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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
sub-chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1979
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study is well documented, meets generally accepted scientific principles, acceptable for assessment. However, a few deficiencies were observed in the study such as tested with reduced number of animals (i.e., 10/group rather than 20/group as per guideline) and histoptahology of limited organs was performed. Hence, maximum reliability rating of 2 assigned according to ECHA guidance.

Data source

Reference
Reference Type:
publication
Title:
Subchronic percutaneous toxicity (twenty-eight days) in rabbits.
Author:
Spicer EJF
Year:
1979
Bibliographic source:
International Research and Development Corporation, Mattawan, MI, USA, Unpublished Report No. 191-217. Cited in 1 and in 54.

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Principles of method if other than guideline:
A 28-day dermal study was conducted in rabbits to evaluate the repeated dose dermal toxicity of the test substance.

GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
not specified
Details on test material:
- Name of test material (as cited in study report): Cetrimonium chloride

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female

Administration / exposure

Type of coverage:
open
Vehicle:
water
Details on exposure:
TEST SITE
- Area of exposure:
- % coverage: 25% of the body surface area.
- Time intervals for shavings or clipplings: all rabbits was abraded with a clipper head prior to the start of each application

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Following the exposure period, the treated skin surface was cleaned with water


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0 or 10 mg/kg bw/day
- Concentration (if solution): 0 or 0.5% aqueous solutions, respectively. The dosage volume was 2.0 ml/kg bw


USE OF RESTRAINERS FOR PREVENTING INGESTION: yes, The animals were restrained with collars during the exposure period
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
6.5 to 7 hours
Frequency of treatment:
5 days/week for 4 wks
Doses / concentrations
Remarks:
Doses / Concentrations:
0 or 10 mg/kg/day
Basis:
no data
No. of animals per sex per dose:
5 New Zealand albino rabbits/sex/group
Control animals:
yes, concurrent vehicle
Details on study design:
- Duration of observation period following administration: All rabbits were examined daily for clinical signs and mortality. Dermal irritation
readings were recorded daily. The animals were weighed weekly during the exposure period. Blood was collected for haematology measurements before initiation of dosing and prior to termination. Liver and kidneys were weighed at necropsy. A complete list of tissues
was collected for histopathological evaluation
- Frequency of observations and weighing: weekly
- Necropsy of survivors performed: yes

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes / No / No data
- Time schedule: twice daily

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: Daily

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Blood was collected for haematology measurements before initiation of dosing and prior to termination

OTHER:
Mortality : twice daily
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes Liver and kidneys were weighed at necropsy. A complete list of tissues was collected for histopathological evaluation

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Description (incidence and severity):
Treated areas of the skin that showed mild to marked acanthosis with active mitosis, hyperkeratosis, and partial to extensive necrosis of the epidermis and hair follicles, partly with encrustation and exudate
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Haematological findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Details on results:
Two control group animals died during the study. Slight to moderate erythema was observed in all treated rabbits between days 4 and 8, but disappeared in 4 rabbits by day 17. Very slight to slight oedema was observed between days 6 and 12 in 4 rabbits and subsided by day 17. Two rabbits had intermittent slight oedema during week 4, and one rabbit developed oedema on day 20. No evidence of desquamation or leather-like skin was present in these animals. In the other rabbits, slight atonia occurred up to week 4 in 3 animals. Slight skin fissuring was observed in most of the rabbits but typically disappeared by the end of the study. There were no treatment-related effects on body weight, haematology, organ weight, gross necropsy findings or histopathology, except for treated areas of the skin that showed mild to marked acanthosis with active mitosis, hyperkeratosis, and partial to extensive necrosis of the epidermis and hair follicles, partly with encrustation and exudate.

Effect levels

Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Under the conditions of the test, the 28 d acute dermal NOAEL of the test substance for male and female rabbits was found to be 10 mg/kg bw/day and does not require a classification under according to EC (67/548/EEC) and CLP criteria (EC 1272/2008).
Executive summary:

A 28 day repeated dermal toxicity study was conducted in New Zealand albino rabbit (both sexes) exposed to C16 TMAC. The purity was not specified and the study included a lower number of animals (i.e., 10/group rather than 20/group as per guideline) and only histopathology of limited organs was performed. The test substance was applied (5 days/week for 4 weeks) to groups of 5 New Zealand albino rabbits/sex/group at the dose levels of 0 and 10 mg test substance/kg bw/day to the shaved, intact skin for 6.5 to 7 hours. Dermal irritation readings were recorded daily. The animals were weighed weekly during the exposure period. Blood was collected for haematology measurements before initiation of dosing and prior to termination. Liver and kidneys weights were recorded at necropsy. A complete list of tissues was collected for histopathological evaluation. There were no systemic treatment-related effects on the body weights, haematology, organ weights, gross necropsy findings or histopathology. Treated areas of the skin showed mild to marked acanthosis with active mitosis, hyperkeratosis, and partial to extensive necrosis of the epidermis and hair follicles, partly with encrustation and exudate. Under the conditions of the test, the NOAEL for male and female rabbits was found to be 10 mg test substance/kg bw/day (Spicer EJF, 1979).