Subchronic Dermal Toxicity 90-Day Study

Subchronic dermal toxicity is the study of adverse effects occurring as a result of the repeated daily dermal application of a test chemical to animals for a part (not exceeding 10%) of the life span. In the evaluation of a chemical s toxic characteristics, the determination of subchronic dermal toxicity may be performed after initial information on toxicity has been obtained by acute testing. This study provides information on health hazards likely to arise from repeated exposure via the dermal route over a limited period of time. 

The housing and feeding of experimental animals should be according to standard animal husbandry conditions described for acute oral toxicity study. 

At least three dose levels with a control and (where appropriate) a vehicle control should be used in a subchronic dermal toxicity study. Expect for treatment with the test chemical, the control group should be handled in a manner identical to the test group. The highest-dose level of the test chemical should result in toxic effects but not produce fatalities, which would prevent a meaningful evaluation of the results. The lowest-dose level of the test chemical should not produce evidence of toxicity. Where there is a usable estimation of human exposure, the lowest level should exceed this. Ideally, the intermediate-dose level(s) of the chemicals should produce minimal observable toxic effects. If more than one intermediate dose is used, the dose levels should be spaced to produce gradation of toxic effects. In the low and intermediate groups and in the controls, the incidence of fatalities should be low to permit a meaningful evaluation of results. 

If application of the test chemical produces severe skin irritation, the concentration should be reduced, although this may result in a reduction in, or absence of, other toxic effects at the high-dose level. However, if the skin has been badly damaged early in the study, it may be necessary to terminate the study and undertake a new study at lower concentrations of the chemical. 

If one dose level of at least 1,000 mg/kg body weight (expected human exposure may indicate the need for a higher dose level), using the procedures described for this study, produces no observable toxic effects and if toxicity would not be expected based on data from structurally related compounds, a full study using three dose levels may not be necessary. A careful clinical examination should be made daily with appropriate actions taken to minimize the loss of animals, (e.g., by necropsy, refrigeration of animals found dead, or isolation and sacrifice of weak or moribund animals). 

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Subchronic Dermal Toxicity 90-Day Study (Original Guideline, adopted 12 May 1981)... 

CMA. 1983. 90-Day subchronic dermal toxicity study in rabbits with ethylene glycol monobutyl ether with cover sheet dated 06/12/89. EPA/OTS Doc 86-890000726. 

Of concern to the group was the proposal to require 90-day subchronic dermal toxicity studies in animals. Current requirements specify a 21-day rabbit dermal study which takes 6 months at a cost of about U0,000. The proposed 90-day study would cost about 100,000 and would provide no additional useful information. The question remains as to whether the study should be done with only the parent compound or with each formulated product due to potential effect of surfactants and solvents on the rate of absorption of the active ingredient(s) into the exposed subjects. 

Much toxicological data are available on this red pigment acute oral toxicity in mice, 90-day subchronic toxicological study, acute dermal irritation and corrosion, acute eye irritation and corrosion, anti-tumor effectiveness, micronucleus test in mice, AMES test Salmonella typhimurium reverse mutation assay), estimation of antibiotic activity, and results of estimation of five mycotoxins. A new patent on Arpink Red was filed in 2001 with claims of anti-cancer effects of the anthraquinone derivatives and apphcations in the food and pharmaceutical fields. 

In the test guidelines for 90-day dermal (OECD TG 411) and inhalation (OECD TG 413) toxicity studies, the following definition in relation to the term subchronic is provided Subchronic dermal/inhalation toxicity is the adverse effects, which follow repeated daily dermal application/ inhalation of a chemical for part (not exceeding 10%) of a life span. ... 

A 90 day subchronic oral study in rat and 21 day dermal study in rabbit provided no-observed-ad-verse-effect levels (NOAELs) of 3.3 and 100 mg kg day , respectively. Prenatal developmental toxicity study in female Sprague-Dawley rats exposed to atrazine during gestation day 6 through day 15 demonstrated maternal and developmental NOAELs of 25 mg kg day ... 

The subchronic toxicity of EGBE has been examined in animals via oral, inhalation, and dermal routes of exposure. The lowest no-observed-effect level (NOEL) in an oral subchronic study was 80 mg kg for rats administered EGBE in feed over a 90 day period. Inhalation exposure of rats for 13 weeks, 6h day , 5 days week to EGBE vapors at 25-77 ppm indicated an NOEL of 25 ppm. In a 90 day dermal study of rabbits, EGBE was applied 6 h day, 5 days week at doses up to 150 mg kg There was no evidence of systemic toxicity or skin irritation at the site of application at any of the dose levels tested. 

Subchronic Oral Dosing Studies Subchronic 21-Day Dermal Toxicity Study Subchronic 90-Day Dermal Toxicity Study Subchronic Inhalation Toxicity Study Subchronic Neurotoxicity Studies... 

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