Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: (meets generally accepted scientific standards and is described in sufficient detail)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1985

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
EPA OPP 82-2 (Repeated Dose Dermal Toxicity -21/28 Days)
Deviations:
no
Remarks:
Not specified in the report.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
TS: 96% pure

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female

Administration / exposure

Type of coverage:
occlusive
Duration of treatment / exposure:
21 days
Frequency of treatment:
Dosed daily, 6 hours per day
Doses / concentrations
Remarks:
Doses / Concentrations:
30, 100, and 300 mg/kg bw /day
Basis:

Control animals:
yes, concurrent vehicle
Details on study design:
Wistar rats (male and female) were obtained from a commercial supplier, and were identified by ear tags. They were quarantined and acclimated to the testing facility for 12 days prior to study assignment. The animals were offered food and water ad libitum, and were individually housed in rooms designed to maintain adequate environmental conditions for the species.

Five days prior to the dose application, the animals were randomly distributed into 4 groups based on body weights. At weekly intervals (for 2 weeks) beginning on the day before the first test material application, the fur was clipped from the upper dorso-lateral area of each animal accounting for approximately 10% of the total body surface. In an attempt to obtain a non-irritating dose, the material was diluted to 2.5%, 5%, 7.5%, and 10%. Three males and females were dosed at each level for 11 days prior to the definitive test. The test material was evenly spread on surgical gauze, which was affixed to aluminum foil with a thin layer of vaseline. The patch was applied to the clipped area of each rat, and was reapplied daily for a 6 hour exposure period.

Cageside observations were performed once daily until sacrifice on day 21. Once weekly, animals were given a detailed physical examination. Body weights were taken on day 0, 7, 14, 20 (prior to fasting), and 21 (fasting). Hematology and clinical chemistry was evaluated using day 21 blood samples collected at necropsy.

A full gross necropsy was conducted, and included external surfaces and openings, and the contents of the cranial, thoracic, and abdominal cavities. Liver, adrenals, kidneys, and testes were removed and weighed.

Means with standard deviation were calculated for all quantitative parameters. One-way ANOVA was used to analyze the results for overall effects of dosage. Significant differences between doses were also assessed by using the F-test where p<0.05. The following variables were selected for futher statistical analyses: body weights, food consumption, organ weights, and organ/body weight ratios of liver, kidney, adrenal, and testes, and all parameters suspected of changes from the hematology and clinical chemistry determinations. A homogeneity of variance test using the Bartlett method was also performed.

Examinations

Statistics:
Means with standard deviation were calculated for all quantitative parameters. One-way ANOVA was used to analyze the results for overall effects of dosage. Significant differences between doses were also assessed by using the F-test where p<0.05. The following variables were selected for futher statistical analyses: body weights, food consumption, organ weights, and organ/body weight ratios of liver, kidney, adrenal, and testes, and all parameters suspected of changes from the hematology and clinical chemistry determinations. A homogeneity of variance test using the Bartlett method was also performed.

Results and discussion

Results of examinations

Details on results:
There were no treatment-related mortalities, and no evident signs of systemic toxicity noted. The treated surface showed dose- or concentration-related local skin irritation, observed as necrotic erythema and topical eschar and scar formation, seen in all animals of both the medium and high dose groups. Most animals of the low dose group showed erythema on three or more occasions, and eschar formation was seen in only two animals. The reported incidence of erythema and crust formation was 56%, 34%, 16%, and 3% for high, mid, low, and control groups, respectively.

There were no biologically-significant effects on body weights or food consumption in any group, nor any changes in hematology parameters or clinical chemistry parameters.

High-dose females showed a statistically-significant increase in kidney/body weight ratio. Gross pathology revealed no significant findings, other than local eschar formation at the test sites. Histopathological findings included erosion, chronic dermatitis, or local subepidermal infiltrate.

The NOEL by dermal application for 21 days was reported to be 100 mg/kg/day.

Effect levels

Dose descriptor:
NOEL
Effect level:
100 mg/kg bw/day
Sex:
male/female

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The NOEL by dermal application for 21 days was reported to be 100 mg/kg/day.