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Toxicological information

Acute Toxicity: dermal

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Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1993
Report Date:
1993

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
other: Crl:CD BR
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River-Kingston, Stone Ridge, New York
- Age at study initiation: approximately 55 days old (males); approximately 65 days old (females)
- Weight at study initiation: 223 to 248 g (males); 206 to 243 g (females)
- Fasting period before study: not reported
- Housing: one/cage in suspended stainless steel cages
- Diet (e.g. ad libitum): Purina certified rodent chow 5002(C)
- Water (e.g. ad libitum): ad libitum
- Acclimation period: approximately one week


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 to 24 degrees C
- Humidity (%): 41 to 46%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 hours light/ 12 hours dark


IN-LIFE DATES: From: July 21, 1992 To: August 4, 1992

Administration / exposure

Type of coverage:
occlusive
Vehicle:
other: Neutral Oil 100 N
Details on dermal exposure:
TEST SITE
- Area of exposure: entire trunk between the flank and shoulders- approximatelly 6 x 6 cm
- % coverage: not reported
- Type of wrap if used: polyethylene sheet covered with Elastoplast (Beiersdorf, Inc. Norwalk, Connecticut) and PEG (Becton-Dickinson Co. Franklin Lakes, New Jersey) elastic bandages secured in place with adhesive tape.


REMOVAL OF TEST SUBSTANCE
- Washing (if done): After 24 hours, the backs were wiped with water-soaked paper towels.
- Time after start of exposure: after 24 hours


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2.0 mL/kg
- Concentration (if solution): none
- Constant volume or concentration used: yes
- For solids, paste formed: not appicable


VEHICLE Neutral Oil 100 N- contains 100% of refined paraffinic distillate
- Amount(s) applied (volume or weight with unit): 2.0 mL/kg
- Concentration (if solution): none
- Lot/batch no. (if required): 8-0419
- Purity: no data
Duration of exposure:
24 hour
Doses:
50, 200, and 400 mg/kg
No. of animals per sex per dose:
36
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical signs observed 0.5, 1, 2, and 4 hr after dosing and once daily for 14 days. Body weights recorded on day 0 (prior to dosing) and on days 7 and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Statistics:
The mortality incidences of males and females were compared across doses with a categorical data modelling procedure using SAS CATMOD (SAS Institute, Inc. SAS User's Guide: Statistics, Version 5 Edition, p 171-253. Cary, NC: SAS Institute Inc., 1985). The criterion of statistical significance was 0.05. If the results indicate a significant difference between the mortality responses for males and females, the LD50 is calculated separately by sex; otherwise the LD50 is calculated on the pooled mortality incidences at each dose.
The LD50, 95% confidence limits, and slope were calculated from the logarithm of the doses and the incidences of mortality using a SAS PROBIT procedure (SAS Institute, Inc. SAS User's Guide: Statistics, Version 5 Edition, p 171-253. Cary, NC: SAS Institute Inc., 1985) based on the method of D.J. Finney (Probit Analysis, Third Edition, London: Cambridge University Press, 1971).

Results and discussion

Preliminary study:
Not applicable
Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
251 mg/kg bw
95% CL:
> 190 - < 322
Mortality:
- Time of death: Males - 1 at 200 mg/kg 4 hr post-dosing (day 0); 3 at 400 mg/kg 2 hr post-dosing (day 0); 3 at 400 mg/kg 4 hr post-dosing (day 0). Females - 1 at 200 mg/kg 4 hr post-dosing (day 0); 1 at 200 mg/kg on day 1; 5 at 400 mg/kg 4 hr post-dosing (day 0). A dose-related increase in mortality was observed in the 200- and 400-m/kg dose groups.
- Number of deaths at each dose: (number of deaths/number treated)
Dose (mg/kg) 50 200 400
Males 0/6 1/6 6/6
Females 0/6 2/6 5/6
Clinical signs:
No mortalities and no clinical signs related to the test substance were seen in the 50- mg/kg dose group. Clinical signs indicative of neurotoxicity (tremors and/or convulsions) were observed in survivors as well as decedents in the 200- and 400-mg/kg dose groups. Surviving animals recovered from the neurotoxic effects by day 1 of the study. Periodically during the study, the fur surrounding the eyes and muzzle was observed to be red-stained; these effects were judged to be caused by the occluded testing methodology and by the use of collars. Numerous skin irritation effects were seen in both sexes at all doses.
Body weight:
There was no apparent test substance related body weight effects in this study.
Gross pathology:
Necropsy of the decedents revealed numerous skin irritation effects related to the test substance. No gross changes observed in survivors.
Other findings:
- Potential target organs: skin
- Other observations: no statistically significant sex-related differences

Applicant's summary and conclusion

Interpretation of results:
Category 3 based on GHS criteria
Executive summary:

The dermal toxicity of the test material was evaluated in Crl:CD BR rats. The test material was dispersed in neutral oil and applied topically to the shaved intact skin of three groups of rats (6/sex/group) at 50, 200 or 400 mg/kg (2 ml/kg) body weight. The application sittes were occluded for 24 hr. After the 24 -hr exposure, the application sites were washed with tap water. No mortalities and no clinical signs related to the test substance were seen in the 50 mg/kg dose group. A dose-related increase in mortality was observed in the 200 and 400 mg/kg dose groups. Clinnical signs indicative of neurotoxicity (tremors and/or convulsions) were observed in survivors as well as decedents in the 200 and 400 mg/kg dose groups. Surviving animals recovered from the neurotoxic effects in this study. There was no apparent test substance related body weight effects in thsi study. Numerous skin irritation effects were seen in both sexes at all doses. No treatment related signs were seen at necropsy (other than skin irritaion). The overall no observed effect level (NOEL) was 50 mg/kg.

Sincec no statistically significant sex-related difference in mortality was observed, the LD50 was calculated from the combined mortality incidence data. The acute dermal LD50 in male and female rats (combined) was 251 mg/kg with 95% confidence limits of 190 and 322 mg/kg.