Registration Dossier

Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Experimental start date (1st exposure to test substance): 2nd March 1998. Experimental termination date (last date data collected): 16th March 1998.
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted to GLP and in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not effect the quality of the relevant results.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1998
Report Date:
1998

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Qualifier:
according to
Guideline:
EPA OTS 798.1100 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
fixed dose procedure
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Storage: The test article was stored at room temperature and humidity.
Description: Yellow crystalline solid.

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Animals were received from Ace Animals, Boyertown, PA.
- Age at study initiation: Approx 8 to 12 weeks.
- Weight at study initiation: Pretest body weight range was 2.1-2.7 kg for males and 2.0-2.4 kg for females.
- Fasting period before study: None, food was provided daily.
- Housing: Animals were housed 1 per cage in suspended wire cages. Bedding was placed beneath the cages and changed at least three times per week.
- Diet (e.g. ad libitum): Fresh Purina Rabbit Chow was provided daily.
- Water (e.g. ad libitum): Water was freely available at all times.
- Acclimation period: At least one week.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Animal room was temperature controlled.
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle.

IN-LIFE DATES: From: Day 1 To: Day 14

Administration / exposure

Type of coverage:
semiocclusive
Vehicle:
other: test artilcel moistened with 1.5 ml of saline.
Details on dermal exposure:
TEST SITE
- Area of exposure: Approximately 24 hours prior to application of the test article, the dorsal area of the trunk of each animal was clipped free of hair.
- % coverage: The prepared site was approximately 10% of the body surface.
- Type of wrap if used: The test article was applied under a 4 layered surgical gauze patch approximately 10 x 15 cm. The patch and test article were moistened with 1.5 ml of saline to enhance contact of the test article with the dose site. Gentle pressure was applied to the gauze to aid in the
distribution of the test substance over the prepared site. The torso was wrapped with plastic which was secured with non-irritating tape.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Residual test article was gently wiped from the treated site prior to dermal observations.
- Time after start of exposure: The test article remained in contact with the skin for 24 hours at which time the wrappings were removed.

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): A single dose of the test article was applied to the prepared site at a dose level of 2000 mg/kg.


VEHICLE
The test article was moistened with 1.5 ml of saline to enhance contact of the test article with the dose site.
Duration of exposure:
24 hour contact period.
Doses:
Single dose level of 2000 mg/kg (dose was based on dry weight).
No. of animals per sex per dose:
5 males and 5 females.
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days.
- Frequency of observations and weighing: The animals were observed 1, 2 and 4 hours postdose and once daily for 14 days for toxicity and pharmacological effects. The animals were observed twice daily for 14 days for mortality.
Body weights were recorded pretest and on days 3, 7 and 14 or at death.
- Necropsy of survivors performed: yes, all animals were examined for gross pathology.
- Other examinations performed:
The test sites were scored for dermal initation at 30 to 60 minutes post patch removal and again at 24, 48 and 72 hours post patch removal and on days 5, 7, 10 and 14 using the numerical Draize scoring code. The skin was also evaluated for ulceration and necrosis or any evidence of tissue
destruction. Additional signs were described. When there were no further positive scores noted in an animal scoring was discontinued in that animal.

An estimate of the LD50 was made based on the survival of animals during the study.

Results and discussion

Preliminary study:
No preliminary study conducted.
Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortalities. All animals survived the 2000 mg/kg dermal application.
Clinical signs:
Dermal Observations ( Table 1 in attached background material):
Dermal reactions were absent to well defined on day 1, absent to slight on day 2, absent to well defined on day 3, absent to moderate on days 4 and 5, and absent to well defined on day 7. By days 10 and 14, dermal reactions were absent to slight.

Systemic Observations (Table 2 in attached background material):
There were no abnormal systemic signs noted during the observation period.
Body weight:
Body weight (Table 1 in attached background material):
Body weight changes were normal in 8/10 animals. One male and one female lost weight at some time during the observation period.
Gross pathology:
Necropsy findings (Table 3 in attached background material):
Necropsy results were normal in 7/10 animals. Kidney abnormalities were noted in two males and treated skin abnormalities in one female.

Any other information on results incl. tables

Please refer to attached background material for Tables 1 -3:

Table 1: Body weights, dose volume in grams and dermal observations

Table 2: Systemic observations

Table 3:Necropsy observations

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The LD50 is greater than 2000 mg/kg of body weight.
Executive summary:

Objective:

To determine the potential for toxicity of the test article when applied dermally. This study was designed to comply with the standards set forth by EPA Acute Dermal Toxicity 40 CFR 798.1100 and EC Official Journal of the European Communities, L 383 A, Part B, Method B.3. Acute Dermal Toxicity, 12/29/92 and OECD Guidelines for Testing of Chemicals, No. 402, Acute Dermal Toxicity,

adopted 2/24/1987.

Method:

Five healthy male and five healthy female New Zealand White rabbits were dosed dermally with the test substance at 2000 mg/kg of body weight. The test article was kept in contact with the skin for 24 hours. Dermal responses were recorded at 30 - 60 minutes and at 24, 48 and 72 hours post patch removal and again on days 5, 7, 10 and 14. Animals were observed for toxicity and pharmacological effects at 1, 2 and 4 hours post dose and once daily for 14 days. All animals were observed twice a day for mortality. Body weights were recorded pretest, and on days 3, 7 and 14 or at death. All animals were examined for gross pathology.

Summary:

All animals survived the 2000 mg/kg dermal application.

There were no abnormal systemic signs noted during the observation period.

Dermal reactions were absent to well defined on day 1, absent to slight on day 2, absent to well defined on day 3, absent to moderate on days 4 and 5, and absent to well defined on day 7. By days 10 and 14, dermal reactions were absent to slight.

Body weight changes were normal in 8/10 animals. One male and one female lost weight at some time during the observation period.

Necropsy results were normal in 7/10 animals. Kidney abnormalities were noted in two males and treated skin abnormalities in one female.

Conclusion:

The LD50 is greater than 2000 mg/kg of body weight.