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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
Study period:
1995-09-21 to 1996-03-05
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to an appropriate national standard method and in compliance with GLP.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1996
Report Date:
1996

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
other: US EPA Pesticide Assessment Guidelines, Subdivision F, Hazard Evaluation: Human and Domestic Aminals, Section 81-2. And: TSCA Health Effects Test Guidelines 40 CFR 798.1100
Qualifier:
according to
Guideline:
other: Japanese Agricultural Chemicals Laws and Regulations Testing Guidelines for Toxicology Studies published by the Society of Agricultural Chemical Industry, under the auspices of MAFF
GLP compliance:
yes
Test type:
fixed dose procedure
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Y-4036
- Physical state: clear, colourless liquid
- Analytical purity: 98.3 %
- Purity test date: 1995-09-27
- Lot/batch No.: 16912-29
- Storage condition of test material: original container at room temperature, under these conditions the substance is stable for several years

Test animals

Species:
rat
Strain:
other: Crl; CD®BR
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc.; Kingston, NY
- Age at study initiation: Young adult
- Weight at study initiation: 261 to 272 grams
- Housing: Individual suspended mesh-bottom cages. The animals were maintained by the animal husbandry staff of WIL Research Laboratories, Inc., in accordance with standard Operation Procedures.
- Diet (e.g. ad libitum): Purina® Certified Rodent Chow® #5002; ad libitum
- Water (e.g. ad libitum): municipal water, ad libitum
- Acclimation period: For a minimum of seven days

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 71.8 - 72.1 °F
- Humidity (%): 21 - 47.4%; The room humidity was slightly below the protocol-specified range on four days. This deviation had no impact on the integrity of the data or objectives of this study
- Photoperiod (hrs dark / hrs light): 12 hours light/ 12 hours dark

Administration / exposure

Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: Clipped dorsal skin
- % coverage: approximately 18 - 23% of the total body surface
- Type of wrap if used: Gauze banding, the bandage was secured with non-irritating tape

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Wiped with disposable paper towels moistened with tepid water
- Time after start of exposure: 24-hour exposure period

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): Individual doses of the test material were calculated based on body weights obtained just prior to dosing, as dose level of 2000 mg/kg and the specific gravity (0.98 g/ml, as determined by WIL Research Laboratories, Inc. pharmacy personnel). The dose volume was 2.04 ml/kg.

Duration of exposure:
24 h
Doses:
2000 mg/kg
No. of animals per sex per dose:
5 males and 5 females
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Mortality: approximately 1, 3 and 4 hours post-dose on day 0 and twice daily (morning and afternoon) thereafter for 14 days. Clinical Observations: approximately 1, 3 and 4 hours post-dose on day 0 and once daily thereafter for 14 days. Dermal Observation: approximately 30 - 60 minutes after bandage removal and daily thereafter for thirteen days. The rats were clipped to facilitate dermal observations on study days 7 and 14. Body weights were obtained and recorded on study days 0 (initiation), 7 and 14 (termination).
- Necropsy of survivors performed: yes

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
There were no deaths during the study.
Clinical signs:
Clinical findings were limited to dried red material around the mouth and/or nose for five rats and wet yellow urogenital staining for three rats. These findings are typically noted in association with the bandage/collar application procedures and were not a result of test material application. There were no other clinical findings. All animals appeared normal by day 1 or earlier and throughout the remainder of the study.
Body weight:
One female lost 4% of body weight between day 7 to day 14. Slight losses are common in animals which have been bandaged and collared for 24 hours. This female rat surpassed the initial day (0) body weight by termination (day 14). There were no other remarkable changes or differences in body weights.
Gross pathology:
Seven rats had reddened cervical lymph node(s) at the terminal necropsy. There were no other gross necropsy findings for any examined tissues.
Other findings:
Signs of toxicity (local): The test material induce very slight erythema on nine animals and very slight edema on three animals. Five rats
had desquamation. All dermal irritation completely subsided by day 8 or earlier, erythema in 3, edema in 2 days.

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: other: Draize, J.H., 1965. The Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics. Dermal Toxicity, pp. 46-59. Assoc. of Food and Drug Officials of the U.S., Topeka, Kansas.
Conclusions:
The LD50 of Y-4036 was found herein to be greater than 2000 mg/kg when applied once for 24 hours to the clipped, intact skin of male and female albino rats. In addition, the 2000 mg/kg dose level was found to be a NOEL for systemic toxicity under the conditions of this study.
Executive summary:

The acute dermal toxicity of Y-4036 was evaluated in this single-dose study in albino rats. The test material was administered once dermally at a dose of 2000 mg/kg to the clipped, intact skin of five male and five female albino rats for a 24 -hour exposure period under semi-occlusive dressing.

Mortality, clinical observations, dermal findings, body weights and gross necropsy findings were evaluated. There were no deaths, test material-related clinical findings or remarkable body weight changes. The test material induced very slight erythema on nine animals and very slight edema on three animals. Five rats had desquamation. There were no other dermal findings. All dermal irritation completely subsided by day 8 or earlier.

Reddened cervical lymph node(s) were observed in seven out of ten rats at the terminal necropsy. While the 70% incidence of this finding is suggestive of a test material-related effect, given the limited scope of this study and the absence of other effects, its toxicological significance is unclear. There were no other gross necropsy findings.

The LD50 of Y-4036 was found herein to be greater than 2000 mg/kg when applied once for 24 hours to the clipped, intact skin of male and female albino rats. In addition, the 2000 mg/kg dose level was found to be a NOEL for systemic toxicity under the conditions of this study.