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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:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1983
Report Date:
1983

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: 16 CFR 1500 "Method of testing toxic substances - Acute dermal toxicity (single exposure)"
Deviations:
yes
Remarks:
Study used less than the recommended number of test animals at each dose level; three male and two female rabbits weighed more than 3000 grams
Principles of method if other than guideline:
New Zealand White rabbits, initial body weights 2611 to 3836 g, were used to evaluate the acute dermal toxicity of the test substance. Test animals were caged individually under a 12-hour light/12-hour dark cycle and were acclimated for at least 32 days prior to testing. Food and water were provided ad libitum. Both sexes were initially tested at dose levels of 1000 and 2150 mg/kg; males were then treated with 4640 and 10 000 mg/kg and females were treated with 215 and 464 mg/kg, based on mortality data from the initial doses. Prior to dosing, the trunk of each animal was shaved and the skin of half the animals in each dose group was abraded. The test material was applied undiluted via occlusive patch around the trunk of each animal and wrapped in a layer of gauze and tape. Animals were restrained and observed for signs of systemic toxicity over the 24-hour exposure period. After 24 hours, the patches were removed, the exposed skin was cleaned, and test animals were observed daily for signs of irritation, systemic toxicity and mortality for 14 days. Animals were weighed and necropsied at death; surviving animals were euthanised, weighed and necropsied at the end of the observation period. Mortality data were evaluated by the method of Weil (1952, Biometrics, 8:249-263).
GLP compliance:
not specified
Test type:
other: Method of testing toxic substances- acute dermal toxicity
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid
Details on test material:
- Name of test material (as cited in study report): 1379-20
- Storage condition of test material: room temperature in a closed glass container

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Clerco Research Farm
- Weight at study initiation: 2611 to 3836 grams
- Fasting period before study: no data
- Housing: housed individually in wire mesh suspension cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 32 days prior to dosing

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

IN-LIFE DATES: From: February 21, 1983 To: March 15, 1983

Administration / exposure

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: trunk
- % coverage: no data
- Type of wrap if used: sleeve of rubber dental damming which was wrapped around the trunk of each rabbit and secured with staples. An outer layer of gauze and tape and was also wrapped around the trunk of each animal.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): gentle sponging with a moist towel
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): Dosages were 215, 464, 1000 and 2150 mg/kg in females; 1000, 2150, 4640 and 10 000 mg/kg in males. Both sexes were initially treated with dosages of 1000 and 2150 mg/kg. Males were then treated with dosages 4640 and 10,000 mg/kg and females were treated with dosages of 215 and 464 mg/kg.
- Constant volume or concentration used: concentration

VEHICLE
-No vehicle used
Duration of exposure:
24 hours
Doses:
1000, 2150, 4640, and 10 000 mg/kg (males);
215, 464, 1000, and 2150 mg/kg (females)
No. of animals per sex per dose:
2
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: animlas were observed for gross signs of systemic toxicity, dermal irritation, and death for 14 days. Animals were weighed at the end of the 14-day observation period.
- Necropsy of survivors performed: yes
Statistics:
no data

Results and discussion

Preliminary study:
not applicable
Effect levelsopen allclose all
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
1 000 mg/kg bw
95% CL:
460 - 2 020
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
2 150 mg/kg bw
95% CL:
1 000 - 4 620
Mortality:
Cumulative mortality (total number of deaths/total number dosed), by sex and dose level:
215 mg/kg: 0/2 females
464 mg/kg: 0/2 females
1000 mg/kg: 1/2 females (day 3); 0/2 males
2150 mg/kg: 2/2 females (days 3, 6); 1/2 males (day 4)
4640 mg/kg: 2/2 males (days 4, 6)
10 000 mg/kg: 2/2 males (day 3)
Clinical signs:
Frequently observed clinical signs included death, uncoordinated movements, and shaking and hypersensitivity to external stimuli. All clinical sign disappeared in surviving animals by the end of the exposure period. The most frequently observed irritative effects were erythema, edema, atonia, desquamation, and blanching.
Body weight:
Males- Body Weight (g)
Animal no. Skin condition Day 0 Day 15 Body Weight Gain Day 0-15 (g)
1000 mg/kg
1 abraded 3836 3866 30
2 intact 3084 3699 615
Mean (SD) 3460 (532) 3782 (62) 322 (414)
2150 mg/kg
5 abraded 2698 2879 181
6 intact 2611 rabbit died prior to observation
Mean (SD) 2964 (446) 2879 181
4640 mg/kg
9 abraded 2818 rabbit died prior to observation
10 intact 3085 rabbit died prior to observation
Mean (SD) 2952 (189)
10 000 mg/kg
13 abraded 2985 rabbit died prior to observation
14 intact 2944 rabbit died prior to observation
Mean (SD) 2964 (29)
Gross pathology:
Gross necropsy results for animals that died during observation included irritated intestines, blanched stomach, reddened lungs, pale or congested kidneys, and oral, ocular, and/or nasal discharge. Necropsies of surviving animals at the end of the study revealed no relevant findings.
Other findings:
Upon removal of the binders from the animals, the binder and the exposed area were dry with no sample apparent on most of the animals. The 10 000 mg/kg males and one 2150 mg/kg female had moist sites with sample apparent after application.

Any other information on results incl. tables

Females- Body Weight (g)Animal no.     Skin condition       Day 0                   Day 15          Body Weight Gain Day 0-15 (g)215 mg/kg15                abraded           2904                     3209                         30516                intact            3201                     3568                         367Mean (SD)                           3052  (210)              3388  (254)                  336 (44)464 mg/kg11                abraded           2783                     2895                         11212                intact            2758                     3065                         307Mean (SD)                           2770  (18)               2980 (55)                    210 (138)1000 mg/kg3                 abraded           3280                     rabbit died prior to observation4                 intact            2649                     3051                         402Mean (SD)                           2964 (446)               3051                         4022150 mg/kg7                 abraded           2955           rabbit died prior to observation8                 intact            2629           rabbit died prior to observationMean (SD)                           2792 (231)

Applicant's summary and conclusion

Interpretation of results:
other: Classified as Category 3 in accordance with EU criteria
Conclusions:
The acute dermal LD50 value was found to be 2.15 g/kg in male and 1.0 g/kg in female New Zealand White rabbits.
Executive summary:

The test material was applied undiluted to the skin of sixteen New Zealand White rabbits (two males and two females per dose level) at dosages of 0.215, 0.464, 1.0, 2.15 (females) or 1.0, 2.15, 4.64 and 10.0 g/kg (males) for 24 hours. Animals were observed for gross signs of systemic toxicity, dermal irritation, and death for 14 days. At the end of the 14­day observation period, survivors were weighed, killed, and given a gross necropsy.

Deaths occurred between days 3 and 6 of the observation period. Clinical changes associated with the test material included death, shaking behavior, uncoordinated movement, ataxia and hypersensitivity. The most frequently observed irritative effects included erythema, edema, atonia, desquamation and blanching. Gross necropsies performed on the animals that died revealed irritated gastrointestinal tracts, pale or congested kidneys and reddened lungs. Gross necropsies performed on survivors at the end of the study revealed no gross alterations. The acute dermal LD50 value was found to be 2.15 g/kg in male and 1.0 g/kg in female New Zealand White rabbits.