPA, 1984 p. 9-13).

1,2-DIchloroethane has been shown to be carcinogenic inexperimental animals producing tumors in rats and mice at multiplesites, and has also given a positive response in several short-termtests. The substance does not seem to adversely affect reproductionexcept at doses toxic to the mother.

F. Discussion of Regulatory Standards

EPA has ranked 1,2-dichloroethane as a B2 carcinogen with a potencyfactor of 0.09 (mg/kg/day)" * associated with ingestion. The CAG hascalculated two upper-bound estimates of the incremental cancer riskfor the inhalation of 1 microgram/m3 of 1,2-dichloroethane: 2.6E-05on the basis of the gavage potency value, and l.OE-06 on the basis of anegative inhalation study. As a first approximation. It seems practicalto use the same potency value for Inhalation as for oral administration.IARC has concluded that there is sufficient evidence of carcinogenicityfor 1,2-dichloroethane in experimental animals.

A Maximum Contaminant Level (MCL) of 0.005 mg/L has been-proposed, but no ambient water quality criterion for the protection offresh water life has been established.

No ADI has been allocated by. the FAO/WHO Panel of Experts onPesticide Residues. Classified as "Harmful" (X) by the EuropeanCommunities (EEC), but proposed for classification as carcinogen.Prohibited for use In cosmetics within the EEC. The ACGIH 8 hr TWA(TLV) is currently set at 10 ppm (40 mg/m3).

Pharmacokinetics and Metabolism

1,2-Dichloroethane Is readily absorbed via the oral, dermal, orinhalation routes. Following oral administration, accumulation is

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1,2-D(chloroethane

mainly observed In fatty tissues as well as in the liver, and thesubstance crosses readily the placental barrier. In the rodentexcretion as unchanged 1,2-dichloroethane via expired air, or in theform of metabolites, is rapid. About 90% of the total body burden iseliminated within 48 hrs in orally dosed mice. In addition tocytochrome P-450 mediated oxidation to give 2-chloroacetaldehydeand 2-chloroethanol, 1,2-dichloroethane is metabolized viaconjugation with glutathlone to form the reactive half-mustard S-{2-chloroethyDglutathione. The carcinogenic and genotoxic properties of1,2-dichloroethane is evidently linked to the formation of the latteralkylating agent.

References

Environment Canada (1984) Environmental and Technical Informationfor Problem Spills, Ethylene Dichloride, Ottawa.

International Programme on Chemical Safety (1987) EnvironmentalHealth Criteria No. 62, 1,2-Dlchloroethane, WHO. Geneva.

USEPA (1985) Health Assessment Document for 1,2-Dichloroethane /(Ethylene Dichloride), EPA/600/8-84/006F, September 1985.

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flR30l*328

fiR30l»329

1.1-DCE

1.1 -Dichloroethene^ hM ^ BBBH ^ M H H0MMBHHtaH H*HHH ^ HIM» ^

CASNo.: 75-35-4Synonyms: 1,1-Dichloroethylene. 1.1 -DCE,

vinylidene chloride


Chemical Formula: C2H2C12Form: Colorless volatile liquid

Chemical Class: Chlorinated olefinic volatile hydrocarbonMolecular Weight: 96.95

Boiling Point: 37CMelting Point: -122.5C

Specific Gravity: 1.218 @ 20CSolubility in Water: 2640 mg/1 @ 20C

Solubility in Organics: sparingly in alcohol, ether, acetone.benzene and chloroform

Organic CarbonPartition Coefficient: 653Log Octanol/Water

Partition Coefficient: 1.843Vapor Pressure: 591 mm Hg @ 25CVapor Density: 3.254









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flR30i*330'

1,1-DCE


ReferencesSax and Lewis 1989, Verschueren 1983, The Merck Index 1983.SPHEM 1986. EPA 1986NA - Not Available


Leaching into ground water can be expected to be a significantpathway of environmental transport of 1,1-dichloroethylene because ofthe compound's relatively high aqueous solubility, and relatively loworganic carbon and octanol-water partition coefficients.

Volatilization from soil arid surface would be expected from thecompound's high vapor pressure and Henry's Law constant.

Information on biodegradation and bioconcentration is lacking, butextrapolation from related compounds would lead to the conclusionthat these processes would be slow and of such low magnitude as to beconsidered insignificant (USEPA, 1984. p.l).

D. Ecotoxicology

1,1-dichloroethylene is only mildly toxic to freshwater species ofplants and animals; its acute LCSO values range from 80 to 200 mg/Ldepending on species. EC50 values of 11.6 mg/L and 79 mg/L werederived for studies on Daphnia magna over 48 hours.

A 96-hour EC50 value for fresh water algae, based on chlorophyll acontent and cell numbers was estimated at higher than 798 .mg/L.Levels of up to 2.8 mg/L produced no adverse effects In the fatheadminnow in one study (USEPA, 1980. p. B1-B8).

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flR30li33!

1.1'DCE

E. Human Toxicology

• Acute and Chronic ToxicologySubchronic oral and inhalation exposures to laboratory rodents havebeen shown to produce renal and hepatic damage. Another study.however, shows no adverse effect to cytology, organ weight, bodyweight or hematology when 1,1-dichloroethylene was administeredorally for 97 days at dosages ranging up to 25 mg/kg day.

Studies on chronic toxicity from oral exposure to the compoundrevealed the predominant effects to be chronic renal inflammation andhepatocellular fatty infiltration along with periportal hypertrophy.

Acute exposure to high doses produces depression of the centralnervous system: low-dose exposure has not been observed to produceacute neurotoxtc effects.

• Carcinogenic ActivityThe evidence regarding the carcinogenic effects of 1.1-DCE isequivocal. Numerous studies of exposure by gavage or by inhalationhave yielded no statistically significant increase in occurrence oftumors in laboratory rodents, while two studies have revealedsignificant increases in kidney carcinomas, total mammary tumors andmammary adenocarcinomas. Other studies showing increased tumorIncidence did not demonstrate a dose- response relationship.Carcinogenic responses in laboratory animals to 1.1-DCE occurprimarily by Inhalation exposure (USEPA, p. 3-17). The compound hastested positive in bacterial and yeast mutagenic assays. The EPA hasdesignated 1,1-DCE a Class C compound: Possible HumanCarcinogenic. No direct evidence of carcinogenicity in humans isavailable (USEPA, 1984. p. 17).

F. Discussion

• Regulations and StandardsThe available data are not considered sufficient by the EPA topromulgate formal ambient water quality criteria. The lowest knownvalue causing toxic effects to fresh water organisms is 11.6 mg/L.

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SR30I<332

1,1 -DCE

• Summary of Risk EstimatesFor protection of human health for consumption of water and aquaticorganisms, EPA has published the following carcinogenic risk levelsand their accompanying concentrations.

Risk Concentration10-5 0.33 mg/L10-6 0.033 mg/L10-7 0.0033 mg/L

(Clement Assoc., 1985)

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flR30t*333

fiR30i*33i*

1 ,2-Dtchloroethene

1.2-Dlchloroethene (totall

CASNo.: 540-59-0Synonyms: 1,2-Dichloroethylene. acetylene

dichloride. dioform


Chemical Formula: C2H2C12Form: liquid

Chemical Class: halogenated aliphatic hydrocarbonMolecular Weight: 96.94

Boiling Point: 47.5°CMelting Point: -50°C

Specific Gravity: 1.2565 at 20°CSolubility in Water: 600 mg/1 at 20°C

Solubility in Organics: benzene, chloroform, alcohol, ether,acetone

Organic CarbonPartition Coefficient: Koc » 59Log Octanol/Water

Partition Coefficient: 1.48 (calculated)Vapor Pressure: 200 mm Hg at 14°CVapor Density: 3.34

Henry's Law Constant: 0.067 (atm-cu.m./mol)Bioconcentration Factor: 48 (microbial)


Safe Drinking Water ActMaximum Contaminant Level Goal(MCLG for-Drinking Water (mg/L): 0.07



Water and Fish Consumption: NAFish Consumption Only: ; NA

Aquatic Organisms {mg/L)Freshwater:

Acute: 1.16E+01 .Chronic: NA -: ;

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flR30i»335

1,2-Dichloroethene

MarineAcute: 2.24E+01 ^

Chronic: NA )

ReferencesSax-and Lewis 1989, Verschueren 1983, The Merck Index 1983,SPHEM 1986, EPA 1986NA - Not Available


Volatilization appears to be the major transport process for trans-1.2.-dichloroethene in surface water and soils. The volatilization half-life insurface water is reported to be 22 minutes. Oxidation and hydrolysisprocesses are important in the atmosphere but do not appear to besignificant in the aquatic environment. Based on its KQC. trans-1.2-dichloroethene probably does not sorb to soils and sediments-to anyextent. Based on its octanol/water partition coefficient (KoW), thiscompound would seem to biodegrade poorly, yet dechlorination tovinyl chloride has been reported under anaerobic conditions.

D. Human Toxicology ****

Animal studies have demonstrated that trans-l,2-dichloroethylenecauses liver, kidney, and lung damage, especially when inhaled. Onlyone study has been reported detailing the toxic effects associated withchronic exposure to this compound. In humans. 1.2-dichloroethylenehas produced adverse central nervous system effects. An ADI of 1.1 x10~2 mg/kg/day was calculated based on a rat subchronic LOEL(Freundt et al [19771 as reported in NRC. 1983).

• Acute and Chronic ToxicologyThe critical experiment on the toxicity of trans-1.2-dichloroethyleneis reported by Freundt et al (1977, as reported in NRC. 1983) inwhich rats were exposed to a vapor of 200 ppm for 8 hrs/day 5days.week for 16 weeks. Rats developed some liver damage (fattydegeneration), and some evidence of lung damage (pulmonary capillaryhyperemia and alveolar system distention).Acute exposure of humans to 1,2-dichloroethylene may producenarcosis and irritation of the central nervous system (Falrhill 1957 as

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I ,2'Dtchloroe thene

reported In ACGIH 1980): 1,2-dichloroethylene has been successfullyused as an anesthetic (Harper 1934 as reported in Torkelsori andRowe 1981). Repeated narcotic doses reportedly cause fattydegeneration of the liver (Carpenter et al. 1949 as reported in ACGIH1980).The only other study of toxic effects following repeated or prolongedexposure to trans- 1,2-dichloroethylene is one reported by Lehman andFlury (1943 as reported in Torkelson and Rowe 1981) in which catsand rabbits were repeatedly exposed to vapor concentration of 0.16 to0.19 percent in air and showed loss of appetite and some respiratoryirritation but no histopathologlcal changes in lungs, liver, or kidneys.The toxic effects of acute inhalation exposure of rats to trans-1,2-dichloroethylene have been studied by Freundt et al. (1977 asreported in NRC 1983). Exposure to 3000 ppm for 8 hours wasassociated with cardiac muscle damage. Exposure to 100 ppm for 8hours was associated with reductions in serum albumin, urea nitrogen,alkaline phosphatase, leukocyte count and erythrocyte count. In.addition, two out of six rats exposed at this level showed fattydegeneration of the liver and five our of six showed histopathologicalchanges in the lungs. Exposure to 200 ppm for 8 hours was associatedonly with decreased leukocyte count, distention of alveolar septae andpulmonary capillary hyperemia.. One out of six rats exposed at thislevel showed slight fatty degeneration of the liver. Acute exposure ofrats to 200 ppm has also been shown to reversibly inhibit mixedfunction oxidases (Freundt and Machblz 1978 as reported In NRC1983).Trans-1,2-dlchlorethyIene was not found to be mutagenic in an in vitroassay with E. coli either In the presence or absence of metabolic.activation (phenobarbital induced mouse liver system) (Greim et al.1975 as reported in NRC 1983).

E. Pharmacokinetlcs

There is no pharmacokinetic data for trans-1,2-dichloroethylene.Therefore, it is assumed that Individuals exposed to trans-1,2-dichloroethylene would absorb 100% of the delivered dose from eitheringestion or inhalation routes or exposure. It Is also assumed thatdermally exposed subjects would absorb 10% of the delivered dose.

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1,2-Dtehloroethene

F. Discussion - Derivation of Target Concentrations

An ADI of 0.0110 mg/kg/day for trans-1,2-dichloroethylene has beencalculated on the basis that exposure of rats to 200 ppm (or 108mg/kg/day) vapor for 16 weeks resulted in liver and lung toxicity(Freundt et al. 1977 as reported in NRC 1983). A safety factor of10.000 was used: 10-fold since the basis was a LOEL of overt toxicity,and 1,000-fold for a subchronic animal study.

References

American Conference of Governmental and Industrial Hygienists(ACGIH) (1986) Documentation of the threshold limit values.Fifth edition. Cincinnati, OH.

National Research Council (NRC) (1983) Drinking water and health.vol. 5. Board on Toxicology and Environmental Health Hazards.Safe Drinking Water Committee. Washington. D.C. NationalAcademy Press.

Torkelson. T.K. and V.K. Rowe (1981) Halogenated aliphatichydrocarbons. In Parry's industrial hygiene and toxicology, vol. 2B.3rd edition. G.D. Clayton and F.E. Clayton (eds). New York, JohnWiley and Sons.

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SR30U339

2,4-Dichlorophenol

2.4-Dlchlorophenol• . • .

CAS No.: 120-83-2 *Synonyms: 2,4-DCP


Chemical Formula:Form: colorless liquid

Chemical Class: halogenated monocyclicMolecular Weight: 163.01

Boiling Point: 210°CMelting Point: 45°C

Specific Gravity: 1.383 at 60/25°CSolubility In Water: 4,500 mg/L at 25°C

Solubility in Organics: alcohol, ether, benzene and chloroformOrganic Carbon


Partition Coefficient: 2.9Vapor Pressure: 1 mm at 53.0°CVapor Density: 5.62

Henry's Law Constant: 2.75E-06Bioconcentration Factor: 41,







Acute: 2.00E+00Chronic: 3.00E+00Marine ;



2,4-D(cMorophenol

ReferencesSax and Lewis 1989. Verschueren 1983, The Merck Index 1983,SPHEM 1986. EPA 1986NA - Not Available


Biodegradation is the primary process controlling the fate of 2,4-Dichlorophenol in the environment. Biodegradation in soils andaquatic systems may be slow or rapid, depending on the pollutantexposure of the microorganisms and other environmental factors suchas pH and oxygen levels. The half-life of the compound isapproximately one week. Volatilization, sorption, oxidation, hydrolysisand bioaccumulation are not significant fate processes according to thelimited available data.

IX Ecotoxicology

Acute sensitivities for 2,4-DCP have been conducted for three species j)which values are summarized in the following table: -

Species Toxlcitv fmg/11Daphnia magna 2.6Fathead minnow 8.2Bluegill 2.0

For the fathead minnow, a chronic toxicity value of 365 g/1 and anacute:chronic ratio of 23 have been reported (EPA, 1985).For saltwater species, the mountain bass (Kuhlia sandvicensis) displayssome response to 2.4-DCP at 20 mg/1.In the freshwater algal species Chlorella pyrenotdosa. chlorophyll isdestroyed at 100 mg/1.The bloconcentration factor for all aquatic organisms for 2.4-DCP hasbeen calculated as 40.7 (EPA, 1985). Apparently the same Is true forterrestrial animals in that residues of 2,4-DCP have been detected inchicken livers, kidneys and eggs and in beef liver and kidneys. These

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2,4'Dichlorophenol

are probably due to exposure to the herbicide 2,4dichlorophenoxyacetic acid (2,4-D).

E. Human Toxicology

• Acute and Chronic ToxicologyLittle data in experimental animals and no data from epidemiologicstudies exist for 2,4-DCP. Although more data exists for the precursorherbicide 2,4-D. since this phenoxyacetic acid derivative catabolizes toother products in addition to 2,4-DCP, any conclusions would beconjectural.Injection of test animals with large doses of 2,4-DCP is sequentiallyfollowed by polypnea, slowed respiration, dyspnea, hypotonia. comaand death (EPA, 1980). A maximal NOAEL of 100 mg/kg/day derivesfrom feeding experiments In mice. Some non-specific microscopicchanges of liver were seen at 230 mg/kg/day. Orally, the LD50 of 2.4-DCP for the rat is 580 mg/kg (EPA, 1985).Subcutaneous injection of 74 mg/kg to pregnant mice between days 6-14 of gestation resulted in abnormal fetuses, mainly extension of leglength. There was no increased mortality, although pup weights atbirth were depressed.

• Carcinogenic ActivityWhereas 2,4-DCP itself is not carcinogenic, it appears to promoteCarcinogenesis by other carcinogenic initiators. Mice Induced to formskin papillomas by. skin applications with dimethylbenzanthracene(DMBA) in benzene as solvent were found to have an exacerbatedpapillomatous response if they were treated subsequently with topicalapplications of 40.8 mg/kg 2,4-DCP. DCP alone in these tests was notcarcinogenic. This promotor activity of 2,4-DCP may be due to itsInducing activity for mixed function oxidases which, in turn,metabolize DMBA to its ultimate carcinogenic form.In the plant Vicia /aba, 2,4-DCP has been reported to affect mitosisand meiosis of flower buds and root cells. No other short-term testshave been performed with 2,4-DCP. Unlike carcinogenic initiators, itis not anticipated that mutations or chromosomal abnormalities wouldbe induced by a promotor of Carcinogenesis.

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AR30W2

2.4-D<chIorophenoI

F. References

EPA (1980) Ambient water quality criteria for 2,4-dichlorophenol.Office of Water Regulations and Standards, U.S. EnvironmentalProtection Agency. Washington, D.C. EPA 440/5-80-042.EPA (1985) Chemical, physical and biological properties of compoundspresent at hazardous waste sites. (Prepared by Clement Assoc.)

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ARSONS

C

DEHP

Bis f2-ethv!hexvn ohthalate

CASNo.: 117-81-7Synonyms: di(2-ethylhexyl)phthalate, DEHP, BEHP,

octoil

A. Phsical and Chemical Proerties

Chemical Formula:Form: light-colored liquid

Chemical Class: phthalate esterMolecular Weight: 391

Boiling Point: 385°CMelting Point: -55°C

Specific Gravity: 0.99 at 20°/20°CSolubility in Water: 0.285 at 24°C

Solubility in Organics: alcohol, ether, acetone, benzeneOrganic Carbon

Partition Coefficient: 2.0E+09Log Octanol/Water

Partition Coefficient: 9.6Vapor Pressure: 1.2 mm at 200°CVapor Density: 13.45

Henry's Law Constant: 3E-07Bioconcentration Factor: 2.3E+08 (microbial)



Maximum Contaminant Level (MCL)for Drinking Water (mg/L); NA




Acute: NA !Chronic: NAMarineAcute: NA

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DEHP

Chronic: NA

References iv j'Sax and Lewis 1989. Verschueren 1983, The Merck Index 1983.SPHEM 1986. EPA 1986NA - Not Available


Sorption, biodegradation, and bioaccumulation of DEHP are competingfate processes in the environment. The predominant fate processdepends upon the type of aquatic and soil environments present at asite. DEHP bioaccumulates in the aquatic food chain and also In highermammals. Bioaccumulation is followed by metabolism and excretion;thus, biomagniflcation in the food chain is not likely. Bioconcentrationfactors range.from 70 to 13,400 times the water concentration. DEHPis readily biodegraded. Limited Information exists concerning thephotolysis, hydrolysis, oxidation, and volatilization of DEHP in theenvironment.

DL Ecotoxicology i

A limited data base exists regarding the ecotoxic properties ofphthalates. The available studies concern single species and no datawere found regarding the effects of phthalate contamination on thehigher levels of organization (e.g.. ecosystems, populations). However,in a model ecosystem (microcosm) study Metcalf (as referenced inHealth and Welfare, Canada 1980) reported significant ecologicalmagnification (biomagniflcation) factors for di-(2-ethylhexyI) phthalate.Additional studies support the postulate of bioconcentration andbiomagniflcation of phthalate esters in various species. The sparseamount of toxicity data available for phthalate esters indicates that di-n-butyl phthalate is the most toxic member of this family ofcompounds.

The saltwater alga (Gymnodinium breve] is the only plant speciestested with phthalates. An LCSO value of 1000 \ig/\ and an EC50(inhibition of growth) value of 3100 ng/1 were reported for this plantspecies (USEPA 1980. 1981).

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DEHP

A phthalate concentration of 1000 ng/I significantly affected thehatching success and was toxic to the larvae of the brine shrimp(Artemia satina). The scud (Gammorus psuedolimnaeus] was the mostsensitive invertebrate (LCSO of 2100 \ig/\}. In addition, an LCSO of10,000 ug/1 phthalate was reported for the crayfish ((Orconectes nais)USEPA 1980, 1981).

Bluegills (Lepomis macrochirus] were the most sensitive fish speciestested (LCSO of 731 ng/1). LCSO values of 1300, 2910, and 6470 Mg/1were reported for the fathead minnow (Pimephales promelas),channel catfish (Ictalurus punctatus], and rainbow trout (Salmogatrdnert), respectively (USEPA 1980,1981). The paucity of dataavailable percludes the comparison of different classes of fish (e.g.roughfish and gamefish, coldwater and warm-water species).

The USEPA (1986) has not established criterion for the protection ofaquatic life. However, acute and chronic responses may occur upon theexposure of freshwater aquatic life to phthalate ester concentration aslow as 940 and 3 jig/1, respectively. Acute toxicity may occur insaltwater organisms at phthalate ester levels as low as 2,994 (ig/1;however, this data does not perclude a toxic response by a moresensitive species occurlng at a lower concentration. No data areavailable to evaluate the chronic toxicity of phthtalate esters tosaltwater aquatic life.

Ring doves (Streptopelia risoria) fed a dietary concentration of 10mg/kg of phthalates exhibited a decrease in eggshell thickness,.reduction in egg weight. Increase in shell permeability to water, andan augmented water loss rate (USEPA 1981).

E. Human Toxicology

Phthalates do not seem to occur in nature. However, the naturaloccurrence of certain phthalic esters has been reported. To excludethe possibility of contamination due to the widespread use of thesecompounds, (especially of di(ethylhexyl)phthalate), these findingsneed further verification. In view of the uses of phthalates as acosmetic ingredient, plasticizer. as well as, textile lubricating agent.skin exposure represents a likely route of exposure.

• Summary of Toxicity Data

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Bis(2-ethylhexyl)phthalate (DEHP) has a low acute as well as chronictoxicity. At high doses this phthalate ester induces testicular atrophyin rodents and causes teratogenlc effects as well as fetal loss in ratsand mice. Long-term dosing studies Indicate reduced fertility in therat associated with fetal toxicity. Although some results suggestive ofCarcinogenesis have been obtained and DEHP is considered by EPA tobe a class C (possible human) carcinogen, the majority of evidenceseems to suggest that DEHP lacks genotoxic properties and inducesperoxlsome proliferation in liver cells of rodents.

• Acute and Chronic Toxicology-Acute oral toxicity of E)EHP in rats and mice has been reported as lowas 8 g/kg. Administration of approximately 1.4 g/day of the compoundby oral intubation for 4 days to groups of 12 rats resulted In decreasedweight of testes associated with severe atrophy of the seminiferoustubules.In a long-term toxicity study in rats reported in the earlier literature,male Sprague-Dawley rats In groups of 10 were fed diets containing 0,0.01. 0.05, 0.25, and 1.25% dibutyl phthalate for a period of 1 year.One-half of all rats receiving the highest dibutyl phthalateconcentration died during the first week of exposure. The remaininganimals survived the study with no apparent 111 effects. There was noeffect of treatment on gross pathology or hematology. While it wasstated that several organs were sectioned and stained, nohistopathologic evaluation was reported (Smith, 1953).Male rats exposed to 1.5 mg dibutylphthalate/m3 for 6 hrs/day, 6days/week for approximately 1 month did not exhibit any significantchanges in body or organ weights compared to controls. In anotherstudy inhalation of 0.5 and 50 mg/m3 for 6 months did affect weightincrease in rats, and greater brain and lung weights were found at bothexposure levels in a dose related fashion. However, the data baseregarding long-term effects must be regarded as Insufficient, and NTPhas recently selected the substance for Carcinogenesis studies.Peripheral neuropathy in man has been reported in the Sovietliterature. However, these workers were evidently exposed to anumber of different substances, including tri- o-cresyl phosphate, andsuch effects could not be substantiated in a study Involving workersexposed to a mixture of phthalates - including DEHP - conducted bythe Kodak Co.

• Carcinogenic ActivityPreviously conducted long-term studies do not permit any conclusionto be drawn concerning the potential carcinogenic effects of mostphthalate esters. However, there are indications that di(2-

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DEHP

ethylhexyljphthalate is a peroxisome proliferator (EPA. 1987)implying that the substance constitutes a potential rodent liver

• carcinogen at high doses. Most phthalates probably share thisproperty and would cause some increase in experimental liver tumorsif only the dose were high enough. In any event, DEHP is a very poorcarcinogen, with a carcinogenic potency of 7.8E-04 (mg/kg/day)" 1only slightly above that of saccharin.

• Genotoxic effects and adverse effects on reproductionAlthough a positive result has been reported with Salmonellatyphimwium TA100 in one Investigation using liquid suspension assay,negative results have, as a rule, been obtained with phthalates .in theAmes' test using strains TA98. TA100, and TA1537 with and withoutmetabolic activation as well as in other microbial mutation assays.Investigations on sister chromatid exchanges (SCE) and chromosomeaberrations In cultured Chinese hamster cells have been inconclusiveand negative in cultured human leukocytes.As mentioned above, di-n-butylphthalate causes atrophy of testes inexperimental animals (rats, rabbits, guinea pigs, and ferrets, but not inthe hamster). Most tubules exhibit a more or less extensive loss ofspermatocytes and of spennatids. The effects seen are very similar tothose seen for diethylhexylphthalate. It should be noted, that suchdamages have been found to be largely reversible, and do not seem to

r . notably affect reproductive performance in the rat.Administration of high doses of phthalate during pregnancy has beenshown to induce an increase in fetal mortality and a reduction in fetalweight, while having no apparent effect on implantation in mice andrats, evidently due to a direct toxic action on the fetus. Upon long-term exposure of rats (days 21-145 of life) to Ig/kg a reduced fertilityIn females was induced (Cummings and Gray. 1987).Intraperitoneal injection of phthalate in doses of 2 and 4 ml/kg topregnant rats resulted in a 50% reduction in the number of pupsweaned per litter. Two male pups, one from each of two litters in thelower dose group, had no eyes. Additional indications of fetotoxic aswell as teratogenic effects (skeletal abnormalities) in rats wereobtained in another study when 0.3-3 ml/kg was injected in pregnantrats. However, the failure to include a historical control data makes itdifficult to evaluate this investigation. When administered by gavage inolive oil 120 or 300 mg/kg/day 3 months prior to mating and for 21days following fertilization, fetuses from treated and control rats didnot differ significantly with respect to the incidence of skeletalabnormalities. However, at 600 mg/kg the number of resorptions wassignificantly increased. When dibutylphthalate was administered in thefeed to pregnant mice throughout gestation at dose levels from 80 to

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DEHP

2100 mg/kg. significant maternal toxic effects were observed at thehighest dose level, and two of three live fetuses from this group hadneural tube defects. 350 mg/kg appears to have been the NOAEL forresorptions, fetal weights, or malformations In this study (Shlota andNishlmura. 1982).

References

ACGIH: "Documentation of Threshold Limit Values and BiologicalIndices", 5th Ed., 1986, pp. 176-177.

Cosmetic Ingredient Review Expert Panel; Final Report on the SafetyAssessment of Dibutylphthalate, Dimethylphthalate, and DiethylPhthalate, . J. American College of Toxicology, 4(1985)267-303.

Cummings, A.M.. and Grey. L.E.; Maternal effects versus fetotoxicity,Toxicol. Lett. 39(1987)43-50.

Shiota, K... and Nishimura, H.; Teratogenicity of di(2-ethylhexyDphthalate (DEHP) and di-n-butyl phthalate (DBP) in mice,Environm. Health Perspectives 45(1982)65-70.

Smith, C.C.; Toxicity of butyl stearate, dibutyl sebacate, dibutylphthalate, and monoethyl oleate. Arch. Ind. Hyg. Occup. Med.7(1953)310-318.

U.S. EPA. Drinking Water Criteria Document for Phthalic Acid Esters.Prepared by the Office of Health and Environmental Assessment.Environmental Criteria and Assessment Office, Cincinnati, OH for theOffice of Drinking Water, Washington, DC. External Review Draft.1987.

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AR304350

Heptachlor epoxide

Hetachlor eo oxide

CASNo.: 1024-57-3Synonyms: Epoxyheptachlor; 1.4,5.6,7,8,8a-

Heptachloro-2.3--epoxy-2,3.3a.4,7,7a-hexahydro-4,*7-methanoindene


Chemical Formula:Form: Rare in solid form, normally amber-

colored liquid in organic solvents

Chemical Class: organochlorine cyclodiene pesticide, ametabolite of chlordane and heptachlor

Molecular Weight: 389.3Boiling Point: NAMelting Point: 157-160flC

Specific Gravity: > 1.0Solubility in Water: 0.35 mg/L © 25C

Solubility in Organics: benzene, fuel oilOrganic Carbon


Partition Coefficient: 2.7Vapor Pressure: 3.00E-04 mm HgVapor Density: 3.72

Henry's Law Constant: 3.9-4.4Bioconcentration Factor: 1.44E+04

E Regulations and Standards

Safe Drinking Water ActMaximum Contaminant Level Goal(MCLG for Drinking Water (mg/L): 0 .

Maximum Contaminant Level (MCL)for Drinking Water (mg/L): 2.00E-04 (proposed)


Water and Fish Consumption: 2.8E-07Fish Consumption Only: 2.8E-07

Aquatic Organisms (mg/L)Fresh Water :j

Acute: 5.2E-04

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fiR30l*352

Heptathlor epoxtde

Chronic: 3.8E-06Marine

Acute: 5.3E-05Chronic: 3.6E-06

ReferencesSax and Lewis 1989. Verschueren 1983, The Merck Index 1983.SPHEM 1986. EPA 1986NA - Not Available


Heptachlor epoxlde is quite stable in the environment due to itstenacity for organic carbon and seven rather indigestible carbon-chloride bonds. Its half-life has been estimated at 14 years in soil(ATSDR, 1988). Although it volatilizes very poorly, undercircumstances where its precursors (chlordane and heptachlor) havebeen heavily inoculated (utz,, for termite control), movement throughsoil gas may be the main route of human exposure. This is especiallyimportant in terms of indoor air pollution when soil gas residuesmigrate centripetally inward from a surrounding wall of injectedtermiticide due to the slight negative indoor air pressure of mosthomes (Molholt, 1986).Heptachlor epoxlde is quite insoluble and rarely is of consequence ingroundwater. Co-solvation by organic solvents, however, may vastlyincrease the mobilization of heptachlor epoxlde or its precursors fromsoil into groundwater. Simon and Parker (1984) have modeled themovement of heptachlor in water, sediment and biota.Heptachlor epoxide bioac cumulates enormously and wildlife inexposed environments present orders of magnitude more residue intheir tissues than found in the environment. Heptachlor epoxide isubiquitous and found at part-per-billion levels in blood and part-per-million levels in adipose tissue of the general population.Biodegradation of heptachlor epoxide is not a very important fateprocess (Mabey et al, 1981).Potatoes grown in soil which had been treated with heptachlor 5-10years previously were found to contain 27 times as much heptachlorepoxide (54 ppb) as heptachlor (2 ppb) by Lichtenstein et al (1970).Similarly, soybeans grown in soils treated with heptachlor 15 yearspreviously were found to have no detectable heptachlor, but up to 237ppb of heptachlor epoxide (Nash and Harris. 1973).

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GHeptachlor epoxtde

IX Ecotoxicology

Heptachlor epoxlde strongly bioaccumulates in shellfish. Geyer et al(1982) calculated a bioconcentration factor (BCF) of 1700 after Just 4days exposure in mussels (Mytt/us edutts). Hawker and Connell (1986)conducted a similar experiment with, heptachlor epoxlde in oysters(Crassostrea virginica) and found a log BCF of 2.93. Similar log BCFsfor heptachlor epoxlde have been calculated for the pinfish (Lagodonrhomboides) and sheepshead minnow (Cyprinodon variegatus] as 3.46and 3.65, respectively (Zaroogian et al, 1985).

E. Human Toxicology

The basic human toxlcities of heptachlor epoxide are neurotoxicity.hepatotoxlciry and carcinogenicity. As usual, the laboratory data inexperimental animals are more precise than available epidemiologicevidence.

• Acute and Chronic ToxicologyNEUROTOXIC EFFECTS

Neurotoxlc symptoms in workers exposed to technical gradechlordane (10 percent heptachlor) include irritability, salivation,lethargy, dizziness, labored respiration, muscle tremors andconvulsions (EPA, 1985). Wang and MacMahon (1979) found astatistically increased incidence of cerebrovascular diseases in'chlordane and heptachlor workers.When CD-1 male mice are given a single oral dose ofheptachlor/heptachlor epoxide;(l/3) at 30-100 mg/kg. they displayinitial hypoactivity which frequently results in death (Arnold et al,1977). Rats given LD50 doses of heptachlor showed neurotoxicsymptoms within 30-60 minutes lasting for 2 days (Lehman, 1951).Significant EEG pattern changes were noted in female Wistar rats fedas little as 1 mg/kg/day heptachlor chronically (Formanek et al. 1976).The basis for neurotoxicity by heptachlor epoxlde is probably acommon mechanism for neurotoxicity by all cyclodienes. Cyclodieneshave been found to bind to the picrotoxin-bindlng-site (PBS) of thegamma-amino-butyric-acld (GABA) rieuroreceptor. resulting in theInhibition of synaptic transmission (Cole and Casida, 1986; Lawrenceand Casida. 1984).

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Heptachlor epoxide

HEPATOXICITY

Inadvertant human exposure has occurred when cattle were fed Jfeedstock grain treated with heptachlor for insectlcidal purposes and ^ ^heptachlor and its epoxide were transmitted via milk and milkproducts. Of 45 individuals consuming contaminated raw milk for twomonths, 10 had serum elevations of liver enzymes (Frumkin et al.1987).Animals fed heptachlor display multiple hepatotoxicities, includingnecrosis, elevated aldolase and cell vacuollzation (Krampl. 1971); liversteatosis and hepatomegaly (Pelikan. 1971); and. elevated serum levelsof SGPT, bilirubin, alkaline phosphatase and cholesterol, all of whichare indicative of hepatotoxidty (Enan et al, 1982).Other toxicities of heptachlor and heptachlor epoxlde in experimentalanimals include adrenotoxicity, renotoxicity and hematopoietotoxicity(ATSDR, 1988). In almost all studies, treated animals also lost weight(anorexia) as compared to controls.

• Carcinogenic ActivityGiven that heptachlor is quickly metabolized to heptachlor epoxide "byhepatic microsomal epoxldases, it is probable that carcinogenicstudies of both substances are germane to this review. Neithersubstance has been studied adequately In exposed human populationsto form any epidemiologic conclusions. However, both heptachlor andits epoxlde have been examined extensively for Carcinogenesis inexperimental animals, with both substances found to be carcinogenicand heptachlor expoxide with twice the carcinogenic potency of itsparent compound.Both C3H and B6C3F1 mice when chronically fed heptachlor developstatististically significant Increases In hepatocellular carcinomas.Heptachlor epoxlde also Increases hepatocellular carcinomas in thesetwo strains and CD-1 mice and CFN rats as well. Both heptachlor andits epoxide have been classified by EPA as class B2 (probable human)carcinogens. For reviews of the carcinogenicitles of heptachlor andheptachlor epoxlde. please consult EPA (1986); WHO (1984); ATSDR(1988); IARC (1979) and Reuber (1978).Due to the carcinogenic risks to exposed human populations fromextensive use of chlordane and heptachlor as termiticides, EPAbanned further manufacture in January 1988 and all sales in April1988. However, It is estimated that considerable residues of theseproducts will remain in soils surrounding nearly 30 million homes inthe U.S. for at least the next decade and that the majority of thesecyclodiene residues will wind up in the form of the more carcinogenicmetabolite, heptachlor epoxide. jG ERM. Inc. AU rights reserved. 1-4

flR30i*355

Heptachlor epoxide

F. Phazmacokinetics

Epoxidatlon is a ubiquitous mechanism for breaking open insolublecyclic compounds in order to solubilize them through conjugation withglucuronic acid. In many cases the epoxlde of a compound isunfortunately more toxic than Its parent, for example, the diol epoxideof benzo(a)pyrene being carcinogenic whereas the parent(unmetabolized) compound is not. Hence, heptachlor epoxlde toxicityis a,dynamic process in which the relative concentration of epoxldaseswhich create the compound from heptachlor are in balance withcatabolic enzymes which further degrade the epoxide. These enzymesare largely found in the liver as members of the microsomal oxidasefamily and are Inducible.Heptachlor epoxlde is the most carcinogenic catabolite of bothchlordane (octachlor) and heptachlor cyclodiene termiticides. It isnot used as a pesticide itself, but may accumulate in the environmentas a biodegradation product of either chlordane and heptachlor. Thismetabolic fate in soil is indicated by the respective half-lives ofheptachlor and heptachlor epoxide (2 years and 14 years,respectively). Given the relative carcinogenic potencies of chlordane(1.4), heptachlor (4.5) and heptachlor epoxide (9.1), it is likely thatheptachlor is the ultimate carcinogen to which chlordane andheptachlor are metabolized.

GL References

Arnold, D.W., G.L. Kennedy, M.L, Keplinger, J.C. Calandra and C.J. Calo(1977) Dominant lethal studies with technical chlordane, HCS-3260.and heptachlor: heptachlor epoxide. J. Toxic. Env. Hlth 2. 547-555.ATSDR (1988) Toxicological profile for heptachlor/heptachlorepoxide. Agency for Toxic Substances and Disease Registry, Atlanta.Cole. L.M. and J.E. Casida (1986) Polychlorocycloalkane insecticide-induced convulsions In mice in relation to disruption of the GABA-regulated chloride ionophore. Life Sci. 39. 1855-1862.Enan. E.E.. A.H. El-Sebae and O.H. Enan (1982) Effects of liverfunctions by some chlorinated hydrocarbon insecticides in white rats.Meded. Fac. Lanbouwwet. Rijksuniv. Gent 47. 447-457.EPA (1985) Drinking water criteria document for heptachlor,heptachlor epoxide and chlordane. EPA-6001X-84-197-1.

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Heptachlor epoxide

EPA (1986) Carcinogenicity assessment of chlordane andheptachlor/heptachlor epoxide. Office of Health and Environmental \Assessment EPA/600/6-87/004. )Formanek, J., M. Vanickova, J. Plevova and E. Holoubkova (1976) Theeffect of some industrial toxic agents on EEG frequency spectra inrats. Adverse Eff. Envlr. Chem. Psych. Drugs 2, 257-268.Frumkln, H. and C.G. Chute (1987) The health effects of heptachlor.JAMA 257, 1900-1901. -Geyer, H.. P. Sheehan, D. Kotzlas. D. Freitag and F. Korte (1982)Prediction of ecotoxicological behavior of chemicals. Chemosphere11. 1121-1134.Hawker. D.W. and D.W. Connell (1986) Bioconcentration of lipophiliccompounds by some aquatic organisms. Ecotox. Envlr. Safety 11, 184-197.IARC (1979) Hepachlor and heptachlor epoxide. In IARC Monographs.Vol. 20, p(p. 129-154, International Agency for Research on Cancer,Lyon, France.Krampl, V. (1971) Relationship between serum enzymes andhistological changes In liver after administration of heptachlor in therat. Bull. Envlr. Contain. Toxicol. 5, 529-536.Lawrence, L.J. and J.E. Casida (1984) Interactions of lindane, j\toxaphene and cyclodienes with brain-specific t- ^-^butylbicyclophosphorothionate receptor. Life Sci. 35, 171-178.Lehman, A.J. (1951) Chemicals in foods. Pest. Assoc. Food Drug Off.US Quart. Bull. 15. 122-133.Lichtenstein, E.P., K.R. Schultz, T.W. Fuhremann and T.T. Liang (1970)Degradation of aldrin and heptachlor in field soils during a ten-yearperiod translocation into crops. J. Agr. Food Chem. 18, 100-106.Mabey. W.R., J.H. Smith, R.P. Podoll et al (1981) Aquatic fate processdata for organic priority pollutants. Office of Water Regulations andStandards. EPA 440/4-81-014.Molholt, B. (1986) Risk assessment of indoor air pollution bytermiticides. Proc. Soc. Risk Anal. 86. Boston.Nash, R.G. and W.G. Harris (1973) Chlorinated hydrocarbon insecticideresidues in crops and soil. J. Envir. Qual. 2, 269-273.Pelikan, Z. (1971) Short-term intoxication of rats by heptachloradminstered In diet. Arch. Belg. Med. Soc. 29. 462-470.Reuber. M.D. (1978) Carcinomas and other lesions of the liver in miceingesting organochlorine pesticides. Clin. Toxicol. 13. 231-256. ^


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Simon, J. and F.L. Parker (1984) Fate of heptachlor, in, Veziroglu, T.N.(ed) The biosphere: Problems and solutions, Elsevler, pp. 453-460.Wang, H.H. and B. MacMahon (1979) Mortality of workers employed Inthe manufacture of chlordane and heptachlor. J. Occ. Med. 21, 745-748.•WHO (1984) Environmental health criteria 38: Heptachlor. WorldHealth Organization, Geneva.Zaroogian, G.E.. J.F. Heltshe and M. Johnson (1985) Estimation ofbioconcentration in marine species using structure-activity models.'Envlr. Toxicol. Chem. 4, 3-12.

(iV J


AR30<i358

AR30i<359

Manganese

frlanganese



Chemical Formula: MnForm: steel-gray, lustrous, hard, brittle metal

Chemical Class: metalAtomic Weight: 54.94Boiling Point: 2095°CMelting Point: 1244°C.

Specific Gravity: 7.21 at 20°CSolubility in Water: Mn and oxides insoluble: halides, sulfates

and permanganates are solubleSolubility In Organics: .0

Organic CarbonPartition Coefficient: NALog Octanol/Water


Henry's Law Constant: NABioconcentration Factor: 12,000 (marine shellfish)



Maximum Contaminant Level (MCL)for Drinking Water (mg/L): ••:>> NA

*Clean Water Act

Ambient Water Quality Criteria (mg/L)Human Health \

Water and Fish Consumption: 0.05*Fish Consumption Only: NA

Aquatic Organisms (mg/L) .-.-'.Fresh Water


Acute: NA

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Manganese

Chronic: 0.1

ReferencesSax and Lewis 1989, Verschueren 1983, The Merck Index 1983,SPHEM 1986, EPA 1986NA - Not Available " "As based upon objectionable taste


Sorption, complexation, oxidation and bioaccumulation are importantfate processes for manganese in the environment. In soil systems.concentrations and mobility of manganese are controlled by soilchemistry (e.g., pH, cation exchange capacity, organic matter contentetc.). The solubility and bioavailabllity of manganese In soils is stronglyenhanced by low pH, reducing conditions and high concentrations ofligands. Sorption In aquatic systems is heavily influenced by pH.dissolved oxygen, and availability of complexing agents. Manganesecan easily be released from sediments under reducing conditons.Manganese dusts and fumes may also undergo atmospheric transport.

IX Ecotoadcology

Although manganese does not occur naturally as a free metal, it isubiquitous In the environment, where it is cycled between theatmosphere, land surface, aquatic systems and oceans. Manganese isan essential micro-nutrient for plants and animals. Manganesedeficiencies may cause chlorosis in plants and adverse effects uponreproductive capacity in animals.According to USEPA (1976, 1986). manganese is rarely found infreshwater at levels above 1 mg/1 while the tolerance limits range from1.5 to over 1.000 mg/1. Therefore, manganese is not anticipated toyield adverse effects in aquatic systems, except possibly in' cases ofextreme pollution. Although permanganates may cause mortality infish, they are relatively nonpersistent In water and rapidly convertedto nontoxic terms.In the marine environment, manganese is pervasive at an average levelof 2 ug/1 and readily forms mineral rich nodules on the ocean floor. A48-hour LCSO of 16 mg/1 and a 168-hour LCso of 30° mg/! werereported for oyster embryos (Crassostrea virgintca) and the soft-shelled clam (Mya arenia). respectfully. (Clement Associates 1985). v


Manganese

However, bioavallable concentrations of this magnitude would not beexpected to occur under normal conditions.In addition, higher organisms appear to homeostatically regulatemanganese while lower organisms (e.g., filamentous algae, molluscs)may bioconce.ntrate high levels (USEPA 1984).

Manganese is a vital micro-nutrient for both plants and animals. Inacid soils concentrations of slightly less than 1 mg/L to a fewmilligrams per liter may be toxic to plants, but hardly so at a neutral orbasic pH. In its divalent state manganese has usually a low toxicity toaquatic organisms. Permanganates have been reported to be lethal tofish at 2-4 ppm (8-18 hrs). but permanganates are rapidly reduced Inpresence of organic matter and, therefore, not persistent. Tolerancevalues reported for various manganese compounds range from 1.5 ppmto over 1,000 ppm (McKee and Wolf, 1963). Few data are available onthe toxicity of manganese to marine organisms. The major problemwith manganese may be concentration in the edible portions ofmollusks, as bioaccumulation factors as high as 12,000 have beenreported. In order to protect against a possible health hazard tohumans by manganese accumulation in shellfish, a criterion of 100ug/L has been recommended for marine waters in the EPA QualityCriteria for Water (1986). r

Considerable exposure of the normal population to manganese occursnormally via food intake, where the highest concentrations are foundin plant products (especially in certain cereals and nuts) as well as inshellfish, where the concentration may exceed 30 ppm. The averagedaily intake by adults in various countries has been estimated to be inthe range 2-9 mg (IPCS, 1981).

E. Human Toxicology

SUMMARY: Manganese and its compounds are poorly absorbed fromthe gastrointestinal tract of man and of other mammals, and theoral toxicity is in general low. Due to its corrosive action,permanganates may damage the lining of the esophagus andgastrointestinal tract when ingested in concentrated solutions (> 4%).Upon high-level exposure via inhalation manganese may concentrateIn the central nervous system, where it can elicit a severe andirrever- sible brain disease, to some extent similar to Parkinson'sdisease. There is no evidence of .carcinogenicity, either from animal


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experiments or from epidemiological studies, nor does manganese orits compounds seem to have any appreciable genotoxic action. Insmall quantities manganese is an essential element for the normalfunction of the human organism.


The acute toxicity of manganese compounds to mammals is low; forthe rat an oral LD50 of 1.3-1.5 g/kg has been determined for thesoluble divalent chloride (Holbrook, D.J., et al.. 1975).

The chronic toxicity aspect of manganese compounds is considerablymore serious (for review, see IPCS, 1981). Thus, irreversible toxiceffects on the central nervous system have been induced in variousanimal species, including the rat and monkey, mainly by theadministration of manganese dioxide or dichloride. Typicalpathological lesions Include degenerative changes primarily in thestriatum and pallidum, but lesions In the subthalamic nucleus, cortex,cerebellum and in the brain stem have also been described. Symptomsof CNS-toxicity. including tremor, ataxia and paralysis of the hindlimbs are often present. Biochemical and hlstopathological changes \have been reported in other organ systems, notably the liver. \^fPulmonary lesions, like inflammatory changes and fibrosis, have beendescribed upon high level exposures to manganese oxide. Testicularchanges have been Induced in the rat upon intravenous administrationof high doses (50 mg/kg) of permanganate.

By inhalation exposure of monkeys to manganese dioxide aerosol atconcentrations of 0.8-3.0 mg/m3 for 95 one hour periods over 4months, typical signs of central nervous system effects have been 'induced. Administration by the oral route seems far less effective.presumably because of poor gastrointestinal absorption. Signs ofneurotoxicity have only been observed upon oral exposure to very highconcentrations. Since no long-term feeding study which satisfiesmodern regulatory requirements seems to have been conducted, aNOEL for this exposure route is not available.

In humans an increased morbidity and mortality rate from pneumoniahas been described among workers occupatlonally exposed to highlevels of manganese containing dusts, and there are reports ofpopulations living close to manganese-emitting plants that have \

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(.0

Manganese

exhibited an increased incidence or respiratory disease. However, itis difficult to determine to which extent other confounding factorshave been involved.

An Irreversible chronic manganese intoxication syndrome, known asmanganisxn - and which resembles Parkinson's disease - has beenknown for a considerable time to occur among workers employe inmining, ore-processing plants, and in ferromanganese plants. Theclinical picture of this poisoning - characterized by both psychiatric

-and neurological manifestations mainly related to the extrapyramidalsystem - may develop after only a few months of exposure. In theabsence of reliable biological indicators of exposure the early diagnosisof manganese poisoning is difficult. Measurement of manganese infeces may here be useful. Initial subjective symptoms, such asweakness and apathy, are later followed by staggering gait,incoherent and slow talk as well as aggressiveness. At furtherexposure these signs become more pronounced: patients will developa fixed facial exression, and increasing clumsiness and Inability tomake certain movements becomes apparent. In general, neurologicalexamination at this stage will reveal no distinct pathological changes.The fully developed manganism is characterized by severe difficultiesin walking caused by muscular hypertonia and tremor mainly in theupper limbs as well as by difficulties in writing and a severe speechimpediment. It should be noted, that the EEG may still be normal.Autopsy reports have shown, that lesions of the central nervous systemare most severe in the striatum and pallidum and may also he found inthe substantia nigra. In addition, a severe reduction in dopaminelevels in the caudate nucleus, putamen. and substantia nigra has beendetected. This biochemical effect may. in part, explain some of theCNS symptoms caused by manganese.

Only. one instance chronic intoxication caused by ingestion seems tohave been reported In the literature (Kawamura et al., 1941). Wellwater had been contaminated with manganese dissolved from dry cellbatteries burled near the well. Analyzed one month after the outbreak.the water had manganese and zinc concentrations around 15 mg/L,but were probably at least 20-30 mg/L at the onset of the exposure.Sixteen people showed various CNS symptoms such as lethargy,increased muscle tonus and tremor, as well as mental disturbances.The most severe symptoms were seen In .elderly people, whereaschildren were affected only .to' .a .small degree. Three persons died,one from suicide. Upon autopsy elevated manganese concentrationswere found In liver, and macroscopic and microscopic pathologicalchanges were' detected in the brain, especially in the globus pallidus.

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Manganese

• Carcinogenic ActivityStudies on induction of tumors following subcutaneous, intramuscular,or intraperitoneal injection of manganese compounds have beenreported (Sunderman et al., 1974. 1976; DiPaolo, 1964; Furst 1978)and manganous sulfate has also been tested in a mouse lung adenomascreening bioassay (Stoner et al., 1976). However, no convincingevidence of carcinogenicity has been obtained from theseinvestigations. Further, there seem to be no epidemiologicalIndications of such effects. In view of the fact that no adequate long-term oral or inhalation studies In experimental animals that fulfillspresent day requirements seem to have been conducted, the data basemust be considered Inadequate to evaluate the potential carcinogenicaction of inorganic manganese.

• Genotoxic Effects and Adverse Effects- on ReproductionThere is little information concerning the mutagenicity of manganese,Manganous chloride has been reported to be muta-genic forEscherichia coli and Serratia marcescens. Negative results have, onthe other hand, been reported in Salmonella typhimurium and inSoccharomyces cerevistae (IPCS, 1981).

Whereas manganese deficiency may cause malformations inexperimental animals, there seem to be no adequate evidence ofteratogenlc activity (IPCS, 1981).

Manganese is essential for normal development of the fetus and thenewborn. In experimental animals deficiency will cause skeletalabnormalities and impaired growth in mice, rats, rabbits, and chicken(IPCS. 1981). A WHO Expert Committee (1973) determined anadequate Intake to be 2-3 mg Mn/day.

F. Phannacokinetics

The respiratory and gastrointestinal tracts constitute the major routesof absorption of manganese. Although quantitative data are notavailable, it seems highly unlikely that the skin is an important route ofabsorption for inorganic manganese. The degree of absorption uponingestion appears to be below 5% in healthy adults, but there is

"•-— 9


AR'30I»365

Manganese

evidence of a considerably higher absorption rate in iron deficiency.The extent of absorption of manganese following inhalation is evidentlyconsiderable but is not accurately known. A certain percentage ofmanganese particles is evidently removed by mucociliary clearanceand swallowed. In guinea pigs, deposited manganese dioxide is rapidlyeliminated.

Manganese is transported in the plasma and widely distributedthroughout the body, where it is mainly found in the liver, pancreas.kidney, and in the intestines. Manganese penetrates the blood-brainbarrier as well as the placenta! barrier. The normal brain load is low.but since the retetlon time is long, manganese is progressivelyaccumulated in this organ after high-level exposure. Thus, while thehalf-time in whole body of monkeys was estimated to be 95 days (slowcomponent of the biphasic elimination process), it was not possibleto obtain an estimate for the brain even after 278 days, indicating anextremely slow elimination from this organ. Urinary excretion islow, and absorbed manganese Is mainly secreted with tiie bile to theintestinal tract.

G. Discussion - guantitation of Risk

The Induction of neurotoxlc effects in man constitutes the mostrelevant toxic endpoint for assessment of risk to humans. The WHOhas compiled data on air concentrations and neurological effects ofmanganese, and has estimated that risk for neurological damage mayoccur already at concentrations of 2-5 mg/m3 (IPCS, 1981).Considering some of the studies and observations in ferromanganeseplants, where workers are exposed to dusts and fumes containingmainly manganese dioxide particles In the respirable range, a value ofO.3 mg'of respirable manganese particles per m3 of air (time-weightedaverage) has been recommended as the health-based limit foroccupational exposure (WHO. 1980).. Assuming 100% absorption inthe lungs and a respiratory volume of 25 L/hr/kg, exposure to 0.3mg/m3 during a working day of 8 hrs (light work) will correspond toan absorbed dose of 3.0 mg/day for a 70 kg man when adjusted forcontinuous exposure. Using this value, a safety factor of 100. a 5%absorption by the oral route, as well as an assumed daily waterconsumption of 2L, a tentative maximum drinking water concentrationof 0.3 mg manganese/L Is obtained. The maximum concentrationproposed in the EPA Water Quality Criteria (1986) - although based onnon-lexicological considerations - should, therefore, offer adequateprotection of public health.

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H. References

Clement Assoc. (1985) Chemical, Physical, and Biological Propertiesof Compounds Present at Hazardous Waste Sites. Prepared for: U.S.EPA. Prepared by: Clement Assoc., Arlington, VA.

DiPaolo, J.A. (1964): The potentlation of lymphosarcomas In mice bymanganous chloride. Fed. Proc. 23,393 (Abstract).

Furst, A. (1978): Tumorigenlc effect of an organoman- ganesecompound on F344 rats and Swiss albino mice: brief communication.J. Nad. Cancer Inst 60(5). 1171-1173.

Holbrook, D.J.. Washington. M.E., Leake. H.B., and Brubaker.P.E. (1975): Studies of the toxicity of various salts of lead,manganese, platinum, and palladium. Env. Hlth. Persp. 10(1975)95-101.

IPCS. The International Programme on Chemical Safety (1981):Environmental Health Criteria No. 17, WHO, Geneva.

Kawamura, R., Ikuta, H., Fukuzimi. S.. Yamada, R., Tsubaki, S. andKurata, S. (1941), Kitasato Arch. Exp. Med., 18. 145-169.

McKee, J.E. and Wolf.H.W. (1963): Water quality criteria. State WaterQuality Control Board, Sacramento, CA. pub. 3A

Shimkin, M.B. and Stoner.G.D. (1975): Lung tumors in mice:Application to Carcinogenesis bioassay. Adv. Cancer Res. 21, 1-58.

Stoner. G.D., Shimkin, M.B.. Troxell. M.C.. Thompson, T.L., and Terry.L.S. (1976): Test for carcinogenicity of metallic compounds by thepulmonary tumor response in strain A mice. Cancer Res. 36, 1744-1747.


Manganese

Sunderman, F.W.. Kasprzak, K.S., Minghetti, P.P., Maenza, R.M,,Becker, N.. Onkellnx, C., and Goldblatt, P.J. (1976): Effects ofmanganese on carcinogenicity and metabolism of nickel subsulflde.Cancer Res. 36,1790-1800.

Sunderman, F.W., Lau. T.J., and Cralley, L.J. (1974): Inhibitory effectof manganese upon muscle tumorigenesis by nickel subsulflde. CancerRes. 34, 92-95.

U.S.EPA, (1976) Quality Criteria for Water. U.S. EPA, Washington. DC

U.S.EPA, (1978) Metal Bioaccumulation in Fishes and AquaticInvertebrates - A Literature Review. EPA-600/3-78-103.

U.S.EPA, (1984) Health Assessment Document for Manganese. U.S.EPA-600/8-83-013F.

U.S.EPA, Office of Water Regulations-and Standards, (1986): Qualityf criteria for water 1986. Washington, D.C., EPA 440/5-856-001. -

U.S.EPA (1988): Drinking Water Criteria Document for Manga- nese.Prepared by the Office of Health and Environmental Assessment.Environmental Criteria and Assessment Office. Cincinnati, OH for theOffice of Drinking Water. Washing- ton, DC. ECAO-CIN-D008.'(External Review Draft).

WHO, World Health Organization (1973): WHO Technical ReportScries No. 532, Trace elements in human nutrition - Report of a WHOExpert Committee, pp. 3836.

WHO (1980) Techn. Rept. Ser.. 647.


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flR30lf369

2-Methylnaphtlialene

2-Methvlnaphthalene

CASNo.: 91-57-6Synonyms: 3-methylnaphthalene


Chemical Formula:Form: solid

Chemical Class: bicyclic aromaticMolecular Weight: 142.21

Boiling Point: 241.1CMelting Point: .34.58C

Specific Gravity: , 1.0058 @ 20/4CSolubility in Water: 6.74 mg/L 0 25C

Solubility in Organics: alcohol, etherOrganic Carbon

Partition Coefficient: 10,000*Log Octanol/Water

Partition Coefficient: 4Vapor Pressure: 0.017 mm Hg @ 20C'Vapor Density: NA

Henry's Law Constant: 5.4E-04*Bioconcentration Factor: NA

E Regulations and Standards






Acute: NAChronic: NAMarine . - ' : " • :


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Qroup

2-Methylnaphthalene

References \Sax and Lewis 1989, Verschueren 1983, The Merck Index 1983, ^ 'SPHEM 1986. EPA 1986NA - Not Available, *based upon 2-chloronaphthalene


The major environmental fate process for 2-methylnaphthalene issorption. It adsorbs strongly to partlculates and suspended matter inthe air and water. Volatilization, however, many compete withsorption. depending on environmental conditions. The roles ofphotolysis, oxidation, hydrolysis, bioaccumulation and biodegradationare probably not significant in the environmental fate of this chemical.

Hitman Toxicology

• SummaryThere is very little data on the toxicology of 2-methylnaphthalene.either from the epidemiology of exposed worker populations or fromexperiments in test animals. Hence, this profile entails the moreprevalent data for naphthalene, which in most physical and chemical.and presumably biological and toxicological, properties stronglyresembles its 2-methylated derivative.Exposure to naphthalene by the ingestion. inhalation, and dermalroutes has been reported to result in intravascular hemolysis. cornealulceration and cataracts, eye irritation, headache, confusion, malaise,nausea, vomiting, and bladder irritation in humans. In severe cases.hemolytic anemia with associated jaundice and. occasionally, renaldisease and death have been reported. Individuals with a deficiency ofglucose-6-phosphate dehydrogenase (G6PD) and Infants appear to beat greater risk of developing hemolytic anemia.The results of mutagenicity testing of naphthalene were negative, withnegative or equivocal results being reported in carcinogenicity studies.When tested for teratogenic effects in Sprague Dawley dams, it wasreported that significant increases in retarded cranial ossification andheart development were detected in offspring after intraperitonealinjections of naphthalene on days 1-15 of gestation. When tested in


HR30U37I

2-Methylnaphthalene

pregnant mice by gavage, a significant reduction In the averagei number of live pups per litter was reported.

An ADI of 5.3 x 10-3 mg/kg/day or 0.37 mg/day for a 70 kg personwas calculated for naphthalene based on a subchronic study wasreported no adverse effects in mice administered 5.3 mg/kg/daynaphthalene dally by gavage for 90 days. 'A safety factor of 1000 alsowas applied. EPA has calculated an RfD of 0.4 mg/kg/day fornaphthalene.

• Acute and Chronic ToxicologyIn humans, exposure to sufficient concentrations of naphthalenethrough inhalation, ingestion, or dermal contact may causeIntravascular hemolysis or the less severe symptoms of eye irritation.headache, confusion, tremors, nausea, vomiting, abdominal pain, andbladder irritation (Sitting 1985). In severe cases, hematologicaleffects have included red cell fragmentation. Jaundice, severe anemia,leukocytosis and dramatic decrease In hemoglobin, hematocrit, andred cell counts. Hemolysis can also lead to renal disease fromprecipitated hemoglobin (USEPA 1982). Poisonings have occurred Inhumans as a result of the ingestion of moth balls as well as fromclothing Infants in materials that had been stored In moth balls. Astudy of workers exposed to naphthalene for a period of 5 years foundcornea! ulceration, cataracts, , and some lenticular and generalopacities in 8 of the 21 employees examined (Ghettl and Marian!1956a).Naphthalene is reported to be a primary skin irritant and causeserythema and dermatitis on repeated contact. It has also beenreported to be an allergen in some cases (Sittig 1985).It appears that there is increased sensitivity to hemolytic effects inindividuals who are deficient in the enzyme gIucose-6-phosphatasedehydrogenase (G6PDJ which is necessary to maintain sufficient levelsof glutathione (GSH) in the body (USEPA 1982, Sittig 1985). TheIncidence of G6PD deficiency Is approximately 0.1% in American andEuropean Caucasians and can approach 20% in certain blackpopulations and over 50% in some Jewish populations (Sittig 1985).Anecdotal evidence also suggests an increased susceptibility innewborn infants to the hemolytic effects of naphthalene exposure(USEPA 1982). Possible reasons for this include reduced thickness ofthe skin in newborns, reduced levels of glutathione reductase, and theapplication of baby oil to the skin of newborns (increasing the dermalabsorption of naphthalene). The acute lethal dose In adults isestimated to be 70 to 210 mg/kg (Sandmeyer 1981).Overall, the results of carcinogenicity testing with naphthalene havebeen negative. Knake (1956) treated 40 white rats with 500 mg/kg of


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coal tar naphthalene in sesame oil subcutaneously every two weeks fora total of seven treatments. Five out of thirty-four rats developed iInvasive or metastatic lymphosarcoma prior to death. These results x*~*"are equivocal, however, because the Injection sites were first paintedwith carbolfuchsin (a known carcinogen) prior to each injection. Thenaphthalene also contained approximately 10% methylnaphthalene.In a second study, Knake (1956) painted a group of mice with either .benzene or a solution of coal tar naphthalene /benzene solution ascompared to those treated with benzene alone (4 vs. 0 casesrespectively). These results are also difficult to Interpret becausebenzene is a known animal carcinogen.Other skin painting studies have been reported in mice Kennaway andHieger 1930 and rabbits (Bogdat'eva and Bid 1955) with negativeresults. Details of the study protocols were not given in the originalpapers.Investigations by Schmeltz and coworkers (1978) indicated that di,tri, and tetramethyl naphthalenes, contaminants of coal tarnaphthalene, all showed cocarcinogenic activity when applied bypainting to mouse skin In combination with benzo(a)pyrene. Purenaphthalene did not show cocarcinogenic activity in this study.In an inhalation study by Adkins (1986) exposure of mice to 30 ppmnaphthalene did not elecit a significant adenoma response. The micewere exposed to 30 h/wk for 6 months. »JHowever, the effects of exposure of mice to 10 to 30 ppm naphthaleneare being examined in a 2-year inhalation study (USEPA 1988). Thefull report on the findings will not be available until late 1988. but theImpression of NTP's principal Investigation was that "naphthalenecaused lung tumors in male mice," according to a report in Pesticideand Toxic Chemical News (Dec. 30, 1987. Vol. 16 No. 8 p. 7"Unconfirmed naphthalene tumors among TSCA section 8(e) reports").A number of animal studies have examined the acute and chronictoxicity of naphthalene. Reported oral LDSO's In the rat range from2.200 to 9,430 mg/kg (USEPA 1980) and the oral LD50 In CD- micewas found to be 533 and 710 mg/kg respectively in male and femalemice (Shopp et al. 1984). Mahvi et al. (1977) administerednaphthalene In corn oil Intraperitoneally to C57 B1/6J mice. Groupsof 21 mice each were given 67.4. 128, or 256 mg/kg. Three animalsfrom each dosage group were sacrificed at ten minutes, 1 hour, 6hours. 12 hours. 24 hours, and 7 days following treatment. Lungtissue was fixed and examined by electron microscopy after eachsacrifice. Minor bronchiolar epithelial changes were noted in thegroup receiving 67.4 mg/kg. Mice in the higher dosage groupsdeveloped necrosis of secretory nonciliated bronchiolar cells.

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2-Methylnaphthalene i

In a study reported by Shopp et al. (1984), male and female CD- micewere exposed for 14 or 90 days by gavage to 3 different doses of thecompound. In the 14 day study both males and females showed a 5-10% mortality and depressed body weights at the high dose of 267mg/kg/day. At this dose the males had decreased thyraus weights andthe females and decreased spleen and increased lung weights. Notoxic effects were observed at the two lower doses of 53 mg/kg/dayand 27 mg/kg/day. In the 90-day study mice of both sexes wereexposed to naphthalene at levels of 5.3. 53, and 133 mg/kg. Notreatment-related deaths were observed and terminal body weightswere not significantly influenced by treatment in either sex.Significant decreases in brain, liver, and spleen weights were reportedin females at the highest dose with the organ to body weight ratiosignificantly different only for the spleen. Hemoglobin levels weresignificantly increased in the high dose females. Female mice showeda significant decrease In BUN at all levels and total serum protein wassignificantly increased in both sexes at daily naphthalene levels of 53and 133 mg/kg. A significant increase in serum creatinlne level wasobserved-in the two high dose male groups and in the low dosefemales. The effect In females, however, does not appear dose-relatedas it was not observed in either of the high dose' groups. Notreatment-related effect on the hepatic mixed function oxidase systemwere observed in either sex. For all exposure groups, no alterationswere observed in the hepatic drug metabolizing system except for adose-related inhibition of aryl hydrocarbon hydroxylase (AHH) activity.Van Heyningen and Plrie (1976) dosed rabbits daily by gavage with1000 mg/kg/day for various periods of time for a maximum of 28 days.They noted lens changes after the first dose and retinal changes afterthe second dose. Ghetti and Marian! (1956b) fed five rabbits 1000.mg/kg/day of naphthalene and noted that development of cataractsbetween days 3 and 46. Topical application of a 10% solution In oil tothe eyes of two rabbits did not produce cataracts after a period of 50days. Intraperitoneal injection of 500 mg/day of naphthalene In an oilysolution to one. rabbit over a period of 50 days produced weight lossbut no cataracts. It is thought that reactive metabolites of naphthalenesuch as 1,2-dihydroxynaphthalene and 1,2-naphthoquinone areformed in the eye and then combine irreversibly with thiol groups oflens proteins to form a brown precipitate. This results Indegenerative changes in lens epithelium (USEPA 1982). Serum lipidperoxide levels were increased in Wlstar rats given naphthalene.These lipid peroxides in the bloodstream may play a role incataractogenesls (Yamauchi 1986).Harris and coworkers (1979) reported a statistically significantincrease in retarded cranial ossification and heart development inoffspring of Sprague Dawley dams that had received intraperitoneal

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2-Methylnaphthalene

injections of 395 mg/kg naphthalene on days 1-15 of gestation. In astudy by Plasterer and coworkers (1985), single doses of naphthalenewere administered by gavage to pregnant CD- mice on days 7 through14 of pregnancy. The compounds was given at a dose estimated to beat or just below the threshold of adult lethality. A significant reductionin the average number of live pups per litter was reported for thenaphthalene-dosed females.In an experimental protocol in which 50 pregnant mice were dosedwith naphthalene at midterm and then allowed to deliver, a reducednumber of liveborn mice per litter were observed as compared to thecontrol group fed corn oil (Hardln 1987).Naphthalene, when combined with rat microsome fractions, has beenfound to be nonmutagenic when tested in bacterial mutagenesis assaysusing various strains of Salmonella typhimurium as well as In vitro celltransformation assays (USEPA 1980).The dose of 53 mg/kg/day from the subchronic study described byShopp et al. (1984) can be used as a NOAEL for calculating an ADI. Asafety factor of 1000 is applied to this to account for the use of asubchronic study and intra and interspecies variability, resulting in anADI of 0.053 mg/kg/day.

E. Pharmacoklnetlcs

Naphthalene Is rapidly absorbed when Inhaled but is more slowlyabsorbed by ingestion or through the Intact skin. Dermal adsorption ofnaphthalene has not been well-characterized; however, available dataon absorption of crude coal tar products. Including naphthalene, inhumans indicate that naphthalene is absorbed to a greater extent thananthracene (Storer et al. 1984). Although data are inadequate toquantify naphthalene dermal absorption directly, they may provide anestimate of absorption relative to anthracene. Anthracene dermalabsorption has been reported to be 52.3% of the total dose appliedafter 6 days of exposure in rats (see separate discussion onanthracene). Therefore, It Is assumed that absorption of naphthaleneis greater than 50% by the dermal route of exposure. The compoundis metabolized in the liver to reactive metabolites that are capable ofcirculating and becoming bound irreversibly in extrahepatic tissues invivo (Richieri 1987). Metabolism occurs rapidly in the adult but veryslowly in the newborn (Sittig 1985). No data were located indicatingnaphthalene to be an hepatic enzyme inducer. The study by Shoppand coworkers (1984) reported a dose-related Inhibition of arylhydrocarbon hydroxylase. It is first metabolized to the highly reactive

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AR304375

2-Methylnaphthalene

epoxlde, naphthalene-1,2.-oxide. The epoxide can be converted tothe dihydrodiol or conjugated with glutathione. The dihydrodiol canbe conjugated with glucuronic acid or sulfate to form the reactive 1.2-dihydroxynaphthalene. This can also be conjugated with sulfate orglucuronic acid or spontaneously oxidized to form the highly reactive1.2-naphthoquinone (USEPA 1980).The epoxide naphthalene-!.2-oxide can also be convertedspontaneously to 1-naphthol or 2-naphthol. 1-Naphthol is excretedunchanged or is conjugated with glucuronic acid or sulfate prior toexcretion. It is also believed that 1-naphthol can be further oxidizedto 1.4-naphthoquinone (USEPA 1980). The naphthols andnapthoquinones are hemolytic agents (Sittig 1985).Naphthalene metabolites can undergo further conversions in the eye.The dihydrodiol can be oxidized to 1,2-dihydorxynaph-thalene whichcan then be oxidized to 1,2-naphthoquinone. 1.2-Naphthoquinone canbind irreversibly to lens protein and amino acids or it can oxidizeascorbic acid to dihydroascrobic acid. In this process 1,2-naphthoquinone is reduced to 1.2-dihydroxynaphthalene (USEPA1980).Skaeggestad (1964) reported that naphthalene has a low nucleic acidPNA and RNA) binding capacity.

F. References

Adkins, B.. E.W. Van Stee, J.E. Simmons, and S.L. Eustis. 1986.Oncogenic response of strain A/J mice to Inhaled chemicals. J.Toxicol. Environ. Health 17:311-322.Bogdat'eva, A.G., and D. Ya. Bid, 1955. Effect of high molecular weightproducts of pyrolysis of petromeim on the animal organism. Gig. Sanit.7:21. (Reported in USEPA 1980).Ghetti, G., and L. Mariani. 1956a. Med. Lav. 57:533. (Reported inSandmeyer 1981.)Ghetti, G,, and L. Mariani. 1956b. Eye changes due to naphthalene.Med. Lav. 47:524. (Reported in USEPA 1980.)Hardin, B. D.. R.L. Schuler, J.R. Burg. G.M. Booth. K.P. Hazelden. K.M.MacKenzie, V.J. Piccirillo, K,N. Smith. 1987:' Evaluation of 60chemicals In a preliminary development toxicity test. Teratogenisis,Carcinogenesis, and Mutagenesis. 7:29-48.Harris, S.J., G.P. Bond, and R.W. Neimeir. 1979. The effects of 2-nitropropane, naphthalene and hexachlorabutadiene on fetal rat

'

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2-Methylnaphthalene

development. Toxicol. Appl. Pharmacol. 48:A35. (Reported inUSEPA 1982.) > j\Kennaway. E.L., and L Hieger. 1930. Carcinogenic substances andtheir fluorescence spectra. Br. Med. Jour. 1:1044. (Reported inUSEPA 1980).Knake. E. 1956. Uber schwach geschwulsterzengende wlrkung vonnaphthalin und benzol. Virchows Archiv. Pathol. Anat. Physlol.329:141. (Reported In USEPA 1980.)Mahvi. D., et al. 1977. Morphology of a naphthalene-Inducedbronchiolar lesion. Am. Jour. Pathol. 86:559. (Reported in USEPA1980.)Plasterer, M.R., W.S. Bradshaw, G.M. Booth, M.W, Carter. R.L. Schuler,B.D. Hardln. 1985. Development toxicity of nine selected compoundsfollowing prenatal exposure in the mouse: naphthalene, p-nitrophenol, sodium selenite, dimethyl phthalate, ethylen thiourea,and four glycol derivatives. J. Toxicol Environ. Health. 15(l):25-38.Richleri, P.R. and A.R. Buckpitt. 1987. Efflux of naphthalene oxideand reactive naphthalene metabolites from isolated hepatocytes. J.Pharmacol. Exp. The. 242:485-92.Sandmeyer, E.E. 1981. Aromatic hydrocarbons. In Patty's industrialhygiene and toxicology, eds. G.D. Clayton and F.E. Clayton, Volume II B.New York: John Wiley & Sons,Schmeltz, I. J. Tosk, J. Hilfrich, N. Hirota. D. Hoffman. and E. Wynder.1978. Bioassay of naphthalene and alkyl naphthalenes forcocarcinogenesis activity. Relation to tobacco Carcinogenesis. InCarcinogenesis: A comprehensive survey, Volume 3. Polynucleararomatic hydrocarbons. Second International Symposium on Analysis,Chemistry, and Biology, eds. P.W. Jones and R.I. Freudenthal. 47-60.New York: Raven Press. (Reported in USEPA 1980.)Shopp. G.M., KL. White, Jr., M.P. Holsapple, D.W. Barnes. S.S. Duke. A.C. Anderson. L.W. Condle Jr., J.R. Hayes, and J.F. Borzelleca. 1984.Naphthalene toxicity In CD- mice: General toxicity andimmunotoxicology. Fundam. Appl. Toxicol. 4(3 Pt. 1): 406:419.Sittig. M. 1985. Handbook of toxic and hazardous chemicals andcarcinogens. Second ed. Park Ridge, N.J.: Noyes Pulications.Skaeggestad. O, 1964. Acta. Pathoi. Microbiol. Scand. 169:1.(Reported in Sandmeyer 1981.)Storer. J.S., I. DeLeon, L.E. Millikan, J.L. Laseter, and C. Griffing.1984. Human absorption of crude coal tar products. Arch. Dermatol.120:874-877.

\ -* f.

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2-Methylnaphthalene

U.S. Environmental Protection Agency (USEPA). 1980. Ambientwater quality criteria document for naphthalene. Office of WaterRegulations and Standards. EPA 440/5-80-058.U.S. Environmental Protection Agency (USEPA). 1982. An exposureand risk assessment for benzo(a)pyrene and other polycyclic aromatichydrocarbons: Volume II. Naphthalene. Final draft report. Office ofWater Regulations and Standards (WH-53).U.S. Environmental Protection Agency (USEPA). 1988. Assessment ofnaphthalene as a potentially toxic air pollutant. Fed. Reg. 53 (March21): 9138.Van Heynlngen, R., and A. Plrie. 1976. Naphthalene cataract inpigmented and albino rabbits. Exp. Eye Res. 22:393. (Reported inUSEPA 1980.)Yamaguchi, T., S.. Komura, K. Yagi. 1986. Serum lipid peroxide levelsof albino rats administered naphthalene. Biochem. Int. 13:1-6.

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<O

CNaphthalene

Nahthalene

CASNo.: 91-20-3Synonyms: tar camphor, moth flakes, moth balls


Chemical Formula:Form: white, crystalline, aromatic odor, volatile

flakes

Chemical Class: polycyclic aromatic hydrocarbonMolecular Weight: 128.16

Boiling Point: 217.9°CMelting Point: 80.2°

Specific Gravity: 1.152Solubility in Water: 30 mg/L

Solubility in Organics: alcohol, benzene, ether, carbontetrachloride. carbon dlsulfide.hydronaphthalene

Organic CarbonPartition Coefficient: KOC • 940Log Octanol/Water

Partition Coefficient; 3.01/3.45Vapor Pressure: 1 mm at 53°CVapor Density; 4.42

Henry's Law Constant: 4.6E-4 (atm-cu.m./mol)Bioconcentration Factor: 420 (microbial)



Maximum Contaminant Level(MCL)for Drinking Water (mg/L): NA .


Water and Fish Consumption: NAFish Consumption Onlyr* NA


"~ ifflR30i*380 Oroup

Naphthalene

Aquatic Organisms (mg/L)Freshwater

Acute: NA jChronic: NA . ^-^Marine


ReferencesSax and Lewis 1989. Verschueren 1983, The Merck Index 1983,SPHEM 1986, EPA 1986NA - Not Available


The major environmental fate process for naphthalene is sorption. Itadsorbs strongly to particulates and suspended matter in the air andwater. Volatilization, however, many compete with sorption.depending on environmental conditions. The roles of photolysis,oxidation, hydrolysis, bioaccumulation and biodegradation are probablynot significant In the environmental fate of this chemical. jD, Human Toxicology

Exposure to naphthalene by the ingestion, inhalation, and dermalroutes has been reported to result in intravascular hemolysis, cornealulceration and cataracts, eye irritation, headache, confusion, malaise,nausea, vomiting, and bladder Irritation in humans. In severe cases.hemolytic anemia with associated jaundice and, occasionally, renaldisease and death have been reported. Individuals with a deficiency ofglucose-6-phosphate dehydrogenase (G6PD) and infants appear to beat greater risk of developing hemolytic anemia.The results of mutageniclty testing of naphthalene were negative, withnegative or equivocal results being reported In carcinogenicity studies.When tested for teratogenic effects in Sprague Dawley dams, it wasreported that significant Increases In retarded cranial ossification andheart development were detected in offspring after intraperitonealinjections of naphthalene on days 1-15 of gestation. When tested inpregnant mice by gavage. a significant reduction in the averagenumber of live pups per litter was reported.

flR30t*38l

jO ERM, Inc. AU rights reserved.

13k-Oroup

Naphthalene

In humans, exposure to sufficient concentrations of naphthalenethrough inhalation, ingestion, or dermal contact may causeintravascular hemolysis or the less severe symptoms of eye irritation,headache, confusion, tremors, nausea, vomiting, abdominal pain, andbladder irritation (Sitting 1985). In severe cases, hematologicaleffects have included red cell fragmentation. Jaundice, severe anemia.leukocytosis and dramatic decrease in hemoglobin, hematocrit, andred cell counts. Hemolysis can also lead to renal disease fromprecipitated hemoglobin (USEPA 1982). Poisonings have occurred inhumans as a result of the ingestion of moth balls as well as fromclothing Infants in materials that had been stored in moth balls. Astudy of workers exposed to naphthalene for a period of 5 years foundcorneal ulceration, cataracts, and some lenticular and generalopacities in 8 of the 21 employees examined (Ghetti and Mariani1956a).Naphthalene is reported to be a primary skin irritant and causeserythema and dermatitis on repeated contact. It has also beenreported to be an allergen in some cases (Sittig 1985).It appears that there is Increased sensitivity to hemolytic effects inIndividuals who are deficient in the enzyme glucose-6-phosphatasedehydrogenase (G6PD) which is necessary to maintain sufficient levelsof glutathione (GSH) in the body (USEPA 1982, Sittig 1985). Theincidence of G6PD deficiency is approximately 0.1% in American andEuropean Caucasians and can approach 20% in certain blackpopulations and over 50% In some Jewish populations (Sittig 1985).Anecdotal evidence also suggests an increased susceptibility innewborn infants to the hemolytic effects of naphthalene exposure(USEPA 1982). Possible reasons for this include reduced thickness ofthe skin in newborns, reduced levels of glutathione reductase, and theapplication of baby oil to the skin of newborns (increasing the dermalabsorption of naphthalene). The acute lethal dose in adults isestimated to be 70 to 210 mg/kg (Sandmeyer 1981).Overall, the results of carcinogenicity testing with naphthalene havebeen negative. Knake (1956) treated 40 white rats with 500 mg/kg ofcoal tar naphthalene in sesame oil subcutaneously every two weeks fora total of seven treatments. Five out of thirty-four rats developedinvasive or metastatic lymphosarcoma prior to death. These resultsare equivocal, however, because the injection sites were first paintedwith carbolfuchsin (a known carcinogen) prior to each injection. Thenaphthalene also contained approximately 10% methylnaphthalene.In a second study, Knake (1956) painted a group of mice with eitherbenzene or a solution of coal tar naphthalene/benzene solution ascompared to those treated with benzene alone (4 vs. 0 cases

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f flR30l*382

Naphthalene

respectively). These results are also difficult to Interpret becausebenzene is a known animal carcinogen. AOther skin painting studies have been reported in mice Kennaway and -Hieger 1930 and rabbits (Bogdat'eva and Bid 1955) with negativeresults. Details of the study protocols were not given in the originalpapers. *Investigations by Schmeltz and coworkers (1978) indicated that di.tri. and tetramethyl naphthalenes, contaminants of coal tarnaphthalene,, all showed co-carcinogenic activity when applied bypainting to mouse skin in combination with benzo(a)pyrene. Purenaphthalene did not show cocarcinogenic activity In this study.In an inhalation study by Adkins (1986) exposure Of mice to 30 ppmnaphthalene did not elecit a significant adenoma response.. The micewere exposed to 30 h/wk for 6 months.However, the effects of exposure of mice to 10 to 30 ppm naphthaleneare being examined in a 2-year inhalation study (USEPA 1988). Theimpression of NTP's principal investigation was that "naphthalenecaused lung tumors in male mice." according to a report in Pesticideand Toxic Chemical News (Dec. 30, 1987, Vol. 16 No. 8 p. 7"Unconfirmed naphthalene tumors among TSCA section 8(e) reports").A number of animal studies have examined the acute and chronictoxidty of naphthalene. Reported oral LDso's in the rat range from 12,200 to 9.430 mg/kg (USEPA 1980) and the oral LDso in CD mice Wwas found to be 533 and 710 mg/kg respectively In male and femalemice (Shopp et al. 1984). Mahvi et al. (1977) administerednaphthalene in corn oil intraperitoneally to C57 B1/6J mice. Groupsof 21 mice each were given 67.4, 128. or 256 mg/kg. Three animalsfrom each dosage group were sacrificed at ten minutes, 1 hour, 6hours, 12 hours, 24 hours, and 7 days following treatment. Lungtissue was fixed and examined by electron microscopy after eachsacrifice. Minor bronchiolar epithelial changes were noted In thegroup receiving 67.4 mg/kg. Mice in the higher dosage groupsdeveloped necrosis of secretory nonciliated bronchiolar cells.In a study reported by Shopp et al. (1984), male and female CD- micewere exposed for 14 or 90 days by gavage to 3 different doses of thecompound. In the 14 day study both males and females showed a 5-10% mortality and depressed body weights at the high dose of 267mg/kg/day. At this dose the males had decreased thymus weights andthe females and decreased spleen and increased lung weights. Notoxic effects were observed at the two lower doses of 53 mg/kg/dayand 27 mg/kg/day. In the 90-day study mice of both sexes wereexposed to naphthalene at levels of 5.3, 53. and 133 mg/kg. Notreatment-related deaths were observed and terminal body weights \

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AR30U383

Naphthalene

were not significantly influenced by treatment In either sex.Significant decreases in brain, liver, and spleen weights were reportedin females at the highest dose with the organ to body weight ratiosignificantly different 'only for the spleen. Hemoglobin levels weresignificantly increased in the high dose females. Female mice showeda significant decrease in BUN at all levels and total serum protein wassignificantly increased In both sexes at daily naphthalene levels of 53and 133 mg/kg. A significant increase in serum creatinlne level wasobserved in the two high dose male groups and in the low dosefemales. The effect in females, however, does not appear dose-related

- as it was not observed in either of the high dose groups. Notreatment-related effect on the hepatic mixed function oxldase systemwere observed in either sex. For all exposure groups, no alterationswere observed in the hepatic drug metabolizing system except for adose-related inhibition of aryl hydrocarbon hydroxylase (AHH) activity.Van Heyningen and Pirie (1976) dosed rabbits daily by gavage with1000 mg/kg/day for various periods of time for a maximum of 28 days.They noted lens changes after the first dose and retinal changes afterthe second dose. Ghetti and Mariani (1956b) fed five rabbits 1000mg/kg/day of naphthalene and noted that development of cataractsbetween days 3 and 46. Topical application of a 10% solution in oil tothe eyes of two rabbits did not produce cataracts after a period of 50days. Intraperitoneal injection of 500 mg/day of naphthalene in an oilysolution to one rabbit over a period of 50 days produced weight lossbut no cataracts. It is thought that reactive metabolites of naphthalenesuch as 1,2-dihydroxynaphthalene and 1.2-naphthoquinone areformed In the eye and then combine Irreversibly with thiol groups oflens proteins to form a brown precipitate. This results Indegenerative changes in lens epithelium (USEPA 1982). Serum lipid.peroxide levels were Increased in Wlstar rats given naphthalene.These lipid peroxides in the bloodstream may play a role incataractogenesis (Yamauchi 1986).Harris and cbworkers (1979) reported a statistically significantincrease in retarded cranial ossification and heart development Inoffspring of Sprague Dawley dams that had received intraperitonealInjections of 395 mg/kg naphthalene on days 1*15 of gestation. In astudy by Plasterer and coworkers (1985). single doses of naphthalenewere administered by gavage to pregnant CD mice on days 7 through14 of pregnancy. The compound was given at a dose estimated to beat or Just below the threshold of adult mouse lethality (as determinedfrom previous studies). A significant reduction in the average numberof live pups per litter was reported for the naphthalene-dosed females.In an experimental protocol in which 50 pregnant mice were dosedwith naphthalene at midterm and then allowed to deliver, a reduced

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flR30U38U

Naphthalene

number of liveborn mice per litter were observed as compared to thecontrol group fed corn oil (Hardln 1987}.Naphthalene, when combined with rat microsome fractions, has beenfound to be nonmutagenic when tested in bacterial mutagenesis assaysusing various strains of Salmonella typhimurium as well as in vitro celltransformation assays (USEPA 1980).The dose of 53 mg/kg/day from the subchronic study described byShopp et al. (1984) can be used as a NOAEL for calculating an ADI. If asafety factor of 1000 Is applied to this value In order to allow for theuse of a subchronic study and intra- and interspecies variability, theresulting ADI is 0.053 mg/kg/day. However. EPA has calculated anRfD of 0.4 mg/kg/day for naphthalene (PHRED, 1986).

E. Pharmacokinetlcs

Naphthalene is rapidly absorbed when inhaled but is more slowlyabsorbed by Ingestion or through the intact skin. Dermal adsorption ofnaphthalene has not been well-characterized: however, available dataon absorption of crude coal tar products, including naphthalene, inhumans indicate that naphthalene is absorbed to a greater extent thananthracene (Storer et al. 1984). Although data are Inadequate toquantify naphthalene dermal absorption directly, they may provide anestimate of absorption relative to anthracene. Anthracene dermalabsorption has been reported to be 52.3% of the total dose appliedafter 6 days of exposure in rats. Therefore, it is assumed thatabsorption of naphthalene is greater than 50% by the dermal route ofexposure. The compound is metabolized in the liver to reactivemetabolites that are capable of circulating and becoming boundirreversibly in extrahepatic tissues in vivo (Richieri 1987).Metabolism occurs rapidly In the adult but very slowly in the newborn(Sittig 1985). No data were located indicating naphthalene to be anhepatic enzyme inducer. The study by Shopp and coworkers (1984)reported a dose-related inhibition of aryl hydrocarbon hydroxylase. Itis first metabolized to the highly reactive epoxlde, naphthalene-1.2.-oxide. The epoxlde can be converted to the dihydrodiol or conjugatedwith glutathione. The dihydrodiol can be conjugated with glucuronicacid or sulfate to form the reactive 1.2-dlhydroxynaphthalene. Thiscan also be conjugated with sulfate or glucuronic acid or spontaneouslyoxidized to form the highly reactive 1.2-naphthoquinone (USEPA1980).The epoxide naphthalene-1,2-oxide can also be convertedspontaneously to 1-naphthol or 2-naphthoi. 1-Naphthol is excreted


flR30l»385

Naphthalene

unchanged or is conjugated with glucuronic acid or sulfate prior toexcretion. It is also believed that 1-naphthol can be further oxidizedto 1.4-naphthoquinone (USEPA 1980). The naphthols andnapthoqulnones are hemolytic agents (Sittig 1985).Naphthalene metabolites can undergo further conversions In the eye.The dihydrodiol can be oxidized to 1,2-dihydorxynaph-thalene whichcan then be oxidized to 1,2-naphthoquinone. 1,2-Naphthoquinone canbind irreversibly to lens protein and amino acids or it can oxidizeascorbic acid to dihydroascorbic acid. In this process 1,2-naphthoquinone is reduced to 1,2-dihydroxynaphthalene (USEPA1980).Skaeggestad (1964) reported that naphthalene has a low nucleic acid(DNA and RNA) binding capacity.

F. Discussion - Derivation of Target Concentrations

The low dose of 5.3 mg/kg that was administered to mice in the 90day study reported by Shopp et al. (1984) can be considered a NOAELfor the purposes of calculating target concentrations. This significantdecrease in blood urea nitrogen (BUN) that was observed in femalerats in not generally considered indicative of a toxic effect. A safetyfactor of 1000 is applied to this to account for the use of a subchronicstudy and intra and interspectes variability, resulting in an ADI of 5.3 x10-3 mg/kg/day or 0.37 mg/day for a 70 kg person.

References

Adkins, B.. E.W. Van Stee, J.E. Simmons, and S.L. Eustis. 1986.Oncogenic response of strain A/J mice to inhaled chemicals. J.Toxicol. Environ. Health 17:311-322.

Bogdat'eva. A.G.. and D. Ya. Bid. 1955. Effect of high molecular weightproducts of pyrolysis of petromeim on the animal organism. Gig.Sanit. 7:21. (Reported in USEPA 1980).

Ghetti, G., and L. Mariani. 1956a. Med. Lav. 57:533. (Reported inSandmeyer 1981.) ;

Ghetti, G.. and L. Mariani. 1956b. Eye changes due to naphthalene.Med. Lav, 47:524. (Reported in USEPA 1980.)

Hardln, B. D., R.L. Schuler. J.R. Burg. G.M. Booth. K.P. Hazelden. K.M.MacKenzie, V.J. Piccirillo. K.N. Smith. 1987. Evaluation of 60

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Naphthalene

chemicals in a preliminary development toxicity test.Teratogenisis. Carcinogenesis, and Mutagenesis. 7:29-48.

Harris, S.J., G.P. Bond, and R.W. Neimeir. 1979. The effects of 2-nitropropane, naphthalene and hexachlorabutadiene on fetal ratdevelopment. Toxicol. Appl. Pharmacol. 48:A35. (Reported InUSEPA 1982.)

Kennaway. E.L.. and I. Hieger. 1930. Carcinogenic substances andtheir fluorescence spectra. Br. Med. Jour. 1:1044. (Reported inUSEPA 1980).

Knake, E. 1956. Uber schwach geschwulsterzengende wirkung vonnaphthalin und benzol. Virchows Archiv. Pathol. Anat. Physiol.329:141. (Reported in USEPA 1980.)

Mahvi, D.. et al. 1977. Morphology of a naphthalene-inducedbronchiolar lesion. Am. Jour. Pathol. 86:559. (Reported inUSEPA 1980.)

Plasterer, M.R., W.S. Bradshaw. G.M. Booth. M.W. Carter. R.L. Schuler.B.D. Hardin. 1985. Development toxicity of nine selectedcompounds following prenatal exposure in the mouse:naphthalene, p-nitrophenol. sodium selenite, dimethyl phthalate.ethyien thlourea, and four glycol derivatives. J. Toxicol Environ.Health. 15(l):25-38.

Richieri, P.R. and A.R. Buckpitt 1987. Efflux of naphthalene oxideand reactive naphthalene metabolites from isolated hepatocytes.J. Pharmacol. Exp. The. 242:485-92.

Sandmeyer, E.E. 1981. Aromatic hydrocarbons. In Patty's Industrialhygiene and toxicology, eds. G.D. Clayton and F.E. Clayton, VolumeII B. New York: John WIley & Sons.

Schmeltz, I.. J. Tosk, J. Hilfrlch, N. Hirota, D. Hoffman, and E. Wynder.1978. Bioassay of naphthalene and alkyl naphthalenes forcocarcinogenesls activity. Relation to tobacco Carcinogenesis. InCarcinogenesis: A comprehensive survey. Volume 3. Polynucleararomatic hydrocarbons. Second International Symposium onAnalysis, Chemistry, and Biology, eds. P.W. Jones and R.I.Freudenthal, 47-60. New York: Raven Press, (Reported inUSEPA 1980.)

Shopp. G.M., K.L. White, Jr., M.P. Holsapple, D.W. Barnes. S.S. Duke, A.C. Anderson, L.W. Condie Jr., J.R. Hayes, and J.F. Borzelleca.1984. Naphthalene toxicity in CD- mice: General toxicity andimmunotoxicology. Fundam. Appl. Toxicol. 4(3 Pt. 1): 406:419.

Sittig. M. 1985. Handbook of toxic and hazardous chemicals andcarcinogens. Second ed. Park Ridge, N.J.: Noyes Pulications.

o


ARSONS?

(G

Naphthalene

Skaeggestad, O. 1964. Acta. Pathol. Microbiol. Scand. 169:1.(Reported in Sandmeyer 1981.)

Storer, J.S., I. DeLeon, L.E. Millikan. J.L. Laseter, and C. Griffing.1984. Human absorption of crude coal tar products. Arch.Dermatol. 120:874-877. •

U.S. Environmental Protection Agency (USEPA). 1980. Ambientwater quality criteria document for naphthalene. Office of WaterRegulations and Standards. EPA 440/5-80-058.

U.S. Environmental Protection Agency (USEPA). 1982. An exposureand risk assessment for benzo(a)pyrene and other polycyclicaromatic hydrocarbons: Volume II. Naphthalene. Final draftreport Office of Water Regulations and Standards (WH-53).

U.S. Environmental Protection Agency (USEPA). 1988. Assessment ofnaphthalene as a potentially toxic air pollutant. Fed. Reg. 53(March 21): 9138.

Van Heynlngen, R.. and A. Pirie. 1976, Naphthalene cataract inpigmented and albino rabbits. Exp. Eye Res. 22:393. (Reportedin USEPA 1980.)

Yamaguchi, T., S., Komura, K. Yagl. 1986. Serum lipid peroxide levelsof albino rats administered naphthalene. Biochem. Int. 13:1*6.

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AR30i*388 '

flR30l*389

Phenol

Phenol

CASNo.: . 108-95-2Synonyms: hydroxybenzene, phenic acid, phenylic

acid, carbolic acid .


Chemical Formula: CgHgOForm: white, crystalline mass, burning taste,

distinctive odor

Chemical Class: monocyclic aromaticMolecular Weight: 94.12

Boiling Point: 182°CMelting Point: 41°C

Specific Gravity: 1.07Solubility In Water: 82 g/L at 15dC

Solubility in Organics: alcohol, etherOrganic Carbon

Partition Coefficient: 14.2Log Octanol/Water

Partition Coefficient: 1.46Vapor Pressure: 0.2 mm at 20°C, 1 mm at 40°CVapor Density: 3.24




Maximum Contaminant Level (MCL)for Drinking Water (mg/L): " NA

Clean Water ActAmbient Water Quality Criteria (mg/L)Human Health ;

Water and Fish Consumption: 3.50E+00Fish Consumption Only: NA

Aquatic Organisms (mg/L)Fresh Water.

Acute: l.OOE+01Chronic: 2.50E+00Marine

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AR30t*390

Phenol

Acute: 5.80E+00Chronic: NA

ReferencesSax and Lewis 1989, Verschueren 1983, The Merck Index 1983,SPHEM 1986, EPA 1986NA - Not Available


Photolysis and biodegradation appear to be major fate processes forphenol in aquatic environment. Overall half-lives have been calculatedfor phenol in air and surface water as 1*9 days In each case. Basedupon the physical-chemical properties of phenol (KoC. KQW, etc.) andlimited data, volatilization, bioaccumulation, and sorption fateprocesses do not appear to be significant.

Pure cresol is a mixture of ortho, meta, and para isomers (o-cresol,m-cresol and p-cresol). Crude cresol (commercial cresol) is a mixtureof aromatic compounds containing about 20 percent of o-cresol, 40percent of m-cresol, and 30 percent of p-cresol with small amounts ofphenol and xylenols.

Crude cresol is a colorless liquid that turns brown upon exposure toair or light; o-cresol, a colorless crystalline compound; m-cresol. ayellowish liquid: and p-cresol. a white crystalline compound. Cresol isreadily soluble or miscible with organic solvents, vegetable oils, orether and alcohol. Cresols have an odor much like that of phenol orcreosote. The odors are easily recognized down to an air concentrationof 5 ppm.

Phenolic compounds are formed naturally upon microblal degradationof the amino acid tyrosine in the mammalian intestine. In mammalsphenol Is therefore excreted together with p-cresol as naturalmetabolites in small amounts with the urine. Intake of certainvegetable products containing derivatives of salicylic acid, e.g.methylsallcylate, may increase phenol excretion. The amount ofphenol normally excreted in the urine ranges from 0.5 up to about 80mg/L (NIOSH, 1976).

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Phenol

IX Ecotoxicology

Phenol and the cresols are easily biodegradable, and have littletendency to accumulate in the ecosystem.

E. Human Toxicology

The lexicological properties of phenol and its methyl- substitutedderivatives - the cresols - are very similar, and are convenientlyreviewed in one context.

Toxicity Summary

Phenol and the cresols are relatively toxic chemicals that may beabsorbed by Ingestion, dermal contact, or by inhalation. They can causelocal as well as systemic effects including neurotoxlc action andsevere damage to internal organs. The handling of these compounds inconcentrated form may constitute a considerable occupational hazard.but low-dose chronic exposure is not considered to Involve anysignificant risks. There is no adequate evidence linking thesecompounds with carcinogenic, genotoxic or teratogenlc effects inmammals.


A considerable amount of information exists on the toxicity of phenolin experimental animals, most of which is found in older literature.However, the lack of studies complying with present day standards isto a large extent compensated by extensive experience from humanexposure.

The acute oral toxicity for phenol has been reported to be about 340mg/kg in the rat. and the corresponding value for dermal contact 670mg/kg. The lowest dose producing death in rabbits by skin absorptionwas given as 380 mg/kg by the same group of investigators(Deichmann and Witherup. 1944; Deichmann et al., 1950), The lowestdoses of phenol to induce signs of central nervous system toxicity(vasomotor center) has been Investigated, and found to be 280 mg/kg


Phenol

by ingestion, 130 mg/kg by skin contact in the rabbit and 107 mg/kgby skin absorption in the rat (Deichman and Witherup, 1944; ADeichmann et al., 1944; Conning and Hayes, 1970). . -

Phenol is corrosive to skin, and when in contact with the eye It cancause severe damage or even blindness. Crystalline phenol hasproduced gangrene after 30 minutes of skin contact. Despite itsirritant properties, this constitutes a definite hazard because of Itslocal anesthetic action (Lambotte and Degroote, 1960). Althoughphenol is only moderately toxic to mammals, the rapid skinpenetration, as well as the absence of any effective treatment of acutepoisoning, makes the handling of phenol an occupational hazard. Inhumans, phenol at high doses usually exerts (directly and indirectly) apredominant action upon the higher centers of the central nervoussystem, resulting in sudden collapse. Concentrated solutions of phenolhave caused death after skin contacts as brief as 5-20 minutes.Regardless of the mode of administration, the signs of acute Illnessinduced by phenol in humans resemble those observed inexperimental animals. Symptoms of acute Intoxication includeweakness, sweating, headache, giddiness, etc., which can be followedby cyanosis, convulsions, coma and death (usually from respiratoryfailure). If death does not occur, kidney damage may be elicited. Darkcolored urine is often a characteristic sign of poisoning (NIOSH.1976).

Exposure of guinea pigs by inhalation of 26-52 ppm phenol 7 hrs/day.5 days/week produced death in about half of the experimental animalsafter 29 exposures. Upon autopsy, pathological examination revealedmyocardial necrosis, lobular pneumonia, vascular damage, and hepaticas well as renal damage. Rabbits, similarly exposed for 63 times in 88days, did not show increased mortality, but had myocardialdegeneration, liver and kidney damage, as well as lobular pneumoniaupon post mortem examination (Deichmann et al., 1944).

No toxic effects could be found in monkeys, rats and mice exposed to5 ppm in the inhaled air 8 hrs/day. 5 days/week for 90 days (Sandage.1961).

In man chronic exposure has been reported to cause loss of appetite,anorexia, dizziness, diarrhea, dark urine, discoloration of the skin,mental disturbances, and signs of liver toxicity (Merliss. 1972).

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Phenol

The predominant signs of local and systemic intoxication produced bycresols are very similar to those produced by phenol. As with phenol,concentrated solutions of cresols have a marked corrosive action ontissues. Acute exposures by all routes of absorption may causemuscular weakness, gastroenteric disturbances, severe depression.collapse, and death. Although the effects are primarily on the centralnervous system, edema of the lungs and injury of the kidneys, liver,pancreas, and spleen may also occur. Repeated exposures may resultin liver and kidney damage. m-Cresol is generally considered the leasttoxic; however, reports differ as to whether o- or p-cresol is themore toxic of the two. For all practical purposes the three isomers canbe considered as having essentially the same degree of toxicity. Thepathological changes induced by these compounds are similar to thosecaused by phenol (Deichmann and Keplinger, 1981).

In a subchronic toxicity study (EPA, 1986) o-. m-, or p- cresols wereadministered by gavage to Sprague-Dawley rats, 30 animals/dose/sex,at 0, 50, 150 or 450 mg/kg/day. During the study body and organweights, food consumption, mortality, clinical signs of toxicity, as wellas clinical pathology were evaluated.

600 mg/kg/day, of o-cresol induced an approximately 50% mortality.and 30% reduction in body weight at week 1 and 10% at finalsacrifice. Food consumption was also significantly reduced duringweeks 1-6 and 9. The kidney-to-body weight ratio was 13% higherthan that of the control value at the end of the study. In addition tothe above effects, CNS effects such as lethargy, ataxia. coma, dyspnea,tremor and convulsions were seen within 15-30 minutes after dosing;recovery occurred within 1 hour after administration. At 450mg/kg/day, mortality was 10% (1/10 male. 1/10 female). In the 175mg/kg/day group, two animals each exhibited tremors on day 1 of thestudy during the hour following gavage administration, and one ofthese animals became comatose during that time. At 50 mg/kg/day,no significant adverse effects were observed.

At 450 mg m-cresol/kg/day there was a 20-25% reduction in bodyweight gain in males and 10-15% in females, food intake was reducedby 10-15% In males, and there was a significant Increase in theincidence of salivation and tremors. At the 150 mg/kg/day dose,weight gain was reduced by 10-15% in males although no reduction

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Phenol

was seen in females. At 50 mg/kg/day no adverse reactions could benoted.

With p-cresol. there was a significant reduction in weight gain (15%for females, 25% for males), significantly reduced food consumption atweeks 1-7 and 9 in males and significant increased incidence of CNSsigns such as excessive salivation, tremors and diarrhea at 60*0mg/kg/day. Also, the liver-to-body weight and kidney-to- body weightratios were significantly Increased. There was also a greaterprevalence of trachea! epithelial metaplasia in this group of animals.At the mid-dose group (175 mg/kg/day) the kidney-to-body weightratio was elevated significantly for males, but no statisticallysignificant effects could be noted at the 50 mg/kg/day level.

In a neurotoxicity study subsequently performed (EPA. 1987).Sprague-Dawley rats, 10 animals/sex/ dose, were administered 0, 50,150 or 450 mg/kg/day o-,m-. or p-cresoi daily by gavage. In additionto the previously mentioned parameters, signs of neurotoxicity suchas salivation, urination, tremor, piloerection, diarrhea, pupil size,pupil response, lacrimatlon. hypothermia, exophthalmia, convulsions(type and severity), respiration (rate and type), impaired gait,positional passivity, locomotor activity, stereotypy, startle response.righting reflex, performance on a wire maneuver, forelimb strength,positive geotrophism, extensor thrust, limb rotation, tail pinch reflex,toe pinch reflex, and hind limb splay were also evaluated.

The lowest dose of o-cresol, m-cresol, or p-cresol (50 mg/kg/day)caused clinical signs of CNS-stimulation after administration such assalivation, rapid respiration, hypoactivity. However, these symptomswere low in incidence and sporadic in nature. Higher doses producedsignificant neurological events, such as increased salivation, urination.tremors, lacrimation, palpebral closure and rapid respiration. Highdosed animals also showed abnormal patterns In the neurobehavioraltests.

In man reported signs of intoxication include irritation, corrosion,hemorrhages of the gastrointestinal tract ..(following oraladministration), kidney tubule damage, pulmonary effects (edema,pneumonia), and congestion of the liver with cellular necrosis andfatty degeneration (Deichmann and Kepllnger, 1981).

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Although phenol appears to possess a certain promoting action forinduction of skin tumors in mice (Boutwell and Bosch, 1959). it didnot Induce carcinogenic effects when administered in drinking waterto rats and mice in a long term study. 50 animals of each sex of theB6C3F1 mouse strain and of the Osborne-Mendel rat strain were givendoses of 2,500 or 5,000 ppm of phenol in the drinking water, 5days/week for 103 weeks. No significant treatment related increasein the tumor incidence could be observed in either of the animalspecies {NCI, 1980).

The cresols are are currently being tested for carcinogenic effectsunder. NTP.

Genotoxic effects and adverse effects onreproduction

Although phenol and cresols induce C-mitosis, a slight chromospmebreaking effect in Allium (Levan and Tjio, 1948). and phenol arelatively weak response in the Ames' tester strain TA98. theevidence of genotoxlcity for these compounds appear to beinsufficient. Thus, phenol has e.g. been found to be negative in theDrosophila sex-linked recessive lethal assay and in the mousemicronucleus test up to a dose level of 188 mg/kg (Gocke et al.,1981). The increased frequency in sister chromatid exchanges inhuman lymphocytes that has been reported, may be due to a generalcytotoxic action, since it was accompanied by a decrease in mitoticIndex and inhibition of cell cycle kinetics (Erexson et al., 1985).

In a three generation study in rats, 5000 ppm in drinking water wassaid to produce no adverse effects, whereas stunted growth evident inthe young of a group exposed to 7000 ppm in water over twogenerations. The offspring of rats at 1000 ppm died at birth (Hellerand Pursell, 1938). Later studies tend to confirm these earlyobservations.


AR30U396 —-«,

Phenol


Phenol is readily taken up by the mammalian organism by ingestion.inhalation, or by skin contact.

Skin absorption often represents the primary route of entry for liquidas well as for solid phenol, but is also important for phenol vapors.Concentrated phenol has a marked corrosive action on tissues,producing burns and dermatitis. Investigations in volunteers to phenolvapors at various concentrations (1.5 - 5.2 ppm). either by inhalationvia a closed mask, or by contact with the intact skin in a whole-bodyexposure chamber, has demonstrated that phenol vapor readilypenetrates the skin. Following inhalation, the subjects retained 60-88% of the Inhaled dose. Urinary excretion of phenols increasedrapidly during exposure and returned to normal within 16 hours postexposure. Virtually all of the inhaled dose was excreted in the urine.Individuals exposed through skin absorption excreted amounts similarto those subjects exposed by inhalation, and the rates of excretionwere about the same by either route of absorption. (Piotrowski. 1971). \

Since porcine skin resembles human skin more closely than that ofrodents, swine has been used for the study of dermal penetration.Application of 500 mg/kg phenol over 35-40% of the total bodysurface area resulted in a rapid absorption through the intact skin. Inthe treated animals, tremors, excess salivation, nasal discharge andrespiratory distress occurred within five minutes. Phenol wasdetectable in the plasma 8.75 hours, but not after 21 hours (Pullin etal., 1976).

Phenol is commonly excreted with the urine as phenylsulphuric andphenlglucuronic acids and is further oxidized to catechols andqulnones, or in small amounts to carbon dioxide. Elimination of freephenol also occurs. It has been suggested, that signs of toxicity onlyappear after absorption of doses which may produce metabolicoverloading (NIOSH, 1976).

Cresols are readily absorbed through the skin and the mucousmembranes of the gastrointestinal and respiratory tracts. They are \

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Phenol

handled metabollcally by the mammalian organism in a way very muchlike phenol. Inasmuch as they are conjugated with sulphuric andglucuronic acids and excreted as such with the urine. To some extentcresols are oxidized to dihydroxy-compounds like 2,5-dihydroxytoluene and, in addition, p-hydroxybenzoic acid has beenidentified as a metabolite from p-cresol (Deichmann and Keplinger.1981).

Discussion of Risk Assessment

Using a NOAEL of 50 mg/kg/day for the cresols with respect todecreased body weights and neurotoxicity in the subchronic studies inrats cited above (EPA 1986. 1987), and using an uncertainty factor of1000 (10 for interspecies and 10 for intraspecies variability and 10for uncertainty in extrapolation of subchronic data to levels of chroniceffects), EPA has derived a RfD of 0.05 mg/kg/day.

Based on a review and assessment of the available literature, primarilythe subchronic inhalation studies of Uzhdavine et al., NIOSH hasrecommended a TLV-TWA of 10 mg /m3 (0.05 mg/kg/day).Uzhdavlne et al. exposed rats and guinea pigs to o-cresol at aconcentration of 9.0 mg/m3. No effect was seen in guinea pigs. Inrats, the authors reported various hematopoietic effects, respiratorytract irritation and sclerosis of lungs. Based on the NIOSH (1978)TLV of 10 mg/m3 (converted to 0.51 mg/kg/day). an RfD of 0,05mg/kg/day can also be derived, which lends support to the RfDderived from the subchronic toxicity studies (EPA, 1986. 1987).However, until additional chronic toxicity studies and reproductivestudies are available, certain reservations should be made with respectto the derived RfD.

Phenol and cresols meet the criteria for proposed OSHA MedicalRecords Rule (Fed. Reg.. 1982), and the current ACGIH 8 hr TWA-TLV is 5 ppm (19 mg/m3).

The ambient water quality criteria for human health of 0.3 mg/L hasonly been based on organoleptic evaluation. However, since phenolpossesses warning properties by odor and taste far below theconcentrations at which toxic effects occur (odor threshold 0,02-0.19mg/m3 (NIOSH, 1976), this level should provide an adequate marginof safety. The AIS and AIC of 0.1 mg/kg/day have, nevertheless, been

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Phenol

based on older literature, and the value has been withdrawn followingfurther review.

The reportable quantity (RQ) for release into the environment iscurrently 1000 pounds, and takes into account the naturalbiodegradation as well as photolysis.

References

Boutwell, R.K., and Bosch, D.K.; The tumour-promoting action ofphenol and related compounds for mouse skin. Cancer Res.19(1959)413-424.

Conning, D.M., and Hayes, M.J.; The dermal toxicity of phenol - Aninvestigation of the most effective first-aid measures, Brit. J. Ind. Med.27(1970)155-159.

Deichmann, W.B.. Witherup, B.S.; Phenol studies. VI. The acute andcomparative toxicity of phenol and o-, m-, and p- cresols forexperimental animals. J. Pharmacol. Exptl. Therap. 80(1944)233-240.

Deichmann, W.B., Kitzrnlller. K.V., and Witherup, B.S.; Phenol studies.VII. Chronic phenol poisoning, with special reference to the effectsupon experimental animals to the inhalation of phenol vapor, Am. J.Clin. Pathol. 14(1944)273-277.

Deichmann, W.B., Miller. T.. and Roberts, J.B.; Local and systemiceffects following application of dilute solutions of phenol in water andin camphor-liquid petrolatum on the skin of animals. Arch. Ind. Hyg.2(1950)454-460.

Deichmann, W.B., and Keplinger, M.L.; Phenols and phenoliccompound^, in Patty's Industrial Hygiene and Toxicology (Clayton,G.D., and" Clayton. F.E.. Edts.) 3rd Ed.. Vol. 2A. John Wiley & Sons,New York 1981. pp. 2567-2627.

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Phenol

EPA, Office of Solid Waste; 6,,m, p-Cresol - 90-Day oral subchronicI toxicity studies in rats, Washington, D.C., 1986.

EPA, Office of Solid Waste; o. m, p-Cresol - 90-Day oral subchronicneurotoxicity study in rats, Washington, D.C.. 1987.

Erexson, G.L., Wilmer. J.L., and Kligerman, A.D.; Sister chromatidexchanges in human lymphocytes exposed to benzene and itsmetabolites In vitro. Cancer Res. 45(1985)2471- 2477.

Federal Register; 47,30420,1982

Gocke, E., King. M.-T., Eckhardt, K., and Wild. D.; Mutageniclty ofcosmetics ingredients licenced by the European Communities. Mut.Res. 90(1981)91-109.

Heller, V.G., and Pursell. L.; Phenol-contaminated waters and theirphysiological action, J. Pharmacol. Exptl. Therap, 63(1938)99-107.

Levan, A., and TJio, J.H.; Induction of chromosome fragmentation byphenols, Heredltas 34(1948)453-484.

Merliss. R.R.. J, Occup. Med. 14(1972)55-56.

NCI; Bioassay of phenol for possible carcinogenicity. National CancerInstitute Carcinogenesis Technical Report Series, No. 203. NCI-TR-203, 1980.

NIOSH, Criteria for a Recommended Standard - OccupationalExposure to Phenol. USDHEW, NTIS PB 266 495. July 1976.

Piotrowski, J.K.: Evaluation of exposure to phenol - Absorption ofphenol vapor in the lungs and through the skin and excretion ofphenol urine. Brit. J. Ind. Med. 28(1971)172-176.

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Phenol

Pullin, T.C. et al.; Decontamination of the skin of swine followingphenol exposure: A comparison of the relative efficiency of waterversus polyethylene glycol/industrial methylated spirits. Toxicol. Appl.Pharmcol. 26(1976)199- 206.

Sandage, C.; Tolerance criteria for continuous inhalation exposure totoxic material, ASD Technical Report 61-519, Kansas City. No,Midwest Research Inst., 1961. pp. 1-29. cited in NIOSH. Criteria for aRecommended Standard - Occupational Exposure to Phenol. July1976, pp. 55-601.

Zangger.H., in Lehrbuch der Toxlkologie (Flury, F., Zangger. H.. Edts.),Springer Verlag, Berlin 1928; Occupation and.Health, InternationalLabour Office. Geneva, 1934.


AR30HOI

PAHS

Polvnuclear Aromatic Hydrocarbons

CASNo.: NASynonyms: Polycyclic aromatic hydrocarbons, PAHs


Chemical Formula: NAForm: slightly bluish solid*

Chemical Class: polycyclic aromatic hydrocarbonsMolecular Weight: 202,26*

Boiling Point: 404C*Melting Point: 156C*

Specific Gravity: 1.271 @ 25C*Solubility in Water: 0. 132 mg/L @ 25C*

Solubility in Organics: benzeneOrganic Carbon

Partition Coefficient: 80,000*Log Octanol/Water

Partition Coefficient: 4.88*Vapor Pressure: 2.5E-06 @ 25C*Vapor Density: NA

Henry's Law Constant: 5.04E-06*Bioconcentration Factor: 12,000 (microbial)*

R, Regulations and Standards



Clean Water ActAmbient Water" Quality Criteria (mg/L)Human Health .

Water and Fish Consumption: 2.8E-06Fish Consumption Only: 3.1 IE-06


Acute: NA >Chronic: NAMarine


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PAHs

References .Sax and Lewis 1989, Verschueren 1983, The Merck Index 1983, . —SPHEM 1986. EPA 1986NA - Not Available *Values for pyrene.


Polynuclear aromatic hydrocarbons (PAHs) bind tenaciously tocarbonaceous sediments and soils and, hence, move very slowly in theenvironment. Since PAHs are natural products which are found ascontaminants of petroleum, tars, coal and forest fires, there are someareas which are heavily contaminated without anthropromorphicintervention. PAHs bloaccumulate significantly such that benthic andother sediment-dwelling organisms initiate a biomagniflcation whichescalates in the predatory cascade ending with man. Thesepolynuclear aromatics are also lipophilic and, as such, are readilyabsorbed across most membranes, facilitating absorption in respiratoryand digestive tracts and by the skin through dermal absorption.Pyrene, at molecular weight 202, is not large enough to findmechanical impediment to membrane penetration, however PAHs âbove molecular weight 300 are mechanically impaired. Being among , ,the smaller of the PAHs, pyrene is also slightly water-soluble (0.13mg/L). although this does not provide a major mechanism ofenvironmental transport, unless there is cosolvation by another moresoluble organic. Larger PAHs are more hydrophobic, tend to travelless in water as medium and bioaccumulate to a higher degree.

IX Ecotoxlcology

The available data for PAHs Indicate that acute toxicity to saltwateraquatic life occurs at concentrations as low as 300 (ig/L and wouldoccur at lower concentrations among species that are more sensitivethan those few which have been tested. No data are availableconcerning the chronic toxicity of PAHs to sensitive saltwater species(EPA, 1986).Pyrene and other mildly aromatic small PAHs (such as naphthalene)are quite noxious to insects and. indeed, may be used as repellants.Higher concentrations of vapors in a confined area may be lethal toinsect larval development.

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PAHs

The primary response in vertebrates to PAH intoxication is theInduction of microsomal oxidase (the P-450 cytochromes). • Thisoccurs mainly in the liver and, hence, chronic intoxication with PAHsmay eventually lead to hepatotoxicity.

E. Human Toxicology

Environmental levels and exposure: PAHs occur ubiquitously in theenvironment as pollutants originating from various combustionprocesses. Thus, they are present in urban atmospheres inconcentrations ranging typically from about 50 to 100 ng/m3. In theatmosphere the PAHs are adsorbed mainly on suspended particles.However, some substances with higher vapor pressures, such as thebenzofluorenes, fluoranthene, phenanthrene. pyrene and their methylderivatives are found to an appreciable extent also in the gas phase.High levels of a complex mixture of PAHs are present in crudepetroleum oils (Pancirov and Brown, 1975) In amounts which may varyfrom 6.000 (Kuwait crude) to 9.000 mg/L (South Louisiana crude).

Ingestion of food constitutes a primary source of exposure of humans.where in particular grilled and smoked food stuffs contain high levels.The concentrations of different PAHs in cliarcoal-broiled steaks aregiven in Table 1. Certain refined oils or fats, like sunflower oil orcoconut fat. may also contain very high levels of PAHs (IARC. 1983).

Table 1: PAHs in charcoal-broiled steaks(Lijinsky and Shubik, 1964).

PAH compound ii/k in steak

anthanthrene 2anthracene 4.5benz(a]anthracene 4.5benzofghijperylene 4.5


HR30H05

PAHs

ben2o[a]pyrene 8benzo(e]pyrene 6 j]chrysene 1.4coronene 2.3dibenz(a,h]anthracene 0.2fiuoranthene 20perylene 2phenanthrene 11pyrene 18

Summary of Toxicity Data

The acute toxicity of PAHs is moderate to low, and the main concernrelated to this group of substances has been the establishedcarcinogenic properties of several members of this category ofchemicals. Some complex mixtures (untreated and mildly treatedmineral oils, shale-oils, coal-tars, coke oven emissions) containing JPAHs are proven human carcinogens. In addition, carcinogenic PAHs —'exhibit several other toxicological effects Including bone marrowdepression, immunotoxlcological, teratogenlc as well as fe to toxiceffects.

Acute and Chronic Toxicity

The acute, oral toxicity of PAHs is usually low. The LD50 ofbenzo[a]pyrene is about 250 mg/kg for the mouse by the i.p. route.Marked genetically determined differences in sensitivity to the toxiceffects are evidently linked to the inducibllity of aryl hydrocarbonhydroxylase, as demonstrated for benzo[a]pyrene In different strains ofmice. Thus, oral administration of 120 mg/kg of the compound to asensitive strain induced aplastic anemia and death within 4 weeks,whereas inducible mice remained virtually unaffected for at least 6months.There is an increasing body of evidence that several carcinogenicPAHs produce severe, long-term immunotoxicity. Exposure to 3-methylcholanthrene, 7,12-dimethylbenz[a]anthracene, and to


PAHs

benzo[alpyrene results in a long-lasting reductions in the activity ofantibody-producing cells. Exposure of pregnant mice to a single dose(100-150 mg/kg) of benzo(a]pyrene gave severe, suppression ofantibody response in pups shortly after birth (Dean et al., 1986).Under certain conditions benzo[a]pyrene seems to be able to cause amitogenic response, and topical application of this PAH to mouse skinhas been shown to stimulate mitosis In the epidermis.


Several PAHs are strongly implicated in the proven associationbetween smoking and lung cancer, between occupational exposure tocoke-oven emissions, coal-tar, pitch, mineral oils and similar productsand cancer of skin, lung, bladder and the gastro-tntestinal tract.However, because of the fact that exposure involves complex mixtureswhere, clearly, there Is Interaction between a number of initiators andpromoters, it is more difficult to assess the activity of Individualmembers of the group.

A number of PAHs have been found to induce tumors in experimentalanimals upon exposure by different routes of administration. Themore active congeners, like dibenz[a,h]anthracene induce tumors inmultiple sites, and do also act as transplacental carcinogens. Forbenzofalpyrene lung and liver tumors have been induced by exposureto pregnant mice.

The skin of many rodent species, like the mouse, is extremelysensitive to chemical carcinogens of this type, and experience fromepldemiological investigations tend to demonstrate a much lowersensitivity of e.g. human skin than that of the mouse, a finding whichhas been corroborated by Investigations In monkeys.

Individual compounds: In Table 2 a summary of the evaluations onindividual PAHs by the International Agency for Research on Cancer(IARC) i s presented. . . ; - ' .


PAHs

Table 2: Carcinogenicity of PAHs as evaluated by IARC (1983; . j)1987). >

PAH cor"p9*flji4 Animal carcinogcnicitv IARC Class

anthanthrene limited evidence 3 *anthracene no evidence 3benz(a]anthracene sufficient evidence 2Abenzo(b]fluoranthene sufficient evidence 2Bbenzo(J]fluoranthene sufficient evidence 2Bbenzo[k]fluoranthene sufficient evidence 2Bbenzo[ghi]fluoranthene no evaluation possible 3benzo(a]fluorene inadequate evidence 3benzo(b]fluorene . Inadequate evidence 3 \benzo[c]fluorene inadequate evidence 3benzofghilperylene Inadequate evidence 3benzofclphenanthrene inadequate evidence 3benzo(ajpyrene sufficient evidence 2Abenzo(e]pyrene inadequate evidence 3chrysene limited evidence 3coronene . inadequate evidence 3cyclopenta[cd]pyrene limited evidence 3dibenz[a.c]anthracene limited evidence 3dibenz(a,h]anthracene sufficient evidence 2Adibenzfajlanthracene limited evidence 3dibenzo(a.e]fluoranthene limited evidence 3dibenzo(a,elpyrene sufficient evidence 2Bdibenzo[a.hlpyrene sufficient evidence 2B

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dibenzo[a,Hpyrene sufficient evidencei , dibenzofaJIpyrene sufficient evidence

1,4-dimethylphenanthrene inadequate evidencefluoranthene no evidencefluorene inadequate evidenceindeno[l,2,3-cd]pyrene sufficient evidence1-methylchrysene inadequate evidence

- 2-,3-,4-,6-methylchrysene limited evidence5-methylchrysene , sufficient evidence2-methylfluoranthene limited evidence3-methylfluoranthene inadequate evidence1-methylphenanthrene inadequate evidenceperylene inadequate evidencephenanthrene inadequate evidencepyrene no evidencetriphenylene inadequate evidence

Group 1 Carcinogenic to humansGroup 2A Probably carcinogenic to humansGroup 2B Possibly carcinogenic to humansGroup 3 Not possible to classify as to human

carcinogenicity

BENZO[A]PYRENE constitutes one of the most extensively studied in thePAH group and has been shown to be a local, as well as a systemiccarcinogen by several routes of administration. It is well known as acomplete carcinogen when applied to the skin of mice, rats, andrabbits. Subcutaneous or intramuscular benzo[a]pyrene injection hasbeen shown to result In local tumors In mice, rats, guinea pigs,monkeys and hamsters. Intratracheal instillation produced increasedIncidences of respiratory tract neoplasms in both male and femaleSyrian hamsters.


PAHs

Upon oral administration to rats and hamsters benzo[a]pyreneproduces stomach tumors'. Given in the diet at concentrations of 0. 1.10. 20, 30, 40, 45, 50, 100, or 250 ppm to male and female CFW-Swiss mice, stomach tumors were observed in mice consuming 20ppm or more of the compound. Incidence was apparently related bothto the dose and to the number of administered doses. Apparentincreased incidences of leukemia and lung adenomas were reported inmice on high (250 and 1000 ppm) benzo(a]pyrene diets (IARC, 1973,1983).

Thyssen et al. (1981) exposed groups of 24 hamsters by Inhalation ofbenzolalpyrene at concentrations of 2.2, 9.5. or 45 mg/m3 for 4.5hours/day for 10 weeks, followed by 3 hours/day (7 days/week) for upto 675 days. No animals in the lowest treatment group developedrespiratory tumors. Those hamsters exposed to the two highestconcentrations developed tumors of the nasal cavity and trachea. Inaddition to. respiratory tract tumors, animals in the 45 mg/m3 dosegroup were seen to have neoplasms of the upper, digestive tract(larynx, esophagus and forestomach), presumably as a result ofexposure to benzolalpyrene that was swallowed following mucociliaryclearance from the respiratory tract.

. ' . OAlthough human data specifically linking benzo(a]pyrene to acarcinogenic effect are lacking, there are multiple animal studies inrodent and nonrodent species demonstrating benzo[a]pyrene to be apotent carcinogenic following administration by oral, intratracheal,inhalation and dermal routes. In addition, the compound hasproduced positive results in several in vitro bacterial and mammaliangenetic toxicology assays. Consequently, benzo [a] pyrene has beenclassified by IARC as a probable human carcinogen (2BJ and by theUSEPA as a B2 carcinogen.

In urban atmospheres benzolalpyrene constitutes only a minor fractionof the total mixture of PAHs, and has been found In concentrations upto several hundred ng/m3; more typical values range from 0.05-74ng/xn3, Benzo[a]pyrene has often been used as indicator substance forthe collective group of PAHs for the purpose of air quality monitoring,etc. The suitability of this choice may be questioned in view of thephotochemical instability of the substance, resulting in large variationsin the relation between the concentration of this substance and thetotal amount of PAHs present.

%*\ _ .-^

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AR30I*UIO.

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PAHs

BENZO(A]ANTHRACENE - Whereas anthracene itself seems to lackcarcinogenic activity. benz[a]anthracene gives such effects in so far asthe compound has been shown to constitute a complete carcinogen forthe mouse skin, but it has also shown activity by other routes ofadministration. Thus, single injections,of 50 ug to newborn miceinduced pulmonary adenomas and adenocarcinomas; repeated oraladministration gave hepatomas and lung adenomas In the samespecies. Consequently. IARC has classified benzo[a]anthracene as aprobable human carcinogen in Group 2B.

DiBENZ[A,HjANTHRACENE has produced tumors by different routes ofadministration in mice, rats, guinea pigs, frogs, pigeons, and chicken.The substance has local as well as systemic carcinogenic effects. Itinduced local sarcomas as well as lung adenomas following a singlesubcutaneous Injection in newborn mice. Rated as 2B carcinogen byIARC.

Q UANTITATIVE RISK ASSESSMENT OF INDIVIDUAL PAHS: Mostinvestigations on the carcinogenicity of PAHs have been directedtowards qualitative assessment of tumorigenicity and were notdesigned for quantitative hazard assessment. Thus, many studies wereconducted using a single dose level. In other cases the route ofadministration has been less relevant to the human exposure situation;e.g. intraperitoneal or subcutaneous injection. Skin painting studiesare difficult to evaluate in this context, and a rough indication of theorder of potency of the tested substance may only be obtained in suchcases where a well investigated standard carcinogen of known potencyhas been incorporated in the,study as a positive control. Adequatebioassays. on which to base quantitative risk evaluation, are availableonly for benzo(a]pyrene. Even for this substance database must beconsidered as far from optimal. Further, the mitogenic responseInduced by benzolajpyrene may cause strongly promotive effects andamplify the carcinogenic response of this PAH at the high dosagesused in animal cancer bioassays. This will result in an overestimationof the carcinogenic effect at lower dose levels. The sharp rise in theinclination of the dose-response curve in the study by Thyssen et al.(1981). on which Clement Associates based their unit risk estimate(Table 3), gives support to this interpretation. In this investigationSyrian golden hamsters were exposed throughout their lives tobenzo(a]pyrene in a sodium chloride aerosol for 4.5 hrs/day, 7days/weeks for 10 weeks and then for 3 hrs/day thereafter.


AR304UI I

PAHs

Table 3: Dose-response relationship between Inhaledbenzolalpyrene and respiratory tract tumors inhamsters (Thyssen et al., 1981).

Exposure f Animals f Tumors #Tumors*fmg/m31 (observed! (predicted!

0 27 0 0.732.2 27 0 1.889.5 26 9 9.0646.5 25 13 12.59

•Respiratory tumor incidence as predicted according to the low-doselinear two-stage, dose- and time-dependent model.

The USEPA has listed the slope factors for ingestion exposure as 11.5.and 6.1 (mg/kg/day)"1 for inhalation (EPA, 1980) - data which arecited In the Superfund Public Health Manual (EPA, 1986). Revisedvalues obtained after re-evaluation of the experimental raw data andby using the two-stage model are 3.2 and 0.45 (mg/kg/day)"1 foringestion and Inhalation, respectively. At present (June 1989). thesecarcinogenic potencies are undergoing review by EPA.

For other PAHs the values presented here (Table 4) are based on thecomparative potency approach based on the most reliable studies asderived by Clement Associates (1988) at the request by the EPA Officeof Health and Environmental Assessment. The two-stage dose-response model adapted by Thorslund et al. (1987) has been utilizedin preference to the conventional linearized multistage modelemployed by the USEPA (Crump. 1982). as having greater biologicalrelevance. Except for benzfalanthracene - where there was an order ofmagnitude difference - comparisons between the two models did notindicate any major deviations.


AR30HI2

PAHs

Table 4: Summary of unit risk estimates for selected PAHs*(based on Clement Associates. 1988).

PAH compound 2 stage model I/MS model**

anthanthrene l.QE+00benzofalpyrene 3.2E+00 3.2E+00benzo(e]pyrene 1.3E-02benzo(a)anthracene 4.6E-01 4.5E-02benzo[b]fluoranthene 4.5E-01 3.4E-01benzo(J]fluoranthene 2.0E-01 2. IE-01benzo(klfluoranthene 2.1E-01 2.7E-01benzo[ghi]perylene ,7.0E-02 8.0E-02chrysene 1.4E-02cyclopentadieno(cd]pyrene 7.4E-02dibenzfahlanthracene 3.6E+00 1.3E+01Indeno[1.2,3-cd]pyrene 7.5E-01 7.9E-01pyrene 2.6E-01

* Based on the revised ingestion unit risk for benzo[a]pyrene andexpressed in units of (mg/kg/day)"1. .

** Linearized, multistage model


AR30UUI3

PAHs

• Quantitative risk assessment of complex mixtures

The estimation of cancer risk from exposure to complex emissionsfrom combustion of organic matter containing PAHs by the addition ofrisk contributions from Individual substances has been attemptedbefore, but with limited success. Carcinogenic testing has only beenconducted for a small fraction of the hundreds of components presentin such complex emissions which, as a rule, also have beeninadequately characterized from the chemical analytical aspect. Thismakes any assignment of potencies much of a guess-work. Claxton'sgroup at the USEPA Health Effects Laboratory in Research TrianglePark has amply demonstrated these difficulties when assessing thegenotoxic potential of tobacco smoke - one of the best studiedcomplex emissions of this kind (Claxton et al, 1988).

In the case of estimating the cancer risk associated with the exposureto mixtures of polynuclear aromatic hydrocarbons, one approach hasbeen to assume that the carcinogenic PAH components are equivalentby weight to benzo(a)pyrene with respect to carcinogenic potency{USEPA 1980. 1984). Such an approach has little scientific support.and as benzo(a)pyrene is one of the most potent carcinogenic PAHstested, the resulting assessment tends to grossly exaggerate the riskassociated with the compounds specified. Instead the "relativepotency model" has now been accepted by the USEPA as the mostappropriate for characterizing the potency of PAH mixtures (Albert etal., 1983).

In Table 5 the relative tumor initiating potency as well as unit riskestimates of various emission extracts are compared to that ofbenzo(a)pyrene. Risk estimates are given as the lifetime probability ofrespiratory cancer death due to lifetime exposure to 1 ig/mSbenzene-soluble organic equivalent emissions in the inhaled air(Nesnow, 1987). It can be seen from these experiments, that extractsfrom these emissions are orders of magnitude less potent thanbenzolalpyrene on weight basis.

Assuming all the polycyclic organic constituents present in theseemissions to be equally active as benzolalpyrene could lead to an over-estimation of cancer risk by a factor of more than two orders ofmagnitude, whereas adding the risk contributions only for suchcompounds with known carcinogenic activity may well under-estimatethe real risk by a similar factor (assuming a relatively good correlation \


PAHs

between mutagenicity and Carcinogenicity for PAHs). If only suchcarcinogens were included for which a potency factor may be derived.the under-estimation will be even greater. Uncertainties as to thechemical composition of the emissions after atmospheric gas-phasereactions will increase the margin of error even further. In summary.it can be expected that the risk-estimate obtained by conventional riskmethodologies for complex emissions may be associated with anuncertainty range that is at least four orders of magnitude. It shouldbe pointed out. on the other hand, that the unit risk for coke ovenemissions, roofing tar. and diesel emissions, respectively, are withinthe same order of magnitude in spite rather wide differences Inchemical composition. The above mentioned situation has providedthe rationale for the USEPA to initiate the Integrated Air CancerProject, where the additivlty concept is replaced by an integratedapproach for the study of complex emissions.

Coke oven and rooting tar emissions contain relatively small amountsof nitroarenes (Lewtas. 1988), whereas diesel emissions containappreciable quantities of PAH as well as of nitroarenes. For quantitativerisk estimation of many complex emissions derived from combustion.the use of the potency factors presented in Table 5 appears to give themost realistic estimates. Pike and Henderson (1981) have derived arisk for liing cancer of about 1.OB-05 at a concentration of 1 ng/m^ ofbenzolalpyrene, using this compound as indicator substance for urbanair pollution.

G ERM. Inc. AU rights reserved.' 1-13

AR30WI5

PAHs

Table 5 - Relative tumor-initiating potency and unit riskestimates of vaibenzo(a)pyreneestimates of various emission extracts and of \

PAH cornpQttnd source Relative carcinogenic potency*

benzo(a)pyrene 1.0roofing-tar emission extract 0.004coke-oven emission extract 0,007diesel exhaust extracts ** 0.0045

* Based on induction of papillomas in mouse skin (ClementAssociates, 1988. Table I on page 1-3).

** Average of extracts of emissions from Oldsmobile and Nissan

Genotoxic effects and adverse effects on reproduction

Several members of the group have shown to be genotoxic in a numberof systems requiring metabolic activation. Benz[alanthracene,benzolalpyrene, and dibenz(a.cjanthracene are mutagenic toS.typhimurium, Drosophila. and to several mammalian cell types invitro; they induce sister chromatid exchanges as well as UDS.

Dimethylbenzanthracene and benzolalpyrene cause gonadal dysplasiaand reduced fertility in males as well as in female mice. Treatmentwith carcinogenic PAHs may induce destruction of primordial oocytes.Benzolalpyrene as well as some other PAHs have been shown to crossthe placenta in mammals. In mice, characterized by induciblearylhydroxylase. active metabolites formed from benzofalpyrene in themother may enter the fetus and cause fetal death or teratogeniceffects. 50-300 mg/kg given intraperitoneally on days 7 or 10 inducesresorptions and skeletal malformations (Shum et al.. 1979). 7,12-


AR30HI6

PAHs

dibenz|a]anthracene produced a high incidence of incomplete neuraltube closure and other defects In the fetuses in rats given an injectionof 25 mg/kg on day 8 or 13 (Currie et al., 1970).

F. Fhannacokinetics

The metabolism of PAHs is complex. The cytochrome P-450monooxygenase system In liver and other tissues catalyzes a variety ofoxidative reactions converting the aromatic compounds to epoxides.phenols, and C inones. Hydrolytic cleavage of epoxides generatedihydrodiols, thai can be further transformed to phenol dlols or to diolepoxides. In addition, phase 2 enzymes catalyze conjugative orsynthetic reactions between the reactive intermediates and smallmolecules of endogenous origin like glutathione and glucuronides. Thecarcinogenic activity of PAHs are linked to the metabolic formation ofreactive Intermediates (e.g. 7.8-diol-9,10-epoxIdes frombenzo(alpyrene) of certain pathways, where the end effect depends ona delicate balance between activating and inactivating reactions.Carcinogenic potency is often strongly dependent on species relatedmetabolic differences.

Metabolism of PAHs occur in a number of tissues like liver, bronchusepithelium, esophagus, kidney, colon, placenta and skin, wherecovalent binding of reactive metabolites to DNA occurs. Thus, suchadduct formation has been found for benzo[alpyrene for almost everytissue that has been examined regardless of species or route ofadministration.

References

Albert, RE., Lewtas. J., Nesnow. S.. Thorslund. T.W.. and Anderson, E.;Comparative potency method for cancer risk assessment: applicationto diesel particulate emissions. Risk Analysis 3(1983)101-117.

Clement Associates, Inc.; Comparative potency approach for estimatingthe cancer risk associated with exposure to mixtures of polycyclicaromatic hydrocarbons, Interim Final Report to the USEPA. April 1.1988.


PAHs

Crump. K.; An Improved procedure for low-dose carcinogenicity riskassessment from animal data, J. Env. Pathol. Toxicol. 5(1982)339-348.

Currie, A.R., Bird. C.C., Crawford. A.M., and Sims. P.; Embryopathiceffects of 7,12-dlmethylbenzIalanthracene and its hydroxymethylderivatives In the Sprague- Dawley rat. Nature. 226(1970)911-914.

Dean, J.H., Murray, M.J., and Ward. E.G. in Casarett and Doull'sToxicology. 3rd Ed.. Macmillan Publ. Co., N.Y.. 1986., pp.271-272.

IARC. International Agency for Research on Cancer; IARC Monographson the Evaluation of the Carcinogenic Risk of Chemicals to Humans -Certain Polycyclic Aromatic Hydrocarbons and HeterocyclicCompounds, Vol.3, Lyon, 1973.

IARC, International Agency for Research on Cancer; IARC Monographson the Evaluation of the Carcinogenic Risk of Chemicals to Humans -Polynuclear Aromatic Hydrocarbons. Vol. 32, Part 1, Lyon, 1983.

IARC, International Agency for Research on Cancer; IARC Monographson the Evaluation of the Carcinogenic Risk of Chemicals to Humans -Supplement 7, Lyon, 1987.

Lijinsky, W., and Shubik, P.; Benzolalpyrene and other polynuclearhydrocarbons in charcoal-broiled meat. Science 145(1964)53-55.

Nesnow, S.. Mouse skin tumors as a predictor of human lung cancerfor complex emissions: An overview. Proc. Dermal Cancer Symp.,Austin. Texas, Dec. 1-4. 1987.

Panclrov. R.J., and Brown, R.A.; Analytical methods for polynucleararomatic hydrocarbons in crude oils, heating oils and marine tissues.Proc. 1st Conf. Prevention and Control of Oil Pollution, Washington,D.C.. American Petroleum Institute. 1975, pp.103-113.

GERM. Inc. AU rights reserved. . 1 - 1 6

PAHS

Pike, M.C., and Henderson, B.. In " Polycyclic Hydrocarbons andCancer" (Gelboin,N.Y., 1981, p. 317.

t Cancer" (Gelboin, H., and Tso, P.O.P., Edts.) Vol.3, Academic Press,

Poirier, L.A.. and Weisburger, E.K.; Selection of carcinogens andrelated compounds, tested for mutagenic activity, J. Natl. Cancer Inst.62(1979)833-840.

Shum, S., Jensen, N.M., and Nebert, D.W.; The murine Ah locus: Inutero toxicity and teratogenesis associated with genetic differences inbenzolalpyrene metabolism. Teratology, 20(1979)365-376.

Thorslund, T.W., Brown, C.C., and Charnley, G.; Biologically motivatedcancer risk models. Risk Analysis. 7(1987)109-119.

Thyssen. J., Althoff, J., Kimmerle, G., and Mohr, U.; Inhalation studieswith benzolalpyrene in Syrian golden hamsters, J. Natl. Cancer Inst.66(1981)575-577.

USEPA; Ambient water quality criteria for polynuclear hydrocarbons.Washington D.C.. EPA 440/5-80-069. 1980.

USEPA; Health effects assessment for polycyclic aromatichydrocarbons (PAH). EPA 540/1-86-013.

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QraT*,

BR30ltU20

PCE

Tetrachloroethvlene

CASNo.: 127-18-4Synonyms: perchloroethylene, "perc," perclene.

PCE, ethylene tetrachloride


Chemical Formula: C2C14Form: colorless liquid, nonflammable.

chloroform-like, odor

Chemical Class: halogenated oleflnic organicMolecular Weight: 165.85

Boiling Point: 121.4CMelting Point: -19C

Specific Gravity: 1.626 @ 20CSolubility in Water: 150 mg/L @ 25C

Solubility in Organics: alcohol, ether, benzeneOrganic Carbon


Partition Coefficient: 2.6Vapor Pressure: 24 mm Hg @ SOCVapor Density: 5.834

Henry's Law Constant: 2.59E-02Bioconcentration Factor: 313




Clean \Vatcr ActAmbient Water Qualify Criteria (mg/L)Human Health


Aquatic Organisms (mg/L)*Fresh Water

Acute: 5.28Chronic: 0.84Marine


PCE

Acute: 10.2Chronic: 0.45 .

ReferencesSax and Lewis 1989. Verschueren 1983, The Merck Index 1983.SPHEM 1986, EPA 1986NA - Not Available, 'lowest effect levels


Volatilization from surface water is considered a significantenvironmental fate for tetrachloroethylene. Volatilization will alsooccur from soil, but at a slower rate than from water.Tetrachloroethylene will also leach Into ground water, as suggested byIts moderate solubility and organic carbon partition coefficient. Withsoils higher in organic carbon, the leaching might be less pronounceddue to Increased soil adsorption. There is some evidence thattetrachloroethylene .Is possibly metabolized by higher organisms(USEPA, 1980. p. 1).

IX Ecotoxlcology )

The 48- hour EC50 from Daphnia magna to tetrachloroethylene is 17.7mg/L; the midge is more resistant, with a 48-hour LCSO of 30.8 mg/L. -For the fathead minnow, a 96-hour LCSO of 18.4 mg/L has beenderived. The blueglll has a 96-hour LC50 of 12.9 mg/L. (USEPA.1980, p. B-l, B-2).

The fathead minnow shows a chronic value of .840 mg/L underembryo-larvae testing. Another LCSO value derived for this species is13.5 mg/L, which yields an acute-chronic ratio of 16. This ratioIndicates considerable cumulative chronic toxicity oftetrachloroethylene in aquatic systems. The acute-chronic ratio formysid shrimp is 23.

Concerning aquatic plant toxicity, no effect on chlorophyll a or cellnumbers of the fresh water alga Selenastrum capricornutum wasobserved with exposure concentrations as high as 816 mg/L (USEPA,1980, p. B3).


PCE

i Tetrachloroethylene does not bioconcentrate to any significant extent.^^ A bioconcentration factor of 49 has been derived from studies

involving 14C - labelled tetrachloroethylene.

In general, acute fresh water toxicity values for tetrachloroethylenerange from 4.8 mg/L to 30.8 mg/L. Of this range, the rainbow trout ismost sensitive; the midge is the least sensitive (USEPA. 1980, p. B-4).

E. Human Toxicology

Most information on the subchronic toxicity of tetrachloroethylene isbased on inhalation exposure.

Studies on the chronic oral noncarcinogenic toxicity of the compoundare limited; toxic nephropathy in rats and mice was observed at allcase levels, which ranged from 300 mg/kg/day to 949 mg/kg/day for78 weeks. The LOAEL (Lowest Observed Adverse Effects Level) forthese groups was 300 mg/kg/day for mice and 471 mg/kg/day for rats.

Human health effects that have resulted from chronic inhalation oftetrachloroethylene include respiratory tract irritation, nausea,headache, sleepiness, abdominal pain and constipation, as well ascirrhosis of the liver, hepatitis and nephritis. Acute effects aregenerally characterized by depression of the central nervous system.

No evidence of teratogenicity from the compound have been reported,but there are indicators of reproductive toxicity in the form of fetaldamage In experimental rodents. (USEPA, 1984, p. 3. 7-8).

Experimental data on carcinogenicity from oral exposure is limited toa bioassay in rodents, where an increase in hepatocellular carcinomaswas observed after oral administration for 78 weeks. Inhalationexposure produced no carcinogenic effects in one study (USEPA,1984. P 10-11).


AR30H23

PCS

Since tetrachloroethylene has demonstrated a limited range ofcarcinogenic effects, the compound is considered a potentialcarcinogen. Given the uncertainty In the data, however, no decisionhas been made on classifying tetrachloroethylene as B2 (probablehuman carcinogen; sufficient evidence of carcinogenicity in animalsbut insufficient evidence in humans) or C (possible humancarcinogen; limited evidence of carcinogenicity in animals. (I.R.I.S.,QI.A.5).

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AR30H25

1 . 2, 4-Trichlorobenzene

1 .2.4-Trichlorobenzene.

CASNo.: 120-82-1Synonyms; 1.2,4-TCB


I ,^

Chemical Formula:Form: colorless crystals melting at room

temperature to. a clear liquid, aromaticodor

Chemical Class: halogenated monocyclic aromaticMolecular Weight: 181.46

Boiling Point: 213CMelting Point: 17C

Specific Gravity: 1.574 © 10/4CSolubility in Water: 19 mg/L @ 22C

Solubility in Organics: benzene and other organicsOrganic Carbon


Partition Coefficient: 4.3Vapor Pressure: 0.29 mm HgVapor Density: 6.25

Henry's Law Constant: 2,3 IE-03Bioconcentration Factor: 2800






Aquatic Organisms (mg/L)


RR30UU26'

J. 2,4-Trtchloroben2ene

Fresh WaterAcute: NA

Chronic: NAMarine


ReferencesSax and Lewis 1989, Verschueren 1983, The Merck Index 1983,SPHEM 1986, EPA 1986NA- Not Available


The major environmental fate processes for 1,2,4-trichlorobenzeneare sorption. volatilization, and bioaccumulation. Although noquantitative sorption studies were found In the literature, thecalculated value of its KQC would indicate substantial. sorptioncapabilities for 1.2,4-trichlprobenzene. Volatilization occurs ratherrapidly from the water to the atmosphere, with the calculatedlaboratory half-life reported to be approximately 45 minutes. 1,2,4-Trtchlorobenzene has a high affinity for lipophillc materials, thus itbioaccumulates in the aquatic environment Insufficient evidence Isavailable to determine whether biomagniflcation, photolysis andhydrolysis of 1,2,4-trichlorbenzene in the environment are significantfate processes.It should be noted that trichlorobenzenes were used In transformercoolants along with PCBs. When these transformer coolant liquidshave contaminated groundwater or surface water, the cosolvationeffect of TCB has often increased PCS solubility, and effectivelyenhanced transport via these normally impervious media.

D. Ecotoxicology

Among the trichlorobenzenes. only 1.2,4-TCB has been studied for itsecotoxicology to aquatic life. Acute LC50 values are as follows:

GERM. Inc. AU rights reserved. 1 -2H

1,2,4-Trichlorobenzene

Species LCso fmg/1)

C j FreshwaterDaphnia magna 50.2Rainbow trout 1.5Fathead minnow '2.9

Salt water ,Mysid shrimp 0.5Sheepshead minnow 21.4

(Ref: EPA, 1985)Chronic toxicity to the sheepshead minnow occurred in the range of0.2-0.7 mg/1 1,2.4-TCB.Freshwater and salt water algae have also been tested for sensitivity to1.2,4-TCB. The EC50 values for toxicity to chlorophyll are 35 mg/1 forfreshwater algae and 9 mg/1 for salt water algae. Similar values areseen when-viability is assessed rather than chlorophyll (EPA, 1985)

E. Human Toxicology

Of the trichlorobenzenes, the 1.2,4- isomer is the most toxic for allspecies tested. 1,2,4-TCB Is not, however, genotoxic (carcinogenic,mutagenic or teratogenic). Although no reproductive effects have beennoted, at concentrations where It is toxic to rat dams, 1,2,4-TCB isalso toxic to their embyos (Kitchin and Ebron. 1983). Thisembyotoxic effect is most likely non-specific and indirect due toimpairment of maternal functions.Inhalation studies of 1.5-6 months duration with 1,2.4-TCB in rats.rabbits, dogs and monkeys have not revealed major Irreversible effects.In these studies, however, some transient effects to liver(hepatomegaly) and kidney (altered histopathology) were seen (Kocibaet al. 1981; Coate et al, 1982). Along with the altered kidneypathology, there was also porphyrinuria noted (Kociba et al, 1981).Mice exposed dermally to TCB showed bone marrow changes (Zub,1978). In additional studies of mice with dermally applied 1.2,4-TCBamyloidosis was seen to affect multiple organs and contribute tolethality (Yamamoto et al. 1982).As an inducer of mixed function oxidases, 1.2,4-TCB may affect themetabolism of many polycyclic compounds and, perhaps, alter the rate


1.2.4-THchtorobenzene

of formation from precarcinogens to ultimate carcinogens for suchcompounds as benzo(a)pyrene. ,

F. PharmacoJdnetics

The trichlorobenzenes. In general, have low water solubility and highlipid solubility. Therefore. 1.2,4-TCB is likely to diffuse through mostbiological membranes, including the surface of the lungs.gastrointestinal tract, and skin. Absorption of 1.2,4-trichlorobenzeneby humans Is indicated by poisonings resulting from Inhalation andingestion exposures, but quantitative studies in humans and animalsare lacking (USEPA 1985). One study In rats (Hawkins et al. 1980)observed greater than 90% absorption of a single dose (250 mg/kg) of1,4-DCB. Hawkins also noted that radiolabelled 1,4-DCB was rapidlydistributed, with the highest concentrations occurring in fat, liver,and lungs. Elimination of 1,4-DCB occurs within 5-6 days of exposure,although elimination from adipose tissue is slowest.

References

Coate. WJ.B.. W.H. Schoenfish, W.M. Busey and T.R. Lewis (1982)Chronic inhalation exposure of rats, rabbits and monkeys to 1.2,4-trichlorobenzene. NTIS PB82-227174.

Hawkins. D.R., L.F. Chasseand, R.N. Woodhouse, and D.G. Cresswell.(1980). The distribution, excretion, and biotransformation of p-dichloro (14C) benzene in rats after repeated inhalation oral, andsubcutaneous doses. Xenobiotica 10(s): 81195. (Reported in USEPA1985).

Kitchin, K.T. and M.T. Ebron (1983) Maternal hepatic and embryoniceffects of 1,2.4-trichlorobenzene in the rat. Environ. Res. 31, 362-373.Kociba. R.J., B.K.J. Leong and R.E. Hefner, Jr. (1981) Subchronictoxicity study of 1,2,4-trichlorobenzene In the rat, rabbit and beagledog. Drug Chem. Toxicol. 4. 229-249.


/1R30H29

1 , 2,4'Trichlorobenzene

U.S. Environmental Protection Agency (1980) Ambient water qualitycriteria for chlorinated benzenes. Office of Water Regulations andStandards, Washington, D.C. EPA 440/5-80-028.

U.S. Environmental Protection Agency (1985) Health assessmentdocument for chlorinated benzenes. Office of Health andEnvironmental Assessment, Washington, D.C. EPA/600/8-84/015F.

Yamamoto. H., H. Ohno, K. Nakamori, T. Okuyama, S. Imai and Y.Tsubura (1982) Chronic toxicity and carcinogenicity test of 1.2,4-trlchlorobenzene on mice by dermal painting. J. Nara. Med. Assn. 33.132-145.

Zub, M. (1978) Reactivity of the white blood cell system to the toxicaction of benzene and its derivatives. Acta Biol. Cracoviensla 21, 163-174.


AR30H30

TCE

Trichloroethene

CASNo.: 79-01-6Synonyms: trichloroethylene, ethylene trichloride,

TCE, acetylene trichloride


Chemical Formula: C2HC13Form: colorless liquid, chloroform odor

Chemical Class: halogenated oleflnic volatileMolecular Weight: 131.51

Boiling Point: 87CMelting Point: -73C

Specific Gravity: 1.4642 @ 20CSolubility in Water: 1.37 g/L ® 25C

Solubility in Organics: alcohol, ether, acetone, chloroformOrganic Carbon


Partition Coefficient: 2.293Vapor Pressure: 100 mm Hg ® 32CVapor Density: 4.544

Henry's Law Constant: 9. IE-03Bioconcentration Factor: 17 (bluegill)

a Regulations and Standards






Acute: 45Chronic: NAMarine

Acute: 2


TCE

Chronic: NA



The most important environmental fate for trichloroethylene insurface water is volatilization Into the atmosphere. Once it volatilizes.which it does rapidly, the compound quickly undergoes degradation inthe air to hydrochloric acid, dichloroacetyl chloride, phosgene, carbonmonoxide and hexachlorobutadiene. Volatilization may also occur fromthe soil, although more slowly than from surface water.

A second means of environmental transport will also occur by leachinginto ground water. This takes place for two reasons: 1) TCE isextremely soluble, and 2) TCE does not significantly bind to soil.

TCE blodegrades to first dichloroethylene (DCE) and subsequently tovinyl chloride under anaerobic conditions. As a potent carcinogenwith a much higher vapor pressure than TCE. vinyl chloride mayrepresent the greatest health risk by inhalation or ingestion ofcontaminated ground water at sites heavily contaminated by TCE.

TCE does not bioconcentrate to any significant extent; its half-life inanimal tissues is less than a day (Clement Assoc., 1985. USEPA. 1980.P. B-2).

IX Ecotoxicology

Photosynthetic algae undergo chlorosis (loss of chlorophyll) at 600 mgTCE/L. The LDlOO (40 hour) for the fresh water cladoceron Daphnia is600 mg/L; the no-effect level for Daphnta is 100 mg/L.

C ERM, Inc. AU rights reserved. 1-2

TCE

The 48-hour ECSO for Daphnia is 85.2 mg/L. For the bluegill(Lepomius macrochirus) the 96-hour LCSO value is 44.7 mg/L. Theguppy (PoecUia reticulata) showed a 7-day LCso of 55 mg/L. Thefathead minnow (Pimephales) shows a flow-through 96-hour LCso at40.7 mg/L (95% confidence limits: 31.4-71.8 mg/L). and a static 96-hour LCso of 66.8 mg/L (95% confidence limits: 59.6 - 74.7 mg/L).

Pimephales also has a 96-hour LCiO of 17.4 mg/L (95% confidencelimits: 9.0-22.9 mg/L) and a 96-hour LC90 of 95 mg/L (95%confidence limits: 59.0 - 419.9 mg/L). In addition, the same speciesshows a 24-hour EC 10 (effect Is manifested as loss of equilibrium) of15.2 mg/L (95% confidence limits: 10.0 - 13.2 mg/L) (Verschueren,1984, p. 1135).

In the mouse, a 30-minute LCSO occurs by inhalation exposure ofambient air at 49.000 ppm; a four-hour LCso occurs at 8450 ppm.

Inhalation exposure in the rabbit produced no effect after 473 hours at1200 ppm ambient air concentration. Six weeks of eight hours perday inhalation exposure at 730 ppm produced no adverse effects inthe ape, rabbit rat and guinea pig. Eye irritation in man begins at 160ppm (Verschueren, 1984, p. 1135).

Most toxicological data on TCE for aquatic organisms is based on acuteexposures. Because of the compound's low bioconcentration factor (17in the bluegill) and short half-life in tissue and in surface water, it isunlikely that chronic effects to aquatic organisms would occur.

Human Toxicology

Trichloroethylene is considered a probable human carcinogen, and ithas been shown to cause renal toxicity, hepatotoxicity, neurotoxicityand, at high levels of exposure, dermatotoxicity. No evidence ofreproductive toxicity or teratogenicity has been shown for -TCE(USEPA, 1984, p. 6).

Experimental data in laboratory rodents indicate that no observedeffects resulted from oral intake of TCE at doses as high as 17.9mg/kg/day for subchronic exposure. Base levels between 17.9 and


AR30H33

TCE

660.2 mg/kg/day by oral exposure resulted in decreased body weights,increased liver and kidney weights and increased urinary protein andketone. .

An increase in hepatocellular carcinomas was observed in laboratoryrodents in one two-year experiment with oral exposure. Oral exposureto 50 and 250 mg/kg for one year produced no effect in Sprague-Dawiey rates (USEPA, 1984, p. 3-5 and p. 14).

Most of the positive evidence for carcinogenicity for trichloroethylenehas come from experimental data on mice, but not all assays forcarcinogenicity have been conclusive. Several mouse studies haveshown an increase In renal adenocarcinomas by oral exposure andmalignant lymphomas by inhalation exposure (I.R.I.S..Trichloroethylene, II.A.3).

No evidence concerning an increased incidence of human cancer as aresult of exposure to TCE-affected water supplies has been discoveredin the available literature (USEPA, 1984. p. 8).Supportive evidence for the carcinogenicity of TCE includes positivebacterial mutagenicity assays and bacterial mitotic recombinationstudies (I.R.I.S. Trlchloroethylene, H.A.4.).

TCE has a low level of acute toxicity. since in several studies the acuteoral LD50 ranged from 6000-7000 mg/kg (Clement Assoc., 1987); the.compound has been assigned an EPA weight-of-evidence of B2:probable human carcinogen. This ranking Is based on positivecarcinogenic responses in two strains of mice by two routes ofexposure (USEPA, 1984, p. 21 22; I.R.I.S. - Trichloroethylene. ILA.1).

Historically, TCE has been used as an anesthetic because of its acutedepressive effects on the central nervous system. Its use for thispurpose has declined, however. Effects from long-term exposure toTCE are believed to result in part from metabolites of TCE, such astrichloroethanol (USEPA. 1980, p. C-13, C-14).

Occupational exposures to TCE result in insomnia, tremors, and otherneurologic and cardiac disorders. Hepatic and renal failure have been


TCS

observed following anesthetic use of the compound (USEPA, 1980, p.C-15).

Dermatological responses have been observed with industrialexposures to TCE, but no such response has been observed withexposures to dilute aqueous solutions. Uver failure in industrialsettings appears to be rare (USEPA, 1980, p. C-18).

TCE has been shown to be rapidly absorbed through the skin, butabsorption by this route is considered to be insignificant whencompared to industrial exposures by inhalation (USEPA, 1980. p. C-4).It is estimated that at least 80 percent of ingested TCE is systemicallyabsorbed (USEPA, 1980, p. C-5). The most serious exposures to TCEresult from inhalation exposure In an Industrial or occupational setting(USEPA, 1980. p. C-3).

P. Regulatory Implications

Until July 1989. EPA listed TCE as a class B2 (probable human)carcinogen upon the basis of its hepatocarcinogenesis In B6C3F1 mice.At that time the carcinogenic potencies by inhalation and Ingestionwere listed (IRIS. July 1989) as 1.3E-02 and 1. IE-02, respectively.which had been In place since March 1988. However, in July 1989,this B2 classification and accordant carcinogenic potency factors byingestion and inhalation were withdrawn by the Agency. As yet (March1990). there has been no new EPA decision regarding thecarcinogenic classification of TCE or, if finally regarded ascarcinogenic, what potencies would be assigned.Discussions of TCE within the Carcinogen Assessment Group (CAG) ofEPA prior to 1989 centered upon whether TCE would be classified asa class B2 (probable human) or C (possible human) carcinogen. Thedistinction regarding risk assessment is Important in that thecarcinogenic potencies of class C carcinogens are regarded tootentative for the calculation of potential carcinogenic risks to exposedpopulations (EPA's Risk Assessment Guidelines. 51FR33992, 1986).This borderline between B2 and C classifications by EPA was similarlymanifest by the International Agency for Research on Cancer (1ARC)regarding potential classification of TCE as either group 2B or 3carcinogen (roughly equivalent to EPA's class B2 or C, respectively).Although extensively studied, the data regarding TCE's potentialcarcinogenicity are weak. Commercial grade TCE Is weakly mutagenic


AR30H35

TCE

in short-term test systems/whereas purified TCE Is not. Hence, IfTCE is a carcinogen, it is not a carcinogenic initiator. Regardinganimal tests, three types of studies have been conducted which utilizedifferent rodent strains:

1) B6C3F1 mice (three studies),2) Han:NMRl mice3) Flscher 344 rats

B6C3F1 mice Two of these were ingestion studies and oneadministered TCE by inhalation. All three studies showed astatistically significant increase in hepatocellular carcinomasin both treated males and females. However, the oneinhalation study was deficient in design and would probablynot stand alone without the two gavage studies.

Han:NMRl mice This inhalation study allegedly showedincreased incidence of lymphomas In females treated withTCE. However, statistical interpretation was rendereddifficult in that 30 percent of the untreated controls alsodeveloped lymphoma.

( F i s c h e r 344 rats A borderline positive response was seen in this' ingestion study which was not statistically significant at the

95 percent confidence level.

Thus, out of all studies conducted on TCE, the only strain and speciesto show a statistically significant response is the B6C3F1 mouse, whichstrain Is obviously predisposed to hepatocarcinogenesis (seeChambers, P.L., D, Henschler and F.'Oesch leds] Mouse Liver Tumors:Relevance to Human Cancer Risk. Arch. Toxicology, Suppl. 10, pp. 1-295, 1986). According to EPA guidelines, this positive carcinogenicityin one species should relegate TCE to class C (possible humancarcinogen) with evidence too weak to perform quantitative riskassessment.Those nongenotoxtc carcinogens, such as TCE, which are positive onlyfor hepatocarcinogenesis in B6C3F1 mice are best considered aspromoters for Carcinogenesis. *Unlike carcinogenic Initiators (e.g.,benzofajpyrene), dose-response curves for promoters in B6C3F1 miceare frequently non-linear. In the TQE inhalation study, for example,the lifetime incidences of hepatocellular carcinomas In B6C3F1 micewere:


AR30H36

TCE

Inhalation Carcinogenesis of TCEIn Male B6C3F1 Mica .

DQSQ fpprrrt ____ HCC* ____ Number/Group ______ Cancer Frequency ^— 40 (control) 18 99 18.2

100 28 95 29.5300 31 100 31.0600 ________ 43 __________ 2Z ____________ 44.3

•Hepatocellular carcinomasIf TCE were a carcinogenic initiator, one would expect to see threetimes the number of tumors at 300 ppm as at 100 ppm, when in factthe percentage responses at these two doses are statisticallyindistinguishable. The best interpretation of these and other TCEresults in B6C3F1 mice is that the compound is increasing thefrequency of natural background Carcinogenesis in this predisposedstrain by promotion and that under a threshold dose of TCE there isno further promotor effect.<A ReferencesDobkin, A. and P. Byles (1963) Trichloroethylene anesthesia. Clin.Anesth. 1. 44-65.Chambers, P.L., D. Henschler and F. Oesch [edsl (1986) Mouse LiverTumors: Relevance to Human Cancer Risk. Arch. Toxicology, Suppl.10. pp. 1-295.EPA (1985) Health Assessment Document for Trichloroethylene.Office of Health and Environmental Assessment, Washington, D.C.EPA/600/8-82/006F.Flshbein, L. (1976) Industrial mutagens and potential mutagens, I.Halogenated aliphatic derivatives. Mut. Res. 32, 267-284.Gehring, P.J. (1968) Hepatotoxic potency of various chlorinatedhydrocarbon vapors relative to their narcotic and lethal potencies inmice. Toxicol. Appl. Pharmacol. 13, 287-298,EPA (1985) Health Assessment Document for Trichloroethylene.Office of Health and Environmental Assessment, Washington. DC.EPA/600/8-82/006F,Silver-man, A. P. and H. Williams (1975) Behavior of rats exposed totrichloroethylene vapors. Br. J. Ind. Med. 32, 308-315.Stewart, RD., H.C. Dodd, H.H. Gay and D.S. Eriey (1970) Experimentalhuman exposure to trichloroethylene. Arch. Envir. Hlth. 20, 64-71,Traiger. G.J. and G.L. Plaa (1974) Chlorinated hydrocarbon toxicity.Arch. Envir. Hlth. 28, 276-278.


Vanadium

Vanadium

CASNo.: '7440-62-2Synonyms: NA


Chemical Formula: V .Form: light gray or white lustrous powder;

fused hard lumps or body-centered cubiccrystals

Chemical Class: metalAtomic Weight: 50.94Boiling Point: 3,380°CMelting Point: 1917°C

Specific Gravity: 6.11 at 18.7°CSolubility In Water: insoluble

Solubility in Organics: NAOrganic Carbon


Partition Coefficient: NAVapor Pressure: NAVapor Density: NA .

Henry's Law Constant: NA "," " .Bioconcentration Factor: NA




*

Clean Water Act ^ 'Ambient Water Quality Criteria (mg/L)Human Health


Aquatic Organisms (mg/L)Freshwater

Acute: NA :Chronic: NAMarine


Vanadium




Sorption, complexation, and volatilization processes contribute to thefate of Vanadium In the environment. Transport in aqueous systems isdependent on chemical speciation, organic matter content and otherparameters such as pH and ligand concentration. Atmospherictransport can occur through volatilization from surface waters. Somebioaccumulation can occur in plant and animal species, althoughmammals appear unaffected.

IX Ecotoxicology

Vanadium occurs widely distributed in low concentrations in theearth's crust. It is present In various minerals, and certain fertilizer1products may account for a high deposition of the metal in agriculturalsoils. Vanadium is also present in fossil fuels in appreciable quantities.

Vanadium occurs In all plants, usually in concentrations of a few ppm(dry weight). Certain mushrooms, like the fly agaric (Amanftamuscarta), accumulate the metal to a high degree (Byrne and Ravnik,1976). Many marine organisms have a high capacity to accumulatevanadium, and the vanadocytes of tunicates (e.g. sea squirts) contain aspecific vanadium-containing respiratory pigment (hemovanadin).Holothurians, like sea cucumbers, also contain very high levels of themetal (1,200 ppm).

The acute toxicity of vanadium salts to aquatic organisms Is moderate;the LCso (7-11 days) for the rainbow trout (Salmo gairdneri} has beenreported to be the range 2-6 ppm depending on the experimentalconditions. Fry and eggs seem to be more resistant to the toxic actionthan larger fish (pentoxide). The 9 day LCso for vanadium (as sodiummetavanadate) for the worm Nereis diversicolor. mussels (Mytilus

G ERM. Inc. AU rights reserved. Ha

Vanadium

gaUoprovincialis), and for crabs (Carcinas maenas) were reported .to be, , 10, 35, and 65 ppm, respectively.

Vanadium may induce iron deficiency chlorosis in higher plants, andthe growth of species like flax, peas, soybeans, and cabbage isinhibited when present in nutrient solutions containing 0.5 ppm ofVOC12 (IPCS, 1988).

E. Human Toxicology

SUMMARY: Vanadium salts are poorly absorbed from the humangastro-intestinal tract but soluble vanadium compounds are taken upto a considerable extent after inhalation. Soluble pentavalent vanadiumcompounds. like the pentoxide, have a rather high acute as well aschronic toxicity. The activity of lower valency state compounds seemto be less. Exposure may elicit local as well as systemic effectsinvolving several organs and tissues. In man long-term exposure tovanadium-containing dust may cause bronchitis, pneumonia, oremphysema. In experimental animals systemic toxic effects have beenobserved involving liver, kidney, nervous system, cardiovascularsystem, and blood-forming organs, as well as a number of metabolicdisturbances. Systemic effects due to vanadium exposure are less welldocumented in man.

C• Acute and Chronic Toxicology

The acute toxicity of vanadium salts for experimental animals Isrelatively high, V5+-compounds being, as a rule, the most toxic.Intragastric LDso's for ammonium vanadate, vanadium trichloride andvanadium trioxide have been determined by Soviet investigators to bein the range 10-25 mg/kg in the mouse, and the inhalation LC50 forthe pentoxide In the rat is about 70 mg/m3. In acute vanadiumpoisoning, death Is preceded by the paralysis of hind legs, depressionof the respiratory center and convulsions (IPCS, 1988).

Basic metabolic effects of vanadium Include interference with thebiosyntheses of Coenzyme Ar cystelne, cholesterol and ofphospholipids. Thus, one of the most sensitive Indices of of vanadiumtoxicity in rodents appears to be a reduction of the cystine content ofthe hair. It Is therefore not surprising, that vanadium compounds mayinduce chronic systemic toxicity Involving several organs and tissues.


Vanadium

In a subchronic feeding study (Mountain et al., 1953). groups of fivemale WIstar rats were fed vanadium pentoxide at levels of 0. 25, or 50ppm for 35 days, after which the dietary concentrations wereincreased to 100 and 150 ppm and continued for 68 days. There wasa decrease in the amount of cysteine In the hair of the high-do'sed (50-150 ppm or about 2.5-7.5 mg/kg/day) rats. For these animals asignificant decrease in erythrocyte counts and hemoglobin levels werealso found. In a chronic study rats and dogs (no. not specified) wereexposed to dietary levels of 10 or 100 ppm vanadium (about 17.9 or179 ppm vanadium pentoxide) for 2.5 years (Stokinger et al., 1981).Growth rate, survival, and hair cysteine content seems to have beenthe only parameters recorded. The only significant change reportedwas a decrease in the amount of cysteine In the hair of animalsIngesting vanadium at the highest dose level.

Fatty changes with partial cell necrosis in the liver have been observedin rats and rabbits as a result of long-term exposure by inhalation tovanadium pentoxide, trioxide and chloride (Roshchin. 1963). Othereffects reported in these studies included a marked reduction Inalbumin/globulin ratio In the serum, and a drastic reduction In theliver tissue respiration. In selenium- and vitamin E-deficient rats.liver necrosis developed when the diet contained 50 ppm of vanadiumpentoxide (Whanger and Weswig, 1978).

When given intravenously, vanadate is a potent diuretic In rats. Thediuretic as well as natriuretic effects of vanadate are probably due toinhibition of Na+-K+-ATPase in the tubuli. thus inhibiting tubularreabsorption. Glomerular hyperemia and necrosis of convolutedtubules has been observed after parenteral administration of vanadiumcompounds in several animal species.

Vanadium pentoxide exerts an irritant action with respect themucous membranes of the respiratory system. Upon exposure ofrabbits for 1 hr/day for several months, chronic rhinitis, emphysema.as well as bronchopneumonia were seen, and in some cases alsopyelonephritis (Sjberg, 1950). In a subchronic inhalation study (IRIS,1988), mice and rats exposed to 1 to 3 mg/m3 vanadium pentoxide for3 months, 6 hours/day developed histopathologic changes in theirlungs and had a decrease in growth rate. Adverse effects were notdetected In either species similarly exposed at 0.1 to 0.4 mg/m3.

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Vanadium

At the beginning of this century, complex vanadium salts were used astherapeutic agents for diseases like tuberculosis and diabetes in dailydoses of 1 to 8 mg, and there is also experience from controlledhuman exposure of a more recent date. Thus, vanadium wasinvestlgatedduring the 50fs and 60's for its effect on serumcholesterol. Soluble vanadates were given orally at dosescorresponding to 0.1-0.4 mg V/kg for up to 6 weeks. The resultsreported concerning effects on the cholesterol levels have beenconflicting, but several patients complained of cramps and loosenedstools, and most developed a green discoloration of the tongue. Thelatter finding has been a common observation in workers exposed tovanadium, and is evidently due to the presence of colored vanadiumcomplexes.

Inhalation of vanadium pentoxide dust initially irritates the nose andthroat, causing coughing and shortness of breath. Short-terminhalation exposure to vanadium pentoxide at a concentration of about0.1 mg/m3 causes Irritation, and continuous exposure to even lowerlevels (0.01 - 0.04 mg/m3) may cause some Irritation, but has beenjudged not to Impair lung function. Chronic occupational exposure hasbeen be accompanied by general subjective symptoms such asweakness, ringing in the ears, nausea, vomiting, and headaches.Higher concentrations Induce bronchospasm and pulmonary edema.Chronic inhalation may cause bronchitis, emphysema, and bronchialpneumonia. Asthmatic reactions in conjunction with non-specificbronchial hyperreactivity have occasionally been reported in refineryworkers exposed to vanadium pentoxide dust. The clinical picture asto the appearance of symptoms of chronic systemic intoxication, e.g.hematological effects, is not clear (IPCS. 1988).

Carclngenic Activity

Vanadium and its compounds have not been adequately Investigatedwith respect to carcinogenic action, In 1985 the National ToxicologyProgram approved vanadium pentoxide for carcinogenicity testing.

Genotoxic Effects and Adverse Effects on Reproduction

The Information concerning the genotoxic properties of vanadiumcompounds is limited. Results for mutation assays in Salmonella andother short-term tests have been conflicting. One Chinese

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Vanadium

investigation reported a positive result in the mouse micronucleus testupon intraperitoneal, as well as subcutaneous injection, after inhalation(0.5-8 mg/m3), but not after oral administration (1.4-11.3 mg/kg).The same investigators obtained negative results In a dominant lethalassay In mice for the pentoxide given by subcutaneous injection (IPCS,1988).

Skeletal malformations have been induced in Syrian golden hamstersand in mice upon injections of vanadates during mid-gestation (Carltonet al., 1982; Wide, 1984). but results from studies employing otherroutes of exposure would be required In order to assess thesignificance of these findings.

Vanadium is considered an essential element for chickens and rats,but there is no certainty about man's dietary requirements.

F. Pharznacokinetics

Vanadium salts are poorly absorbed from the human gastrointestinaltract. Upon administration of the labeled pentoxide. uptake has beenfound to be in the range 2-3% of the administered dose. Althoughsome skin absorption may occur (Stoklnger. 1967). dermalpenetration evidently represents a minor exposure route. Pulmonaryabsorption of various vanadium compounds is dependent on particlesize and solubility. The international Commission on RadiationProtection (ICRP, 1960) estimated that about 25% of soluble vanadiumcompounds is absorbed.

Absorbed vanadium is transported in the serum mainly bound totransferrin. After administration to rats by various routes, the highestamounts of vanadium are detected in lung (after intratrachealinstillation), bone, kidney, liver and spleen. Brain levels of vanadiumwere found to be considerably lower than in the other organs.suggesting a blood-brain barrier for vanadium, and the metal ispreferentially accumulated in the placenta rather than in the fetusitself. Absorbed vanadium is mainly excreted via the urine. Biologicalhalf-times have not been determined with any higher degree ofaccuracy, but limited animal data Indicate that excretion may occur inat least two phases, the initial, fast phase having a half-time in theorder 20-100 hrs.


Vanadium

C

Discussion - Quantification of Risk

r The data base for deriving a reference dose for vanadium must beconsidered as very limited. Although several epidemiologic studieshave been conducted on factory workers exposed to vanadiumpentoxide for several years, the air concentration levels of vanadiumpentoxide were measured only at scattered intervals, and no

„ assessment of lowest observed effect levels (LOEL) can be made.

Of the subchronic and chronic animal studies available. EPA (IRIS,1988) has used the lower dose level (17.9 ppm vanadium pentoxide;0.89 mg/kg/day) reported by Stokinger et al. (1981) to derive an RfDof 0.009 mg/kg/day (0.62 mg/day for a 70-kg person) by applying anuncertainty factor of 100. Because of the lack of details in thereference study 'and the scarcity of data available on vanadiumpentoxide, EPA has assigned a low confidence to the derived RfD.

EL References

Byrne, A.R., and Ravnik, V. (1976): Trace element concentrations Inhigher fungi, Sci. Tot. Env. 6, 65-78.

Carlton, B.D., Beneke, M.B., and Fisher, G.L. (1982): Assessment of.the teratogenicity of ammonium vanadate using Syrian goldenhamsters. Environ. Res., 29(2), 256-262.

ICRP (1960): Report of Committee II on Permissible Dose for InternalRadiation (1959). Recommendations of the International Commissionon Radiological Protection. Oxford, P.ergamon Press (ICRP PublicationNo. 2).

IPCS, The International Programme on Chemical Safety (1988):Environmental Health Criteria No. 81, WHO. Geneva.

IRIS, The EPA Integrated Risk Information System (1988).

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Vanadium

Mountain, J.T.. Delker. L.L.. and Stokinger. H.F. (1953) Studies Invanadium toxicology. I. Reduction in the cystlne corAm. Med. Assoc. Arch. Ind. Hyg. Qcccup. Med., 8. 406.vanadium toxicology. I. Reduction in the cystine content of rat hair. \

Roschin, A.V. (1968): Vanadium and Its compounds, Moscow,Medidna Publishing House (in Russian).

Sjoberg. S.-G. (1950): Vanadium pentoxide dust: A clinical andexperimental investigation on its effect after inhalation. Acta Med.Scand., 138(Suppl. 238), 1-188.

Stokinger, H.E., Wagner. W.D., Mountain, J.T., Stockell, F.R.,Dobrogorski, O.J.. and Keenan, R.G. (1981) Unpublished results. InPatty's Industrial Hygiene and Toxicology (Clayton, G.D., and Clayton.F.E., Eds.), 3rd ed., Interscience,

U.S.EPA, Office of Water Regulations and Standards. (1986): Qualitycriteria for water 1986, Washington, D.C., EPA 440/5-856-001.

U.S.EPA (1988): Drinking Water Criteria Document for Manganese,Prepared by the Office of Health and Environmental Assessment.Environmental Criteria and Assessment Office, Cincinnati, OH for theOffice of Drinking Water, Washington, DC. ECAO-CIN-D008. (ExternalReview Draft).

Whanger, P.D. and Weswig. P.H. (1978). Nutr. Rpt. Int. 18, 421-427.

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AR30«t>*l»6

Zinc

Zinc



Chemical Formula: ZnForm: bluish-white, lustrous metal: distorted

hexagonal close-packed structure

Chemical Class: metalAtomic Weight: 65.38Boiling Point: 908°CMelting Point: 419.5°C

Specific Gravity: 7.14 at 25°CSolubility in Water: Insoluble: some salts are soluble

Solubility in Organics: acetic acid and alkaliOrganic Carbon

Partition Coefficient: "NA .Log Octanol/Water

Partition Coefficient: NAVapor Pressure: 1 mm at 487°CVapor Density: NA

Henry's Law Constant: NA .Bioconcentration Factor: 47


Safe Drinking Water ActMaximum Contaminant Level Goal(MCLG for Drinking Water (mg/t): NA




Aquatic Organisms (mg/L) .Freshwater ,Acute: 1.80E-01

Chronic: 4.70E-02Marine

Acute: 1.70E-01 *


AR30i»lfl»8

Zinc

Chronic: 5.80E-02

References ^Sax and Lewis 1989, Verschueren 1983, The Merck Index 1983,SPHEM 1986. EPA 1986NA - Not Available


The major environmental transport processes for zinc are sorption onto soils, sediments and /or suspended particles and bioaccumulation inorganisms. Bioconcentration factors ranging from 102 to 105 havebeen reported for zinc. No evidence of biodegradation of zinc in theenvironment Is noted In the literature. Minor environmentalsignificance is placed upon the role of volatilization, biodegradation.hydrolysis, photolysis and oxidation of zinc.

D. Ecotoxicology

Zinc, a naturally occurring element, is pervasive In all environmentalmedia. The literature contains an extensive array of data concerningzinc toxicity in aquatic species: however, the effects of zinc on theIntegrity and function of the higher levels of organization (e.g.,communities) lacks documentation.Zinc Is an essential nutrient for the biosynthesis of numerous enzymes;therefore, biological variability in homeostatic control among differentgenus, and species may account for differences in tolerance.Similar to other heavy metals, the toxicity of zinc is influenced by anumber of physical chemical parameters (e.g.. pH, alkalinity,competing ions and ligands, salinity, hardness) among which hardnessis the most Important.The LCso values for freshwater aquatic plants range from 0.0075 to750 mg/1. However, the lower values are reported for euglenoids andother flagellated forms which lack thick cell walls (enhancing zincmigration into the cell) and possess high metabolic rates, allowing forincreased uptake (Moore & Ramamoorthy 1984). Excluding thesensitivity of the above simple plants, the lowest sensitivity reportedwas growth inhibition in an alga (Selenastrum capricornutum) at 30ppb. A saltwater counterpart (Skeletonema costatum) demonstratedgrowth inhibition at 50 ppb (USEPA, 1980. 1980a).


CZinc

Acute effects were reported for freshwater invertebrates atconcentrations from 100 to 58.000 ug/1. The most sensitive specieswere cladocerans. Cairns, et al. (1976) as referenced in USEPA(1980a) indicated acute toxicity increased with increasingtemperature in the two cladocerans (Daphnia magna, Daphnia putexltested. Chronic values of 47 to 136 . ug/1 were reported for acladoceran (D, magna}. .In saltwater tests, larval molluscs were the most sensitive organismstested. LCsos of 166 ug/1 and 310 ug/1 were reported for the hard-shelled clam (Mercenaria mercenaria) and oyster (Crossostrea gigas),respectively. In adult tests, LCSO values range from 2,500 ug/1 for theblue mussel (Mytilus edilus planulates] to 7,700 ug/1 for the soft-shelled clam (Hya arenaria). The only chronic data available indicates231 ug/1 yielded a reduction in broodsize and number of spawns inmysid shrimp (Mysidopsis bahia) {USEPA 198Qa).The concentration range for acute effects in fish are similar to thelevels for invertebrates (90 to 40.900 ug/1 and 100 to 58,100 ug/1.respectively). Cutthroat trout, a salmonid species. (Salmo darfcO, wasthe most sensitive fish tested with an LCSO of 90 ppb (USEPA 1989.1980a).Goldfish (Carassius auratus) and bluegill (Lepomis macrochirus) aretypically more tolerant than salmonids. LCsos for rainbow trout(Salmo gairdneri] range from 2140 to 7,210 ug/1 at hardness levels of5 to 500 mg/1 (CaCOa). While LCsos for bluegills, (L. macrochirus)were 1930 to 23,000 ug/1 at 20 to 360 mg/1 CaCOa and 6.440 to103,000 ug/1 and 20 to 50 mg/1 CaCOa in goldfish (C. auratus) (USEPA1980, 1980a).Low levels of zinc may cause behavioral changes, growth inhibition,decreased fecundity, tissue hypcoda as well as mortality. Unlike acuteeffects, chronic responses do not appear to be as strongly influencedby hardness. At 5.6 ppb, rainbow trout (S. gairdneri) demonstrated anavoidance response. Reproductive output was affected in fatheadminnows (Pimephalas promelas) at 106 ug/1. Similar to other metals.necrosis of gill may occur In chronic exposures leading to tissuehypoxia and gradual asphyxiation.Limited data is available regarding the toxicity of zinc to saltwater fish.A 96 hour LCso 9f 60,000 ug/1 was reported for the mumichog(Funduius heteroclitis). In tests with anadromous fish, a greater zincresistance was reported for exposure In saltwater. In a chronic study.histopathologtcal damage was reported after 24 hours In 60.000 ug/1(USEPA 1980a).


AR30H50

Zinc

According to USEPA (1980b), aquatic systems potentially at risk tozinc include those which are located in regions with naturally elevatedzinc levels, prevailing low water hardness, and Indigenous speciessensitivity (e.g., salmonids).Perhaps the most interesting ecotoxicology of zinc is to plants, bothaquatic and terrestrial, where, unlike the animal kingdom, zincinhibits metalloenzymes. It has been reported that a single galvanizednail is capable of killing a full grown white oak tree, and similarsensitivities to zinc are seen throughout the terrestrial plant kingdom.Regeneration of new growth appears to be especially sensitive to zinc,apparently mediated by inhibition of rootlet formation In germinatingseedlings.In tests of zinc tolerance in saltwater plants, seven species wereaffected at concentrations ranging from 19 to 10,100 iig/1.Bioaccumulation data are available for seven species of saltwater algaeand five species of saltwater animals. Steady-state zincbioconcentration factors for these 12 species range from 3.7 to23.800.

Human Toxicology

The ecotoxicology of zinc is much more Interesting than its effect inhumans, where it is an essential mineral. Zinc is an essential elementprimarily because of its function in "zinc fingers," regions of proteinswhich fold into projected orientations only in the presence of zinc. Inman the average daily Intake of zinc is about 10-15 mg/day.

By the oral route or by inhalation the acute as well as chronic toxicityof inorganic zinc is extremely low. Zinc salts of strong mineral acidsare astringents and solid zinc chloride is corrosive to skin and mucousmembranes. Respirable particles of zinc oxide (or hot zinc fumes inpresence of oxygen) may cause metal fume fever. However, these areeffects of little interest in the current context.

Drinking acidic beverages made In galvanized containers have causedsigns of acute poisoning involving vomiting and diarrhea. Only by theparenteral routes do zinc salts have an appreciable toxicity.

In chronic animal experiments high concentrations in food ordrinking water are tolerated. Symptoms of toxicity after subchronic or

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AR30i»l»5l

Zinc

chronic exposure at dietary levels above 0.1 - 0.5 % Include anemia aswell as impaired growth and adverse effects on reproduction.

Testicular tumors have been induced by direct intratesticular injectionin rats, a finding of questionable significance for risk assessment inman. Zinc salts administered by other routes have not producedcarcinogenic effects (Furst, A., 1981). The antagonistic effect of zincin relieving certain effects of intoxication caused by agents likecadmium is well documented.

F. Discussion of Risk assessment

The present threshold limit value - time weighted average (TLV-TWA)for zinc oxide fumes is 5mg/m3. In the Superfund Public HealthEvaluation Manual (USEPA, 1986a) the listed oral AIS and AIC valuesfor zinc and zinc compounds are 0.21 mg/kg/day, whereas thecorresponding value for the Inhalation route is 0.1 mg/kg/day.

Pharmacokinetics

Many zinc salts are water soluble. Including organic salts such as zincglucuronate. Hence, excess zinc in the human system is easilyexcreted in urine. Zinc bound up in metalloproteins is quite stable.dependent upon the stability of the protein Itself. It may be that someregulatory "proteins are quite conformationally dependent upon zinc asregulatory co-factor.

H. References

Furst. A. (1981) Environ. Hlth. Perspect. 40. 83-91

Moore, J.W.. and S. Ramamoorthy (1984) Heavy Metals in NaturalWaters, Applied Monitoring and Impact Assessment. Springer-Verlag,NY.

U.S. EPA (1980) Ambient Water Quality Criteria for Zinc. EPA-440/5-80-079.


Zinc

U.S. EPA (1980a) Exposure and Risk Assessment for Zinc. EPA440/4-81-016.

U.S. EPA (1986a) Superfund Public Health Evaluation Manual.

U.S. EPA (1986b) Quality Criteria For Water 1986. EPA-440/5-86-001

U.S. EPA (1978) Metal Bioaccumulation in Fishes and AquaticInvertebrates - A Literature Review. EPA-600/3-78-103.


AR30l»l»5l»

APPENDIX ISUMMARY TABLES:

CALCULATION OF CARCINOGENIC RISK ANDNONCARCINOGENIC HAZARD INDICES

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9 aa BJM9 3JM ADULT!

LB ADULT 1

5 9M *4 OSgia

Tablal*CalerUaUo-i «f Cualae(«ala Rfek

Maximum Canal* Expoetwe F« SonVUlteB Dlek Lagoon*

Adult* CAf« 12-70 Twn)

Rente «f Cfcatatoal «f yai*M»» Ckroato Uo«t ProbabI* * Carelaogeal* "•**••<"•• Mo*t PmbablaDally iBtaktw Dally Intake Poteaey Pa«tM C*niBOf*aJ« Canioogeal*

Rbk

Denrnl Conlact chkwofcnn 1.07C-07 192E-08 6.10B-03 5.39B-10 1.471-10MehlorotthetM 1.50C-O8 3-22E-Ofl 1.10E-03 1.45C-O7 2.04E-08tetrMhloreethera . I.43E-O7 3.17E-08 5.10E-03 8.04C-00 IJ34E-OQWM2-«ttiylh«ynphth «« 5.S6C-06 3.676*06 1.40E-03 8.WK-06 3.10E-084.-4'-DDt S.73&OS X32E-06 3.40C41 1.61C-06 8.55E-07benofolpynm equivalent 1.30e<O7 S.20&08 1.13E+01 1.33C-06 4.95E-07twpMcntor epojrtd* 3.90C-09 1.42E-09 9. IOE*00 X94B-08 1.07E-08

3.64B-O7 1.82S-O7 1.75E+00 5.28C-07 2 5E-07

To«4l C«relaog«ai« Rick: 3.73B-04 1.4AC-04

IncldenUl IngnUon cMorafarm 2.25C-07 6.15E-06 6.106-03 1.14E-OQ 3.1 IE-10trtchloraethene 3.34E-OS 6.80E-Ofl 1.10B-03 3.0SE-07 6.19E-OStetnchlonwthnw 3.0 IE-07 6.67E-08 5.10E-03 1.37E-06 2.82E-09bl*2-<thylhexynphih*)«M L.26E-05 5.64E-00 I.40E-02 1.46E-07 6.S4E-084.4--DDC 1.2 IE-OS 4.90E-06 3.40E-OI 3.4OE-06 I.38E-06berao(ft)pyraM equivalent 2.94E-O7 I.10E-07 1.15E*01 18OE-06 1.04E-06hepuchlor epoxlde 8.22E-O9 3.00E-O9 9.10E*00 6.20E-08 2.26E-08anenle 7.67E-07 3.42E-07 1.75E+00 I.I IE-06 4.96E-07

T«Ul C«relao|«ate Rteb 7.S3E-04 3.07K-O*

Deer Meat IngecOon cMorafcrm 6.09C-13 1.67E-13 6.10E-03 3.O8E-14 8.42E-15 " ^trlehloroethem I.41C-O9 2.88&10 1.10E-03 I.29E-H 2.62E-13tetraehloraethene 1.62E-11 3.58E-13 S.10E-03 6.83E-13 1.5 IE-13bl 3-ethylhexyDphthatate 5.78E-O4 X56E-04 I.4OE-02 6.69E-06 2.99E-064,4'-DDE 1.36B-06 5. ME-07 3.40E-01 3.84B-07 1.56E-07beraoMpyrene equlvaknt 1.18E-O7 4.4 IE-08 I.I5E*Ol 1.12E-06 4.20E-07hef tachlor epoxlde 4.91E-13 1.79E-13 9.10E*00 3.70E-12 , 1.35E-12ancnle 2.56E-07 1.14E-07 1.75E*00 3.72E-07 1.66E-07

Total Carelnofeale Rlaki ».57C-06 3.73E-04

MAXIMUM ADULT (AC* 13-70 TEAM) CAJtCCIOGEHIC RISC TOR DERBUL CONTACT AND racmENTAL OVCX8TION OP SOILi 1.181-05MAXIMUM ADULT (ACC 13-70 TEARS) CARCINOCCTaC RISK FOR DEER MEAT IWGMTTON: t.STE'OC

MOOT PROBABLE ADULT (ACE 13-70 TEARS) CARCINOGENIC RISK FOR DERMAL CONTACT AND INCIDENTAL NCESTION OF SOILi 4.53E-00HOST PROBABLE ADULT CAGE 13*70 TZARS) CARCINOGENIC RISK FOR DEER HEAT CfCESTIONt 3.731-09

References:ATSDR Tox. ProAleafHIEM 1989IIEASTIRIS. December 1969 update

TaMo I-S CoatlauodCftleulatfoo of Carcinogenic Rick

Maximum Ckfoale Expoaurta For SodWUIlam Dlek Lafooaa

CUU *-I3 (A<e 6-13 T«a»)

Rent* tt Cfc*mleal of Maximum Cfcmtlc Mo«t ProbAbl* Carctno(«alo Maximum Me*t ProbabUExpoeitf* Conooia Dafflr latak** Daflf mtako Potency Factor Caieiaoftmlc Caiclaofaate

_ Img/kg/dar) (l/taeyfcg/aayl lUik Rbk

Dennal Contact ehlorofenn 8.3CE-07 1.74E-07 6.IOE-03 3.32E-10 9.08E-Utnchloroethene 9.46E-09 1.93E-OS 1.10E-03 8.9 IE-06 1.8 IE-06tetrachlOKMthene 8.33E-O7 1.99E-07 3.IOE-03 3.73E-09 9.25E-10bU(2-ethylh«yl)PhthaUtB 3.S7E-06 1.99E-05 1.4OE-02 4.2SE-06 19 IE-064.4'-DDE 3,4 IE-05 1.30E-05 3.40E-01 9.94E-07 4.04E-07bemofalpyrene tqutvaknt 8.3IE-07 3.10E-07 1.1SE«OI- 8.18G-07 3-06E-07twptachlor epoxlde 133E-O8 8.4SE-09 9.10E+OO 1.81E*08 6.62E-OQaraenM 3.17B-06 0.87E-07 1.79E*00 3.ME-0? 1.43E-07

le Rbki X39E-O6 »-»9C-07

Inetdenttl Inge.tlon ehlorofenn 1.16E-06 3. lTE-07 6.10E-03 8.07E-10 1.66E-10trichloroethenc 1.73E-04 3.51E-OS 1.10E-02 1.63E-07 X31E>08Utrachloroethene 1.56E<06 3.40E-07 S.10E-02 6.80E-O9 1.5 IE-09bU(2-cthylhexyl)phthalate 5.5 IE-05 2.91E-05 .1.40E-02 7.81E-O8 3.49E-084.4'-DOE 6.33E-09 2.S3E-OS 3.40E-01 1.8 IE-06 7.37E-07beraofalpyrenc equivalent 1.52E-06 S.66E-07 1.15C+01 1.50E-00 3.58E-07heptachhM-epoxlde 4.25E-08 1.S5E-08 ».IOE*00 3.3 IE-OS 1.2 IE-08anente 3.96E-06 1.77E-06 I.73EKW S.94E-07 X85E-07

Total Caremofealo Ri*fc 4.19E-O6 U4E-04

Deer Meat Ingestton chloroform 1.47E-U 4.02E-12 6.10E-O3 7.68E-IS 3.10E-15tnchlorMthene 3.43E-09 6.94E- 10 1. 10E-02 3.22E- 13 6.5SE- 13tetnchloroethene 3.90E- 1 1 8.65E* 13 5. 10E-02 1 .71E- 13 3. 78 E- 14bW(3-ethylhexyl)phthaUtt 1.30E-O3 6.23E-04 1.40E-02 1.67E*06 7.47C-074,4'-DDE 3.29E-OS 1.34E-06 3.40E-01 ' 9.6OE-08 3.90E-06bemo(a)pyrerM equivalent 2.85E-07 1.06E-07 l.I5E*Ol ' 2.8 IE-07 1.05E-0?hepUchlor epoxtde 1. 19E- 13 4.33E- 13 9. IOE+OO 9.25E- 13 3-37E- 13arwnlc 8.19E-07 2.76E-07 1.75E+00 8.28E-08 4. HE-06

Total CaremOfeaie Ri»fc 2.14E-06 9.33£-07

MAXIMUM CHILD «-13 (ACE 6-13 TEARS) CARCINOGENIC RISK FOR DERMAL CONTACT AND INCIDENTAL DIGESTION OF SOIL: 6.48E-06MAXIMUM CHILD 6-12 (AGE 6-12 TZARS) CARCINOGENIC RISK FOR DEER MEAT DfCESTION: 3.14E-06

MOST PROBABLE CHILD 6-13 (ACE 6-13 TEARS) CARCINOGENIC RISK FOR DERMAL CONTACT AND INCIDENTAL INGESTION OP SOIL; 3.S4E-06MOST PROBABLE CHILD 6-13 [ACE 6-13 TZARS) CARCINOGENIC RISK FOR DEER MEAT INCESTION: 9.32£-07

Reference*:ATSDR Tbx. ProfilesHHEM 1989HEASTIRIS. December 1969 update

Table I-S Continue*:Calculation of Carcinogen!* Rl«k

Maximum Chronle Expocurti For SonWQHam Dlek Lagoons

Child 3-0 CAg« 2-6 Tears)

Root* of Cbemloal of Mailmum Chrenle Moat Probable Careinogeaie "•»<"••"• Hoot ProbableaUpaaufe Concern DaUj Intake* DaHy Intake Potaney Factor Carelnogenle ' Carcinogenic

___ _____•_______(mg/fcg/oay) (mc/kg/day) (l/mg/kg/day| Risk________ Rl»k

Dermal Contact chloroform 3-SS£-07 9.30E-08 * 6.10E-03 1.25E-10 3.42E-11trtchloraetheM 5.33E-OS 1.03E-05 I.10E-02 3.3SK-08 6.81E-C9tctmdiloroetherw 4.6 IE-07 1.06E-07 S.10E-02 1.40C-09 3.10E-10bM3-ethylhexyQphthaJau 2.0 IE-OS 8.99E-08 1.40E-02 1.61E-00 7.19E-094.4--DDE 1.93E-05 7.6 IE-06 3.40s>01 3.74B-07 1.52E-07benao(«)pyreiw oqulvmtent 4.S3E-07 1.7SE-07 1.15E*O1 3.08E-07 I.15E-07heptachiorepoxid* 1.3 IE-06 4.79E-09 9.10E+OO 6.82E-09 X49E-09anente 1 2E-06 S.45E-07 1.73E*OO 1.22E-07 5.45E-08

Total cuebaogmla ttlak: 8.63E47 3.38E-07

Incidental Ingeatton ehJorofiirm 1.96E-O8 S.37E-07 6.10E-03 6.85E-10 1.87E-10trtchloraetheM 2.92E-04 5.94E-05 I.IOE-02 1.84E-07 3.73E-08tetnehloroetneM 2.63E-06 S.S3E-07 S. IDE-02 7.68E-00 1.TOE-09bMS thylhexynphthalate 1.10E-04 4.93E-OS 1.4OE-02 8.8 IE-08 3.94E-084.4--DDE 1.05B-04 4.28E-05 3.40E-OI 2.05E-06 &32E-07benxo(a)pyreM equivalent 2.57E-06 9.58E-07 1.15E*01 1.69E-06 6.30E-07heptachlor epoxlde 7.19E-08 2.62E-08 9.10E+00 3.74E-08 1.36E-08anente 6.71E-O6 2.99E-O6 l.TSE OO 8.7 IE-07 X99C-07

Total C*rcfnofrale Rlab 4.72E-O6 1.4SE-06

Deer Meat Ingestion chloroform 1.33E-11 3.64E-12 6.10E-03 4.S4E-1S 1.27E-15trtchloroethene 3.10C-09 6.29E-IO 1.10E-O2 1.9SC-13 3.95E-13tetrachloroethene 3.54E-11 7.84E-12 5.10E-02 1.03E-13 X2SE-14 , /'bla(2-«thylhexyl)phthalate 1.26E-03 . 5.64E-04 1.40E-02 1.0 IE-OS 4.5 IE-07 ~ ^4.4--DDE 2.99E-06 1.2 IE-06 3.40E-OI 5.80E-08 2.36E-08betuofalpymM equivalent 3.58E-07 9.65E-06 1.15E*O1 1.70E-07 &34E-08heptachlor epexlde 1.07E-12 3.92E-13 9. lOEÔO S.59E-13 Z04E-13arsenic 5.6 IE-07 2.50E-07 1.75E*OO 5.S1E-08 2.SOE-08

Total Carcinogenic Rlak: 1.29&V06 S.63E-07

MAXIMUM CHILD 2-6 (ACE 34 TIARflJ CAXCZNOG£NIC RISK TOR DERMAL CONTACT AND INCIDENTAL INCESTXON OF SOIL; S.S6E-06MAXIMVU CHtLD 3-6 (ACS 3-« TZARB) CARCINOGENIC RISK FOR DEER UXAT IMGESTION: 1.28E-06

PROBABIX CHILD 3-6 (ACS 3-4 TZARS) CARCINOGENIC RISK FOR DEHMAL CONTACT AND INCIDENTAL mCBBTION OF SOIL: 3.19E-06MOST PROBABLE rrTfT.T) 3-« (AGE 3-6 TEARS) CARCINOGENIC RISK FOR DEER MZAT INGESTION: S.63E-07

References:ATSDR Tox. ProfilestlHEM 1969tlEASTIRIS, December 1989 update

BMttftuw|ial0 Buvd tadie**Canal* xxpnun* t» Sail

AdulU

Dcnml Contact etdorafam 1.07B-07 X93B-OS l.OOE-03 1.07E-OS 3J3E-OSl»«ehlo«wtb«nt M3B-07 XlTt-Ot 1,008-03 1.43C-OB 3.1TE-M•UonbmMiw l.WC-07 3.OOE-OS 100E-03 *.33B-OS l.SOE-OSk&4-aichlMab*iu«w 4.43E-OS 9.34 E-07 3.00C-O3 8.3 IB-04 4.S3B-O8aa»hUMbM UOE4S t.OSB-0* 4.00C-O3 I.3OC-03 S.BU-04

C74S-07 U0E-07 S.70C-03 L1M-04 XttC-05&MC-07 MIX-OS 8.70B43 a.t3E-08 1J6C-OS

taM3 ttiyftayDphtl»ku 6M&-06 3.67E-OS iOOtXW 3.t«-O4 IJ4E-04*.4'-DOC &73£-M aj2£-0e 9.00B44 1. MI-03 44BE-03•anaohuMiM 1MC47 •.UB-OS S.TOB43 4.58B-06 1.0ft OB•uomn Z46C-07 <43B-OS 6.70B-03 S.O»-Oa 1.1 IE-OB•Khnom I.04B47 XSTt-W i-TOC W LOB-OS 4J1B-OBa*puchlM-«»arida UOS-09 U3E-0* 1JOB-OS 3.00C-O4 1.10B-04

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MOST PBOBAUB ADULT BAZABD INDEX TO*. DCXMAL CONTACT AMD INCIDEWTAt INOIST1ON Of MIL: 1.B3BXMMOST PVOBABLB ADUtT BAZARD INDEX FOR DUB MEAT INCUTTOffi S.T7B-03

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1.08E-O5 X14B-08 4.00B-O3 XSSB-03 9.38E-04I.3SE-OS 3.0BE-07 5.TOE-03 X43E-04 S.3SE-OSS.93E-07 l.SSE-OT 5.TOE-O3 1.3IE-M 3.3OE-OS

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5J3B-07 i:38E-OT 9.TOE-03 9.34E-OB X30E-OSSJ6B-OT I.30E-07 5.TOE-03 1.03E-O4 X3SB OSXI3B-O7 S.STE-OS S.70B-O3 3.74B-OS 9.34B-OS

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MAXIMUM CSILD S-ll BABABO INDBX FOB OCKMAL CONTACT AND mClDBNTAt D»GMTJON OP SOILl X87S-01ATSOR To*. PrafllM MAXIMUM CHEO a. 13 HAZARD INDEX FOB DESK MEAT DIOBSTIONi S.49B-OIKHEM 19M MOSTFIIOBABtB CHILD «-13 HAZARD MDBX FOB DERMAL CONTACT AND INCIDENTAL, WCMTtON OF SOILi 1.04B-01HEAST HOST PRORARLS CHILD S-13 BAZARD DTDEX FOB DEER MBAT tNCSSTlOH OFi 8.1 IE -02IMS. Deeembtr 19S9 updau

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Refcrenca: MAXIMUM CBSJ) 3-6 BA2ARD INDEX FOR DERMAL CONTACT AWD INCIDENTAL BtOtaTIOff OF tOJLi ».7IB-01AT30R Tw. Pmflb» MAXIMUM CHILD 34 BAZARD INDEX FOR DBBR MBAT WeBSTlON: 8. IB-01HHRM 19W MOST PROBARLB CHILD «•• HAZARD INDEX FOB DERMAL CONTACT AND INCfflENTAL tNOESTION OF SOB,: (JaS-OlHEAST HOST PROBABLB CHILD 34 BAZARD INDEX FOR DBBR MBAT INGB8TION OP: 8.36B-03IRIS. December 1969 update

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Table 1-6Calculation of Carclno(*ale Xak

Maximum Chroole ExpoMirea For Air V JVOUarn Dick LafOOB* ~~

Atfulta (If admum Expoved Individual)

Route of CfcoauaileC Uaximam QroeJe Hoot Probable Cantoofeale . Maximum Moat ProbableCeaeem Dafljr tatafcae Oaflr Intake . *ot«o«r P«eter Carolaegeale CaNlaogeale

Rbk

VolaUltaatton ehwracbrm 8-9 IE- 13 6.9 IB- 13 B.IOC*03 5.96E-14 5.96E-14tj tehlerocthaiii 6-S6C-00 6.66&OB B.10E-03 5.17C-IO S.ITC-IOtrtchlorovthnie 3.80K-05 3.80C-09 1.70E-O3 5.35£ 7 5.3SE-07bcnwfw J.41E-08 2.4 IE-00 2.00E-O3 S.78E- 1 1 5.78E- 1 1tetrachloroethem 4.83E-06 4.83E-O6 3.308-O3 1.33E-10 1.328-10

Total CanlaogMle lUalo 5JMB-OT SJ6B-O7

Inhakdon of chtoromnn 4.23E-00 1.15E-09 B.IOE-03 X84C-tO 7.75E-1 1FugadveDuat Mchloroethene 6.29E-O7 1.28E-07 1. TOE-03 8.8SE-09 I. SOB-09

letrachlorTMthme 5.66E-O8 1.26E-09 3.30E-03 1.5SE-11 3.44E-12btaf3-«thy(he nphthalate 2.37E-07 1.06E-07 1.40E-02 2.73E-08 1.33E-094.4--DOE 2.37E-O7 9.20E-08 3.40E-01 6.38C-08 2-59E-08beniofalpyrene equtvatent 5-5IE-O9 2.06E-09 1.15E*O1 5.25E-08 1.96E-06heptachlor epoxtde 1.55E- 10 5.60E- 1 1 9. lOE+00 1. 17E-0« 4.34E- 10aracnte 1-44E-O8 6.43E-09 5.00E+01 5.96E-07 3.66E-07chramhim 3.60E-O7 B.46E-06 4.IOB«01 1.23E-OS

Total Canlao|eale Rwkt 1.30B-OS 3.53B-06

KAZDIinf ADULT -CARCmOCBNIC RISE FOB Affl: 1.33B-031I06T PROBASLt ADULT CARCDfOGBMC RIB81 POM AQL- 4.06B-OB

Refercncea:ATSORToK, ProflleaimEM 1969HEASTIRIS. December 1989 update

The

Orma*

Table 1-9 Continued4ril-f*Tht'*ii ef Carelnoganle Xbk

•taxtanam Ckranie Bxpoauroa Per Air1 Wmiam Olek Laf oooa

CUd 6-13 (Haxtauoi BxpOMd XadfrfduaO

Boot* ef Cbemleal *f Maximum Ckrenle Ha*C Probable Carelno enie Maximum MoaC Probable•xpomue Ceaeem Daflr wtaltaa • OaB> atake Poteney Paetor Careawfenle Canloofanle

' f c n g / k g / d a y )

Volatlltzatlon ehkmferm - 1.19E-13 I.19C-12 t.tOE-03 S.35B-15 8.25E-151.3-dfchloraethane 9.14E-OQ 9.14E-09 9.10E-03 7.13E-11 7.13E-11MehtoroetlMiM S.06E-OS S.06E-OS 1.7DE-O2 7.36E-06 7J6E-08bciMnw 3.21E-00 3.aiE-OC 3.90E-03 7.97E-13 7.87E-12atraehloraetheM 6.43E-06 6-43E-08 3.30E<03 I.83E-I1 1.82E-11

Total CaremefenJe Rlakt 7 8£VO6 7J9B-0*

tahaJadonof difcm»form 8.63E-09 1.54E-09 8.10E-03 3.9 IE-II 1UJ7E-UPugadveDuat trlehloroethene 8-38E-07 1.TOE-07 1.TOE-02 1.33E-09 2.48E-10

tetnchloreetherM 7.54E-09 1.68E-09 3.30E-03 2.13E-13 4.74E-13bW2-ethyJhexyl)phthalate 3.16E-O7 1.4 IE-07 1.40E-03 a79E-lO 1.09E-104,4'-DDE 3.02E-07 1.33E-07 3.40E-01 8.80B-09 3.57E-08bencofalpyrene equivalent 7.3SE-09 2.74E-O9 1.1SE+OI 7.24E-09 2.7IE-09heptachlor tpoxlde 2.06E-IO 7.SOE-I1 9.IOE>00 I.61E-10 5.8SE-I1araenlc I.93E-06 8.37E-09 5.CWE+01 , 8.34E-06 3-67E-08Chromium 4.80 E-07 1.26E-07 4.10E+01 J.69E-06 4.43E-Q7

Total Carelaofeale ftkki 1.79B-O6 4.66X-07

MAXIllUMCHaO6-t3CAllCINOOBKIC JU3KFORAIRJ 1.66B-06HO6T PROBABLB CHILO 6*12 CARdNOOZNIC RUB; POR AtRi 8.60B-O7

References:ATSDR Tox. ProniesHHEM 1989HEASTIRIS. December 1989 update

Table 1-9 CootmueeCalculation *f Caremogeale Rak

Maximum Ckrenle Bxpoaurea For Air i /Vffllam Dlak Lafoona —'

CaOd 3-6 (Maximum Expoaod IndlvtduaQ

Ro«U ef Cbeaaleal of Maximum Cfcroole Moot Probable Canlnofanle Maximum Moat Probablefayoaeae Ceaeem . Deflpmtakee . Dafly Intake Peteney Paetec Carelaogeule Canmogenle

H/t«<Ag/-laTl_____Rtofc_______ Kkfc

VolaUUcatwn chlorofcnn 1.17C-13* 1.17E-13 8.10E-03 5.42E-19 5.42E-ISU-dlchlonxrtham 9.00E-O9 9.00E-09 9.10E-03 4.68E-U 4.88E-11trlehloraethem 4.99B-OS 4.99E-08 1. TOE-03 4.8SE-O8 4.S5E-08beimme 3.16E-O9 3.16E-09 Z90&%03 5.23E-12 S.23C-12tetnehtoraethene 6.34E-06 8.34E-06 3.30E-03 1.306-1 1 1.30E-I1

Total Caremogenla Rlak) 4.MB-O6 4.8Sa OB

Inhaladon of chlorofcnn 5.55E-O9 1.52E-09 8.10E-03 X57E-11 7.01 E-12FugaOveDuet trfchloroethene 8.25E-07 1.66E-07 1.TOE-03 8.0 IE-10 1.63E-10

tetrachloroethem 7.43E-O9 1.65E-OQ 3.30E-03 1.40E-12 3.1 IE-13ble(3-ethylheicyl)phthalau 3.1 IE-07 1.39E-07 1.40E-O2 149E-10 1.11E-104.4'-DDE 2.97E-07 1.2 IE-07 3.40E-01 S.78E-09 2.35E-09benao(a)pyrene equivalent 7.34B-09 1 TOE-09 1.15E+01 4.76E-09 1.7BE-09heptachlor epoxtde 3.03B-10 7.39E-U 9.10E*00 LOSE* 10 3-S4E-11anenle 1.89E-O6 8.44E-09 3.00E+OI S.4IE-O6 • 2.4 IE-08ehromhira 4.73D-O7 1.34E-07 4.10E+OI 1.11E-O6 3J1E-07

Total Caretoofeale Rakt 1.17K-O6 3.16B-07

MAXIMUM* CHILD 3-6 CARCIWOCBHIC RISK POR ADt: 1.23B-06MOBT PROBABLE CHILD 2-6 CARCZNOGBHIC RISK POR AIR: 3.68C-07

Reference*ATSDR Tox. PraniceiniEM 1989HEASTIRIS. December 1989 update

The

Onxa*

f••!• Buu4 tatfaMIfaaam Cbrealc BKBMVM T« Air

VUBwa Die* U|**uMulU (Miri-", BrpoM

•*•"*• C«a«™ owly Mak..

IJ-dkbbmmbnw U IB-08 I JIB-08 tOOE-03 B.SaB-07 8J3B-07•bJonfenn U1B-U 8.9 IS- 13 l.OOE-03 B.I1E-U IJ1E-113-btttaiwm 19 IB-07 U IB-07 S.OOC-O3 S.83B-00 SJ3C-MUttKU*ra«hnw 4J3B-08 4J3E-OB I.OOB-O3 4.83B-O6 4J3B-O6akMM l.Oae-08 LOBE-08 XOOB-OI W IB-06 W IB-08•alenbratM U1SHM ' 13IB-08 LOOS-03 L1BE-06 l.leB-08

8J7B-08 • 8J7B-08 1.006-O1 8J7E-07 8J7B-07U1B-07 1 JIB-07 XOOB-OI 6.S4B-07 63<E-07U86B-08 t.ME-08 a.OOE«00 8.9Qg-O7 ^ •.•06-07

Baiat UHV-O6

of ehatMbrm 4J3t08 1.18E-OB l.OOB-03 4.33S-07 1.15B-07IMC MVMMMMthMtt S46B-OB l BE-00 LOOS-03 S.88B-07 1 .98E-O7

•UMftbMHiM 640B-08 1.40B-OB a.OOB-02 3.30B-07 T.18E-08LX4-tMMwobm«M L7SE-07 3.86E>08 ZOOB-03 8.70B-06 1.83B-06aaphthalHM 106E-07 4.14E-08 4.00B-O1 8.1SB-07 t .048-07PbmaathnM X6SB-08 U IB-08 9.70BXU 4.70B-06 L04B-O8

LMB-08 3A4B-08 S.70C-03 138E-O8 8J3E-07Mi(3-«tiylh«yDphthaku X371-O7 1.08E-07 . X 006-02 1. 18B-08 5.30E-084.4--OOE &37E-07 .- 8 DE-08 8.00B-04 4.S3B-04 1.84C-04

I.03E-08 X43B-08 S.70S-03 I.80C-O6 4J7E-071.19B-08 U1B-08 S.70IC 03 I.98B-0> 4.4 IE-074.1IB-O8 I.03B-00 8.70B-03 7.33B-O7 1.T8E-07| ME- 10 9.83B- 1 1 l.ME-OS U19E-O5 4.33E-08

Z4-dkhlonpheiMt •.77B-09 X30E-09 O.OOE-03 3.36B-Oe T.34C-07•nmu M4B-08 8 36-08 l.OOE-03 1.44B-O5 8.43E-06bartum 8.81S-O7* X 171-07 I.OOB-04 8.8 IB-03 2.17E-03«hw«Uum 3.80B-07 - 8.48E-08 9.00E-03 7.90E-09 1.88E-OSmnawMM I.80E-IO 8.80 £• 08 3.00E-O4 5.506-07 2J7E-04*v<aaUum 110B-08 1.44B-OB 7.00E-O3 3.08B-06 a.OOB-08««« XaiB-07 8.74E-08 XOOE-OI 1.30C-06 __ 4.3TS-07

T»U1 Baauai 741B-OS 8.83K-09

HMOUUU ADULT BAZABO OIDBX FOB AOL- T.8SE-03MOOT PBOBABUI ADULT HAZARD IKPCX FOB AOf *.84B-oa

ATSDR Tax. Profile.HHEM 1989HEASTIKS. December 1089 update

The

Oxoup,

Madaum Cbr*ate BBMMBM T» AirwutlMa Dtek U|*«w

Chad 8*19 tMHiaoa BOM* laaMautl)

C O*Uy alafeM Drily lataJw BTO Xuv4

Vataalauttn L3-dkhlotMdMm X54E-08 X54B-06 XOOE-03 1.37S-O6 1J7E-08chbmfcrm * 1.198-13 1.19B-L2 l.OOB-03 1.19E-10 1.196-103-ButtfBM 3.88B-07 3.WB-O7 S.OOS-O3 7.77B-08 7.771-06

C43S-O6 . 6X3B-OB LOOS-09 6.43S-O6 6.436-06I.36B-0* IJ6B-08 3.00B41 4.54B-08 4J4E-083.08B-08 X08B-O8 XOOE-O3 U4B-06 I .MS-08l.l3B-Ot 1.13B-07 l.OOB-Ol 1.13B-08 ' 1.12E-061.74B-07 1 .748-07 XOOS-01 8.73B-07 8.73B-07X84B-06 X64B-08 XOOB*00 t.32B-06 1J3C-08

TMal Baauai 2.40B-O8 X49B-O8

5.63B-O* 1J4B-08 I.OOOO2 5.83B-O7 IJ4E-O77A4E-0* 1.68S-09 LOOBH18 7.S4E-07 1.88B-07

•hluiuhiiiiini 8.79B-0* 1 JIB-09 XOOB-03 4.40B-O7 9.54 C- 06X43B47 4J7S-08 XOOB-03 1.17E-O8 3.44S-06X74B-07 SJ3B-08 4.00B-01 6.a0S-O7 1.38E-073J7B-0* 7.86B-08 &70B-Oa 8.386-06 1.38E-08

(hionathMM 1.79B-06 4 .726-09 9.70B-03 3.13B-06 8.38E-07baO-ethrlheqrllphthateH 3.16E-O7 t .4 IE-07 XOOB-03 1.S8B-06 7.08E-064.4*-OOB X03E-07 1.33B-07 5.00B-04 6.04S-04 3.45B-04

1J7C-08 3JMS-08 5. TOE-03 X40S-08 5.686-07UIB-O8 3.33E-09 5. TOE-03 X64B-06 5.67B-07

HWhraeuM 9.48B-09 1.36E-09 8.7OE-03 8.62B-07 3.38E-07tMpMebtercpomd* X06E-IO T.SOE-U 1.3OE-O9 1. 361-06 5.77E-06X4-dtohl»mphmol 1JOB-O8 2.948-09 3.00E-O3 4.34 E-06 9. TIE-07•nettle 1.92B-08 8J7B-09 I.OOE-O3 1.92B-06 6.57E-06bartiu* 8J IB-07 X88B-07 l.OOB-04 9.3 IE-03 2.89E-O3

4.8OB-OT IJ6C-OT S.OOe-03 O.S0E-06 3J3E-06X30B-IO 9.068-08 3.00B-O4 T.32E-O7 3.028-04

-MMdtum X88B-08 1.92B-08 7.00E-03 4.13B-O8 X 758- 06MM 3.478-07 1.166-07 XOOB-OI 1.74E-06 S.82BJI7

TMalKmmrai 1.00B-O9 3,5OC-03

MAXIMUM CHILD 6-13 HAZABD INDEX FOB ADU 1.00B-O2 V J<U>-A* ^ ÛOer HUXUBLB CBtLO 6-13 BAZABD INDEX FOB AIBl

ReferenceATSDR Tax.HHEM I960HEASTIRIS. December 1989 upd*u

The

AR301A82

Imak MS

aa Cbroate BoMmv** T« AllVtDUa DUk L*|««u

CalU 9-6 OUBAoa, B«P»M* ladMduftO

tod..

VcfeaittaCkm 1.3-dtehleroeditm XSOB-08 XSOE-08 XOOE-03 L35B-06 1. 238-06•tdorafcrm L17B-13 1.17B-13 LOOS-03 LITE- 10 1-lTE-tO3-buaaotM 3.83B-O7 X83E-07 5.00E-O2 7.6SE-06 7.I5C-06

&MS-08 6J4E-08 l.OOB-03 6.34S-Oa BJ4B-06L348-06 IJ4B-06 4.008-01 4.48B-M 4 8E-08

eUMDbmanw 3.03S-08 3.UB-06 XOOB-03 LS3E-06 1J3B-06L10B-07 L10B-07 LOOS-0 1 L 10E-O6 LUB-06I.73E-07 1.73B-07 XOOB-OI 8.50B-O7 8J9E-07X60E-OB X60B-06 XOOB*00 1.30C-06___ ^

TMalBmwdt B.4804* X48K-06

BABE-08 1J3B-08 l.OOB-03 6.5SE-07 IJ3E-077 438-09 I.6BE-09 l.OOB-03 7.43S-O7 1J5E*OTBME lB 1J8E-09 XOOB43 4.33B-07 8J9E-08

lA4-BtehlonbenanM 3JOB-07 4 .608- 08 XOOS-O3 1.15B-W X40E-08S.70S-07 ' 544 C- 08 4.00B41 • 8.768-07 IJ6E-079J1B-08 7.7SE-09 S. TOE-03 6. 168-O6 l.ME-06

•uomnthcm I.76B-00 4J5E-09 8.T08-O3 X08B48 8.16E-07bMa-tdirflMQrDphttMku X11B-O7 1. 39 E- 07 XOOE-02 L6BE-OS 6.96E-064.4--DOE X97B-07 IJ18-OT 5.00E-04 S.85E-O4 X42E-04aMnaphthem 1 J5C-08 X I9B-DB ft, TOE-03 X37B-06 5.00E-07OuoraM U9C-08 3JOE-OB S. TOE-03 X8 18-06 S.T8E-07MtHncMM &40B-00 1J4E-09 5.70803 8.47EK)7 XME-07atpnehler «a«dde X03S-10 7J9E- L 1 I.90E-05 L96E-OS 8.ME-06X4-dJchtore»h«ool 1J6C-08 X89E-OD 3.0OE-03 4.3BE-06 9.648-07•wnk I49E-O8 6X4E-08 l.OOE-03 1.89E-OS 8.44E-06baitim 9.088-07 X88E-07 1.00E44 9.08E-03 X88E-03

4.73B-O7 1.34B-07 5.008-O3 9,458-05 2.46 E-OSX 168- 10 8.93E-06 3.00E-04 7.31E-07 X98B-04X64B-08 IJBB-08 T.OQE-03 4.06B-06 2.71 E- 08X43B-07 1.ISB-07 XOOB4I 1.718-06 8.746-Q7

Total BMW* 8.808-03 —— 8.4U.03

HAXOfUM CaOD 34 BACABD INDEX FOB AflL 8.6U-O3MOoT FBOBABLB CHILD 3-4 BAZARD OfDEX FOB AOtt S.47B-O3

Referencei:ATSDR TOK. Profile.HHEM 1969HEASTIRIS. December 1989 update

EPA REGION IIISUPERFUND DOCUMENT MANAGEMENT SYSTEM

DQCJDPAGE ft

IMAGERY COVER SHEETUNSCANNABLE ITEM

SITE NAME.

OPERABLE UNIT

ADMINISTRATIVE RECORDS* SECTION_llLVOLUME_F

REPORT OR DOCUMENT TITLE

DATE OF DOCUMENT

DESCRIPTON OF IMAGERY.

NUMBER AND TYPE OF IMAGERY ITEM(S)

EPA REGION IIISUPERFUND DOCUMENT MANAGEMENT SYSTEM

DOCPAGE tf

IMAGERY COVER SHEETITEM

SITE NAME

OPERABLE UNIT

ADMINISTRATIVE RECORDS* SECTION_!iJ_VOLUME__F

REPORT OR DOCUMENT TITLE

DATE OF DOCUMENT

DESCRIPTON OF IMAGERY

NUMBER AND TYPE OF IMAGERY ITEM(S)