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J. ToxicoL-Cut. & Ocular Toxicol., 10(4), 279-287 (1991)
CLINICAL SAFETY TESTING OF COSMETICS A N D PERSONAL CARE PRODUCTS GARY L. CURTIS, Ph. D. * Hams Laboratories, Inc . Lincoln, Nebraska
Abstract An alternative to animal testing currently being conducted for dermal safe- ty in the cosmetics and personal care products industries may be the use of trained physician principal investigators, facilities, and oversight systems similar to those used in phase I “first time in humans” drug studies. A method is proposed using a classification of ingredients/products based upon available technical information and phase I level of testing in humans necessary to demonstrate safety while minimizing and managing the potential for compromising the safety of participants.
Introduction
Requirements for demonstrating that a proposed cosmetic or personal care prod- uct is safe for consumers are not well defined. The statement that “each ingredient used in a cosmetic product and each finished cosmetic product shall be adequately substantiated for safety prior to marketing,”’ without further definition of what con- stitutes a demonstration of safety, leaves it to the manufacturer to determine what constitutes “adequate testing.” In an attempt to establish safety of the ingredients and finished products marketed to consumers of cosmetics and personal care prod- ucts, manufacturers have historically performed acute and chronic animal testing in- cluding the Drake test,2. although the correlation of the response in rabbit eye is more severe than that found in h~rnans .~
*Address reprint requests to: Gary L. Curtis. Ph.D., Harris Laboratories, Inc., 624 Peach Street, P.O. Box 80837, Lincoln, NE 68501.
279
Copyright 0 1991 by Marcel Dekker, Tnc.
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280 CURTIS
There is considerable public interest in eliminating the use of animal testing in the cosmetics and personal care products industries. This has presented manufac- turers with the problem of, on the one hand, demonstrating their products are safe and, on the other, responding to public concern to eliminate certain forms of animal testing. In response to this public concern, most cosmetic manufacturers have significantly reduced the amount of animal testing they conduct. Some companies have eliminated animal testing in their research laboratories and sought animal testing by independent contract laboratories or require that their suppliers of ingredients con- duct animal testing.
There is also an effort to explore nonanimal testing alternatives. One alternative is the possibility of substituting in vitro cell culture for animal testing of ingredients and finished product^.^. Cell culture studies may have a place in determining cellular toxicity but cannot substitute for in vivo testing, in which the total dermal structure and complex biological systems of the body play such a critical role in the responses to an ingredient.
The objective of animal testing in the cosmetic and personal care products industries is to predict the reaction of humans to the ingredient and final product. Before any ingredient can be considered for use in a cosmetic, a significant amount of informa- tion about its acute, chronic, and subchronic toxicity, carcinogenicity, teratogenici- ty, and effect on fertility can be obtained from the literature or the manufacturer. Often the additional animal testing performed by the cosmetics industry is to deter- mine further the ingredient’s potential for irritation on human skin.
A suitable alternative to animal testing is to conduct tests on ingredients and finished products in humans under critical observation, similar to what is done in “first time in humans,” phase I testing in drug devel~pment.~-~ Phase I drug studies are de- signed to establish, in healthy adults, the safety of a drug leading to determination of its risk vs. benefit ratio. These studies evaluate the systemic toxicology of the drug. Preclinical evaluation is conducted to determine the systemic pharmacologic and toxicologic effects of the drug on organ systems before they are administered to humans. The dosage chosen for phase I study in humans is calculated to be 1/10 of the “no effect” systemic subacute toxicologic dosage in rodents.
During phase I drug development, exceptional care is exercised in observing par- ticipants by trained physician principal investigators and technologists in specially designed and monitored facilities. This report outlines a procedure similar to phase I “first time in humans” drug testing modified for the cosmetic and personal care products industries. It describes a method for classifying ingredients and, where ap- propriate, testing procedures using phase I facilities and personnel.
Method
This method is based on a system for classifying ingredients/products and then conducting the degree of testing necessary to demonstrate safety while minimizing
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SAFETY TESTING OF CONSUMER PRODUCTS 281
and managing the potential for compromising the safety of participants. Our pro- posal for classifying and testing ingredientdproducts is described here.
Ingredients/products are classified into one of the following three classes depend- ing on the information available:
I.
II.
m.
Extremely limited or no in vivo animal or human toxicologic data are available. The manufacturer would provide a description of known toxicology to the prin- cipal investigators in the contract laboratory. This would include acute, chronic, subchronic toxicity, carcinogenicity, teratogenicity data, and effects on fertili- ty. The manufacturer and contract laboratory would jointly evaluate the feasibility of testing these ingredients, similar to phase I pharmaceutical drug develop- ment studies in which low doses are used on a few (five) participants who are carefully monitored. The major ingredients are known but with limited animal and toxicologic in- formation; however, considerable data on similar compounds are available. The manufacturer would provide a description of known toxicology. Testing for this category includes a modified phase I primary irritation study. Ingredient or combinations are well known and a significant amount of tox- icologic studies have been completed: generally recognized as safe (GRAS).
A project team including principal investigators, scientific and clinical staff from the contract laboratory along with the manufacturer would agree upon the feasibility of the studies and review data from the phase I primary irritation studies before pro- ceeding to subsequent studies. This provides assurance of gathering scientifically rele- vant data without compromising participant safety or requiring unnecessary testing.
Testing for each class is described in the following sections.
Class I
Identification of Ingredient
The manufacturer would identify the ingredient/product to be tested. The sponsor would provide adequately detailed product content information necessary to design and execute a safe study. The manufacturer provides any available relevant scien- tific literature and toxicologic information for the class of compound and rational basis for evaluating the feasibility of safely conducting the study, and assists in deter- mining the concentration of the ingredient or finished product to be used.
In Vitro Test Results
The manufacturer would provide the results from any in v i m testing on the ingre- dient. Several in v i m tests are a ~ a i l a b l e . ~ , ~ If data are available, the laboratory would have the tests and the scoring system the manufacturer uses identified.
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282
Test Conditions
CURTIS
All testing would involve exclusive panels (singular @ent/product tested). Each patch test listed below would use a negative control of distilled water.
Base I primary Im'tation
This is a primary irritation test and is conducted under phase I conditions. It deter- mines the primary irritation potential of the ingredientlpoduct. It is conducted in a fully equipped phase I facility and uses monitoring systems under the direction of a trained physician investigator. This allows for immediate observation of side effects (systemic as well as local) and immediate medical attention if required. In this phase I study, the concentration of ingredient used in the final product or some other agreed upon concentration is applied by an occlusive patch to five participants. Patch ap- plication is monitored by a physician within the phase I clinic. Following applica- tion, participants will remain in the phase I clinic under medical observation. After 3 hr, each patch is removed and the skin is evaluated for irritation. If no dermal reaction or systemic side effects are observed, a new patch is applied to the same site and the participant is dowed to leave and return in 6 hr for an additional evalua- tion for irritation. If no irritation is observed, a new patch is applied to the same site and participants are allowed to go home and return 15 hr later (24 hr after initial application) for another evaluation of irritation (patch removed). Then the following regimen is followed: days 2 and 3, no patch; day 4, evaluate and apply new patch to be worn for 24 hr; day 5, patch off; day 6, evaluate and apply new patch to be worn for 24 hq day 7, patch off; day 8, final evaluation. Vital signs and any adverse drug effects are recorded at each evaluation period. A 1/2 point grade scale (0-4) is used in evaluating the irritation potential. A patch is not reapplied when a reaction of grade 2 or more is observed.
Participants of either sex who are in good health as demonstrated by results of general physical examination, blood chemistry, hematology, and urinalysis are entered into the study. The physical and laboratory data are obtained prior to entry and at the conclusion of the test. A serum pregnancy test is required for female participants. Participants cannot be taking any chronic medications and cannot have taken any medication within 7 days prior to the study or during the course of the study (with the exception of birth control pills). Female subjects will be allowed to participate only if surgically sterile or taking birth control pills. Participants would be between the ages of 19 and 55 years for this test, and must be white.
Cumulative Im'tation
If the average irritation score for the phase I primary irritation study is less than 1 .O, a 14 day cumulative irritation study will be conducted with 10 participants who did not participate in the phase I study and meet the same study inclusiodexclusion criteria described for the phase I primary irritation study.
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SAFETY TESTING OF CONSUMER PRODUCTS 283
This study evaluates the amount of human skin irritation induced by repetitive topical application of the test substance.1° A control of 0.2% aqueous sodium lauryl sulfate and a control of distilled water are used in this test in addition to the test substance. Participants receive a total of 14 applications (applications are to be of approximate- ly 23 hr each over a period of 14 consecutive days). Occlusive patches are used. Each application is approximately 23 hr and sites are graded approximately 1 hr after removal. The 1/2 point grade scale used in the primary irritation study is also used in this study. A patch is not reapplied when a grade of 2 or greater is observed. For statistical purposes, once a grade of 2 or greater is observed, that grade is used to the study completion.
If the results of the cumulative irritation test (according to descriptive words cor- related with values of the average irritation scores) are slightly irritating, mild, or very mild, the human repeat insult patch test (HRIPT) is conducted. If the results of the cumulative irritation test are mildly irritating, a decision is to be made by the manufacturer and investigator if they wish to continue with the HFUFT or stop to reformulate the product. If the results of the cumulative irritation test are moderate- ly irritating or higher, it is suggested that the sponsor reformulate the product before advancing to the HRIFT. This is becuase it is difficult to differentiate between irri- tation and sensitization at this grade level and there is an increased risk to participants for permanent pigmentation changes, scarring, susceptibility to infections due to broken skin barrier, and sensitization.
Human Repeat Insult Patch Test
The purpose of the human repeat insult patch test (HRIPT) study is to determine the human skin sensitization (delayed contact allergy/hypersensitivity) potential of a test substance. The HRIPT study takes 6 weeks. Participants receive patches on Monday, Wednesday, and Friday of the first 3 weeks, which are worn for 24 hr and the skin site is evaluated 24 hr after removal (48 hr on weekends). A 2 week rest period with no application follows. On the sixth week, two sets of patches are applied on Monday that are worn for 24 hr. The skin sites are graded on Wednesday and Friday (48 and 96 hr after application). The HRIPT should involve 50 panelists completing the test. Participants in this study cannot have participated in the irrita- tion studies for the test substance. Female subjects cannot be pregnant or nursing and must be practicing an acceptable form of birth control to participate in this study. Participants are to be in general and good health as demonstrated by results of a ques- tionnaire designed to cover inclusion and exclusion criteria. Participants in this test are to be between the ages of 19 and 55 years inclusive.
In-Use Study
If there is no evidence of sensitization in the HRIPT, an in-use study is initiated. The purpose of this study is to determim any irritation when the product is used as intended. If there is any question of sensitization in the HRIPT, the participant
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284 CURTIS
with the questionable reaction should be rechallenged and participate in an in-use study before an in-use study is undertaken in any other participants. If the panelist is able to use the product in normal fashion without response, the in-use study in a new group of participants may proceed. In general, the in-use study design is to be ingnxhent/product specific, involve a small number of participants (20), be relatively short (7 days), and determined following discussion with the sponsor before study initiation. Depending upon the ingredient being tested, the use test could be extend- ed up to 30 days to obtain relevant information. Additional variations of use testing can be used.ll
The 20 participants are given the product to take home and use as indicated. Par- ticipants in this test will not have participated. in any of the prior testing on this substance. The participants use the product as directed daily, returning each day for evaluation by trained personnel. At the conclusion of 7 days, the participants are asked to fill out a questionnaire about the product concerning irritation, discomfort, product attributes, and other variables.
The conclusion of the study report would be approved by the physician principal investigator. A lapse of approximately 1 week would take place between each of the 4 tests to allow sufficient time to evaluate test results and determine the appro- priateness of proceeding with the next test.
Class II
Phase I Primary Irritation
The procedure is similar to class I, phase I testing: it is initiated in a fully equipped, properly monitored, phase I facility under the observation of a trained physician prin- cipal investigator. This allows for observation of immediate side effects (systemic as well as local) and immediate medical attention if required. The procedure and number of participants are as described for class I with the following exceptions:
1. No blood chemistry, hematology, urinalysis, or pregnancy testing is performed. 2. A medical history and abbreviated physical examination are conducted rather
than an in-depth history and physical. 3. Participants may be taking chronic medications to control certain chronic
conditions.
Cumulative Irritation
Same as that described for class I with the following exceptions:
1. Participants may be taking chronic medications to control chronic conditions such as hypertension, hypothyroidism, and others.
2. The use of medications restricted 7 days before and during the study will be limited to anti-inflammatory agents, antihistamines, and antiasthma medications.
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SAFETY TESTING OF CONSUMER PRODUCTS 285
HRIPT
Same as that described for class I.
In-Use Study
Same as that described for class I. The conclusion of this study report would be approved by the physician principal
investigator. A lapse of approximately 1 week would take place between each of the 4 tests to allow sufficient time to evaluate test results and determine the ap- propriateness of proceeding with the next test.
Class 111
Primary Im'tation
No primary irritation testing is conducted.
Cumulative Irritation
Same as that described for class I.
HRIPT
Same as that described for class I, with the following exception: female subjects do not have to be surgically sterile or practicing an acceptable form of birth control; however, they may not be pregnant or lactating.
In-Use Study
Same as that described for class I. A lapse of approximately 1 week would take place between each of the 3 tests
to allow sufficient time to evaluate test results and determine the appropriateness of proceeding with the next test (see simplified schematic in Fig. 1).
In comparing classes I, 11, and I11 testing, the exclusion criteria for classes I and 11 are more stringent than in general testing to safeguard participants and eliminate factors deemed to influence test results. The exclusion criteria for class 111 maintain the exclusion criteria planned as a safeguard for participants and eliminate only those medications lmown to influence test results.
Manufacturers of cosmetics and personal care products need to determine the safety of proposed products before they are sold to consumers. Manufacturers in these in- dustries are currently examining the process they use for determining this safety. Phase I drug testing facilities, oversight, and experienced investigators have been used successfully in establishing safety in the investigational drug process for many years. We believe that this process can be used in the cosmetic and personal care products industries with the same success.
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CURTIS 286
CLASS I CLASS I1 CLASS I11
TIME -
I I 1 I I
T ,
1 I I I
-L I I
Figure 1.
Acknowledgments
I acknowledge the support and suggestions of Ann H o h t e h , Jim McClurg, Ph.D., and Lew Harris, Sc.D.
References
1. 21 Code of Federal Regulation, Food & Drugs, Part 740.10
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SAFETY TESTING OF CONSUMER PRODUCTS 287
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