Registration Dossier

Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
From 22 February, 1988 to 24 March, 1988
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
KL2 due to RA
Justification for type of information:
Refer to the Quaternary ammonium salts (QAS) category or section 13 of IUCLID for details on the category justification.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1988
Report Date:
1988

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPP 81-2 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
other: Toxic Substances Control Act (TSCA) acute dermal toxicity guideline
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Test material form:
solid

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Mochican Valley Rabbitry, Loidonville, Ohio
- Weight at study initiation: 2140 to 2990 g
- Housing: individual suspended wire-mesh cages
- Diet (e.g. ad libitum): Purina Certified rabbit chow # 5322, ad libitum
- Water (e.g. ad libitum): Tap water ad libitum
- Acclimation period: Minimum 7 d

ENVIRONMENTAL CONDITIONS
- Humidity (%): 49-74%
- Photoperiod (h dark / h light): 12 h / 12 h

Administration / exposure

Type of coverage:
semiocclusive
Vehicle:
water
Details on dermal exposure:
TEST SITE
- Area of exposure: Shaved intact dorsal skin
- % coverage: 20%
- Type of wrap if used: Test substance was applied under gauze binders that were secured with non-irritating tape.
Duration of exposure:
24 h
Doses:
0, 520, 1020 and 2000 mg/kg bw.
No. of animals per sex per dose:
Five animals per sex per test group, three animals per sex in control group.
Control animals:
yes, concurrent vehicle
Details on study design:
- Duration of observation period following administration: Animals were observed at 1, 3 and 4 h post-dosing on Day 0 and twice daily for mortality and once daily for clinical observations for 14 d. Application sites were examined for erythema, oedema and other dermal findings at 30−60 min after bandage removal and daily thereafter for 13 d. Erythema and oedema were graded according to Draize method.
- Frequency of observations and weighing: Day 0, 7 and 14
- Necropsy of survivors performed: yes
Statistics:
LD50 and slopes (with 95% confidence limits) were calculated by method of Litchfield and Wilcoxon.

Results and discussion

Effect levelsopen allclose all
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
1 300 mg/kg bw
Based on:
test mat.
95% CL:
ca. 800 - ca. 1 900
Remarks on result:
other: i.e., equivalent to 429 mg a.i./kg bw
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
1 900 mg/kg bw
Based on:
test mat.
95% CL:
ca. 1 500 - ca. 2 400
Remarks on result:
other: i.e., equivalent to 627 mg a.i./kg bw
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
1 600 mg/kg bw
Based on:
test mat.
95% CL:
ca. 1 200 - ca. 2 100
Remarks on result:
other: i.e., equivalent to 528 mg a.i./kg bw
Mortality:
Control: 0/6 animals
520 mg/kg bw: 0/10 animals
1020 mg/kg bw: 2/5 males and 0/5 females
2000 mg/kg bw: 4/5 males and 3/5 females
Clinical signs:
Lethargy and ataxia were major clinical findings. Other findings included hypothermia, decreased respiratory rate, laboured respiration, nasal discharge, decreased defecation, emaciation, red staining around the mouth, diarrhoea.
Body weight:
Treatment-related body weight loss in one animal each at two higher doses throughout the 14 d. For other eight rabbits body weight was decreased during first wk with a subsequent recovery in the second wk and net gain in the entire 14 d study period.
Gross pathology:
Treatment-related abnormality on the application sites of all rabbits. No substance-related internal abnormalities in rabbits that died during study or terminally sacrificed.
Other findings:
Test substance induced moderate to severe erythema and oedema with other significant dermal findings such as necrosis, desquamation, scabbing, eschar, exfoliation, fissuring and blenching. Subcutaneous haemorrhage was present on the application sites of one rabbit in the 2000 mg/kg bw group that survived and all animals that died.

Any other information on results incl. tables

Only (systemic) pathology observed in animals sacrificed at termination were kidney abnormalities (pale, reddened, pitted) in 5/21 of the terminally sacrificed dosed rabbits. Pale kidneys were also observed for one female in the control group. The skin of the animals that died showed eschar, subcutaneous haemorrhage, blanching and thickening. Internal abnormalities included hemorrhagic thymus glands (6/9) (typical agonal change), red foci or dark red area in the stomach (3/9), brain haemorrhages (3/9) and liver soft or pale and soft (2/9). No internal abnormalities were observed among rabbits that died which could be attributed to the test substance. There were no test substance related internal changes for rabbits that were terminally sacrificed.

Considering the generally low dermal absorption of Coco TMAC (<10% in Bartnik and Wingen, 1979 study), it is likely that severe corrosive effects upon the 24 h exposure of the concentrated product were more cause to the death of the animals, than real systemic toxicity. This is supported by the relatively limited observations on internal organs upon necropsis of the animals that died. The most commonly observed internal abnormalities were hemorrhagic thymus glands (6/9), which is a typical agonal change, and likely not a specific sign of toxicity.

Mortality and other observations

Table 1.                           Table for Acute Toxicity

Dose [mg a.s./kg bw]

Number of dead /
number of investigated

Time of death (range)

Observations

0

0/6

 

Pale kidneys were observed for one female in the control group. No other changes were noted for control group.

172

0/10

 

Eschar and thickening on the application site.

Decreased defecation primarily early in the study period(7/10). Also observed in one or two animals: clear wet matting around the mouth, clear wet ventral abdominal matting, clear nasal discharge, diarrhea, scabbing on the right hind leg and hair loss and desquamation in the urogenital area.

337

2/10

Found dead morning 1stand 2ndday

Eschar, subcutaneous hemorrhage, blanching and thickening were noted on the application sites of rabbits that died, and Eschar and thickening on the application site of the other animals.

Decreased defecation primarily early in the study period(4/10). Also observed in one or two animals: clear wet matting around the mouth, clear wet ventral abdominal matting, clear nasal discharge, diarrhea, scabbing on the right hind leg and hair loss and desquamation in the urogenital area.

660

7/10

Found dead morning 1stday.

Lethargy, ataxia, laboured respiration, purulent nasal discharge on day 1, emaciated appearance.

Necrosis, desquamation, scabbing, eschar, exfoliation, fissuring and blanching. Also, subcutaneous hemorrhage was present on the application sites of one rabbit in the 2000 mg/kg group that survived and all animals that died.
No internal abnormalities were observed among rabbits that died which could be Attributed to the test material.

LD50value

Male & female combined: 528 (396 – 693) mg a.s/kg bw

 

For further details on result tables, kindly refer to the attached background material section of the IUCLID.

Applicant's summary and conclusion

Interpretation of results:
other: Category 3 based on CLP criteria
Conclusions:
Based on the results of the read across study, the acute dermal LD50 for male and female albino rabbits were determined to be 1,300 mg/kg bw (i.e., equivalent to 429 mg a.i./kg bw) and 1,900 mg/kg bw (i.e., equivalent to 627 mg a.i./kg bw) respectively, and the combined dermal LD50 was determined to be 1,600 mg/kg bw (i.e., equivalent to 528 mg a.i./kg bw).
Executive summary:

A study was conducted to determine the acute dermal toxicity of the read across substance, Coco TMAC (33% active in water), in albino rabbits according to OECD 402 Guideline, in compliance with GLP. Semi-occlusive patches of the read across substance at 0, 520, 1,020 or 2,000 mg/kg bw (i.e., equivalent to 0, 172, 337 and 660 mg a.i./kg bw) was applied to the shaved, intact skin of groups of 10 rabbits (five per sex) for 24 h. Animals were observed at 1, 3 and 4 h post-dosing. Following the 24 h exposure period, animals were observed for mortality, clinical signs and skin response for 14 d. There was no mortality in the control or 520 mg/kg bw (or 172 mg a.i./kg bw) group. Two males died in the 1,020 mg/kg bw (or 337 mg a.i./kg bw) group while 4 males and 3 females died in the 2,000 mg/kg bw (or 660 mg a.i./kg bw) group. Under the study conditions, the acute dermal LD50 for male and female albino rabbits were determined to be 1,300 mg/kg bw (i.e., equivalent to 429 mg a.i./kg bw) and 1,900 mg/kg bw (i.e., equivalent to 627 mg a.i./kg bw) respectively, and the combined dermal LD50 value for males and females was determined to be 1,600 mg/kg bw (i.e., equivalent to 528 mg a.i./kg bw). Considering the generally low dermal absorption potential of Coco TMAC (<10% in Bartnik and Wingen, 1979 study), the observed systemic effects and mortality were attributed to the severe corrosive properties of the read across substance following 24 h exposure rather than real systemic toxicity. This is supported by the relatively limited observations on internal organs upon necropsis of the animals that died (Naas, 1988). Based on the results of the read across study, similar LD50 can be expected for the test substance.