Approaches to the Threshold of Toxicological Concern

Clif McLellan

Director of Toxicology Services

NSF International

March 16, 2010

Overview of Presentation

Who is NSF and how do we use health based risk assessments ?

Setting Health based criteria when no chemical specific toxicology data is available.

Threshold of Evaluation

Threshold of Toxicological Concern

Class Based Evaluation Levels

NSF International

• Independent, private, not-for -profit organization which provides third party services through programs which focus on public health and environmental quality

• Test & certify products• Inspect production facilities• Register quality systems• Develop and maintain consensus standards; many

of which are related to drinking water and food

NSF Was Established In 1944 To Develop Standards, And Test And

Certify Food Equipment.

- 3 public health experts found the National Sanitation Foundation (NSF) in the University of Michigan’s School of Public Health 66 years ago.

- Initially serviced the food industry

- Developed more than 72 national consensus standards

- Utilize more that 200,000 square feet of laboratory space

for chemistry, engineering and microbiology

- Client base over 12,000 companies

- Certified more than 225,000 products made in more than 100 countries

NSF International in 2010

Certification Process for Products Contributing Direct or Indirect

Additives- Review each material formulation to the individual chemical

level, to identify potential leachates based on material formulations and manufacturing processes

- Perform material leachate tests based on established protocol

to match end use to potential contaminants

- Normalized test results to determine potential “at the tap” contaminants for regulated and unregulated chemicals

- Determine whether the “at the tap” concentrations exceeds health based criteria

What are the results of Material Extraction Testing?

More than 2,500 different chemicals have been identified as a result of material leachate tests.

- 41 have MCL’s

- 109 IRIS or Health Advisories

- 300 have sufficient toxicology data

- > 2000 insufficient data for assessment

Process of Setting Acceptance Criteria for Unregulated Substances With Data

Perform literature search for compound Determine the quality of data Use appropriate data to arrive at an RfD or Cancer

Risk Level, using the EPA guidelines Internal Peer Review External Peer Review Publish on ITER and adoption for use in appropriate

standards

Total Allowable Concentration (TAC)Total Allowable Concentration (TAC)

RfD(mg/kg/day) x BW(70 kg) x Relative Source Contribution (2 L/day)

Total Allowable Concentration (Equivalent to a DWEL) is the maximum concentration of a nonregulated expressed in mg/L and calculated as follows:

Setting Health based criteria when no chemical specific toxicology data is

available.

The Threshold of Evaluation

The Threshold of Toxicological Concern

Class Based Evaluation Levels

The Threshold of Evaluation (TOE)The Threshold of Evaluation (TOE) is based on the FDA’s Threshold of Regulation (TOR).

Prior to 1958, the Food Additives Amendment to the Federal Food, Drug, and Cosmetic Act (FFDCA) considered all substances food additives if they were found in food. As analytical limits of detection improved, FDA had to come up with a paradigm to address these low-level migrants. Thus the Threshold of Regulation (TOR) was developed.

– In 1958, an exemption (Delaney Clause) was created which stated that if a chemical was present at less than 0.5 ppb in food it was not considered a food additive and would be exempt from the regulation.

To qualify for the exemption– The substance could not be a known carcinogen

The Threshold of Evaluation (TOE)

The Threshold of Regulation of 0.5 ug/ kg food or 1.5 ug/person/day was converted to a drinking water concentration based on the following conversion.

0.5 ug/ kg food/ day * (3 kg food / day) / (2 L water / day) = 0.75 ug / L

The Threshold of Evaluation (TOE)

Exclusion to the use of The Threshold of Evaluation

Not applied to any substance for which available toxicity data and sound scientific judgment such as structure activity relationships indicate that an adverse health effect results at these exposure concentrations.

Threshold of Toxicological Concern (TTC)

The TTC approach is used as a substitute for evaluating health risks in the absence of complete substance-specific health effects data

TTC risk assessments are based on an analysis of toxicological and/or structural data of a broad range of different chemicals including carcinogenic and non-carcinogenic endpoints

The TTC approach is used in the U.S. and Europe– FDA allows the use of a TOR when evaluating health risks from food contact

materials (e.g., sandwich bags, retort cups)– JECFA uses a TTC when evaluating health risks from food additives

“ Threshold of Toxicological Concern” (TTC)

The Threshold of Toxicological Concern (TTC) is based on a number of published papers.

Estimation of Toxic Hazard-A Decision Tree Approach (Cramer and Ford, 1978).

Correlation of Structural Class with No-Observed-Effects Levels: A Proposal for Establishing a Threshold of Concern (Munro et al.,

1996)

A Tiered Approach to the Threshold of Regulation (Cheeseman et al., 1999)

Structure Based Thresholds of Toxicology Concern (TTC): Guidance for the applications of substances present at low levels in the Diet (Kroes et al., 2004)

Threshold of Toxicological Concern (Noncancer)

The first steps is a determination of the structural classes identified according to the Cramer et al. (1978) decision tree – Class I – Simple chemicals, efficient metabolism, low oral toxicity– Class II – May contain reactive functional groups, slightly more toxic

than Class I– Class III – Substances that have structural features that permit no strong

initial presumption of safety or may even suggest significant toxicity– Organophoshates (Added Munro et al. (1999))

Cramer evaluated the published literature to classify hundreds of chemicals, including 247 carcinogens, food additives, drugs, industrial chemicals and pesticides.

Step One: TTC Approach (Noncancer)

The Cramer et al. (1978) decision tree comprises 33 questions related to chemical structure, functional groups, and source of the chemical

Threshold of Toxicological Concern (Noncancer)

For each group, the 5th percentile of the distribution of NOELs from the subchronic and chronic animal studies were determined. The NOELs from the chronic study were divided by a 100-fold safety factor and the NOELs from the subchronic studies were divided by a 300-fold safety factor. Body weight of 60 kg was used.

Group # of compounds

Human Exposure Thresholds

(ug/kg/day)1 137 1800

2 28 540

3 448 90

Organophosphates 31 18

Threshold of Toxicological Concern (Cancer)

FDA’s TOR was reviewed by Rulis et al. (1986, 1989) and extended by Cheeseman et al. (1999)– A threshold value of 0.5 ppb in the diet based on

carcinogenic potencies of 500 substances from 3500 experiments of Gold et al.’s (1984, 1989) Carcinogenic Potency Database

– The distribution of chronic dose rates [mg/kg bw/day] that

would induce tumors in 50% of test animals (TD50s) was plotted

– This distribution was extrapolated to a Virtually Safe Dose (10-6 risk of cancer) in humans

Kroes Decision-Tree (Kroes et al., 2004)

TTC Acceptable Drinking Water Levels

Calculation

[X] µg/person/day x 0.20 = acceptable level in mg/L 2 L/person (60 kg/ 70 kg)

Where: – X = 1800 µg/day for class I compounds, 540 µg/day for class II compounds, and 90 µg/day for class III compounds– Relative Source Contribution = 0.2– Drinking water intake = 2 L/day

– Human body weight of 70 kg

Group Total Allowable Concentration (ug/L)

1 200

2 50

3 10

Organophosphates 2

Carcinogens 0.6

Analysis of TTC against Previously Established Risk Levels

Procedure: NSF evaluated each EPA and NSF established risk level against the TTC approach to compare the established risk level with what would have been derived if no information was available for that compound.

Limitations using the TTC approach:

1. TTC does not address a number of chemical classes. Not all functional groups are included in the classification scheme.

2. Naming convention used in scheme does not follow IUPAC nomenclature and can be ambiguous.

3. Halogenated compounds may result in underestimated values. The toxicity class that would allow an acceptance level which exceeds potential health effects.

4. It is possible to interpret questions differently and arrive at a different Cramer class classification. Inconsistencies are possible between reviewers.

Class Based Evaluation Levels (CBEL)

Establishment of the chemical class

The chemical class shall consist of a clearly defined and closely related group of substances, and shall be defined according to chemical structure (e. g., aliphatic or aromatic), primary chemical functional group(s) (e. g., alcohol, aldehyde, or ketone), and molecular weight or weight range.

Class Based Evaluation Levels (CBEL)

Review of all toxicity information for each chemical in the class including all risk values including:

– USEPA risk assessments, including MCL’s, Health Advisories and IRIS entries,– Health Canada risk assessments,– risk assessments previously performed to the requirements of annex A;– state or provincial drinking water standards and guidelines; and– World Health Organization (WHO) or other international drinking water standards and guidelines.

Class Based Evaluation Levels (CBEL)

Review of chemical class toxicity information

Carcinogenic potential shall be evaluated using QSAR (e. g., OncoLogic®) and all other non cancer data shall be evaluated to verify that the toxicity potential of the chemical without data is no greater than that of the chemicals being used to define the class-based evaluation criteria.

Class Based Evaluation Levels (CBEL)

Determination of the class-based evaluation criteria

The class-based evaluation criteria shall not exceed the lowest MCL or TAC in the defined chemical class until such time as sufficient toxicity data are available to determine chemical-specific evaluation criteria.

EXAMPLE:

Aliphatic glycol ethers and their acetates

This CBEL class includes aliphatic glycol ethers and their acetates with constituents of methoxy, ethoxy, propoxy and butoxy groups as part of the general identification as a glycol ether also including the corresponding methyl, ethyl, propyl and butyl acetates.

This class also includes compounds identified as ethyl, propyl or butyl isomers or -ethyl, -propyl or –butyl glycols polymers, oligomers and dimers.

Chemicals Identified to be Included in This Class.

107-98-2 Propylene glycol monomethyl ether 24800-44-0 Tripropylene Glycol

108-65-6 Methoxypropylacetate 2516-93-0 2-Butoxyacetic Acid

109-86-4 2-methoxyethanol   Polybutyleneoglycol- Multiple CAS#'s

110-71-4 Ethylene Glycol Dimethyl Ether 25265-71-8 Dipropylene Glycol

110-80-5 2-ethoxyethanol 25322-68-3 Polyethylene Glycol

111-15-9 Ethylene Glycol Monoethyl Ether Acetate 25322-69-4 Polypropylene Glycol

111-46-6 Diethylene Glycol 2807-30-9 Ethylene Glycol Monopropyl Ether

111-55-7 Ethylene Glycol Diacetate 29387-86-8 Propylene Glycol Monobutyl Ether

111-76-2 Ethylene Glycol Mono-N-Butyl Ether 29911-28-2 Dipropylene Glycol Butyl Ether

111-77-3 Diethylene Glycol Monomethyl Ether 34590-94-8 Dipropylene Glycol Monomethyl Ether

111-90-0 Diethylene Glycol Monoethyl Ether 4792-15-8 Pentaethylene Glycol

111-96-6 Diethylene Glycol Dimethyl Ether 5131-66-8 Propylene Glycol Butyl Ether (a-isomer)

112-27-6 Triethylene Glycol 52125-53-8 Propylene glycol monoethyl ether

112-34-5

Diethylene Glycol Mono-N-Butyl Ether (butoxyethoxyethanol) 54518-04-6 Dibutoxymethanol

112-35-6 Methoxy Triethylene Glycol 57018-52-7 Propylene Glycol T- Butyl Ether

Chemicals Identified to be Included in This Class.

112-50-5 Ethoxytriethylene Glycol 57-55-6 Propylene Glycol

112-60-7 Tetraethylene Glycol 60-29-7 Ethyl ether

112-73-2 Diethylene Glycol Dibutyl Ether 629-14-1 Ethylene Glycol Diethyl Ether

12002-25-4 Dipropyleneglycol Methyl Ether 68551-13-3Alcohols, C12-C15, ethoxylated propoxylated

124-17-4

Diethylene Glycol Monobutyl Ether Acetate 6881-94-3 Diethylene Glycol Monopropyl Ether

13429-07-7 Dipropylene Glycol Monomethyl Ether 73467-18-2 Tetrapropylene Glycol, Methyl Ester

142-96-1 Dibutyl Ether 74367-33-2Methyl propanoic acid, dimethyl (hydroxy methylethyl) propyl ester

143-22-6 Triethylene Glycol Butyl Ether 7580-85-0 Ethylene Glycol, Mono-Tert-Butyl Ether

151911-67-0 Polyethylene glycol monobutyl ether 7795-91-7 Ethylene Glycol -Sec Butyl Ether

15764-24-6 Dipropylene Glycol, Ethyl Ether 9003-13-8 Polypropylene Glycol Butyl Ether

15821-83-7 Propylene glycol butyl ether (b-isomer) 9004-74-4 Polyethylene Glycol, Monomethyl Ether

1638-16-0 Tripropylene Glycol 9004-81-3 Polyethylene Glycols Monolaurate

20178-34-1 Tripropylene Glycol Butyl Ether 95-08-9 Bis (2-Ethylbutyrate) Triethylene Glycol

20324-33-8 Tripropylene Glycol Methyl Ether 98516-30-4 Propylene Glycol Acetate Ethyl Ether

Surrogates with Quantitative Risk Assessment Values

.

Departure Point

mg/kg-day1000

(NOAEL)1000

(NOAEL)500

(NOAEL)5.1

(PBPK and BMD 05)

1000(NOAEL)

Key Study Information on the Selected Surrogates

0.5 NSF, 1998

Methoxypropyl acetate

A LOAEL was not identified

1000 1 USEPA,

0.3 NSF, 2002

Ethyl etherDepressed body weight

3000x 0.2 USEPA, 1988

Oral RfD mg/kg-day

Reference

Dipropylene glycol n-butyl

A LOAEL was not identified

3000x 0.3 NSF, 2002

Surrogate Critical Effect UF

Propylene glycol n-butyl ether

A LOAEL was not identified

3000x

Ethylene glycol mono-n-butyl ether

Changes in mean corpuscular volume

10

Total Allowable Concentration (TAC) for Aliphatic glycol ethers and their

acetates based on ethyl ether

RfD(mg/kg/day) x BW(70 kg) – total contribution of other sources(mg/day)DWI (2 L/day)

0.2 (mg/kg/day) x BW(70 kg) * 0.2 (RSC) DWI (2 L/day)

= 1.4 (mg/kg/day) rounded to 1 (mg/kg/day)

Other CBEL’s that have been developed at NSF

Aliphatic hydrocarbons including alkanes, alkenes, and cyclic compounds.

Aliphatic diols (1,6-hexanediol, etc.)

Aliphatic and alicyclic alcohols (n-butanol, n-heptanol, n-octanol, etc.)

Aliphatic ketones (Decanone, heptanone, hexanone, etc.)

Alkyl substituted phenolics (2-tert-butyl-phenol, 4-nonyl-phenol, 3,5-dimethylphenol, etc.)

Fatty acid ester (methyl adipate, dimethyl adipate)

Isothiocyanates, alkyl substituted (Isobutyl-isothiocyanate, n-butyl isothiocyanate, etc.)

Naphtha-derived alkylated benzenes, C8-C10 (n-butyl benzene, n-propyl benzene, etc.)

Phthalate esters

Quinolines, alkyl substituted ( Methyl quinoline, dimethyl quinoline, trimethyl quinoline, etc.)

Questions???