Quaternary ammonium compounds, (C16-18 and C18-unsatd. alkyl)trimethyl, chlorides

Repeated dose toxicity: dermal

Administrative data

Endpoint:

sub-chronic toxicity: dermal

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Study period:

1979

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

However, few deficiencies were observed in the study such as tested with lesser number of animals (i.e., 10/group rather than 20/group as per guideline) and histoptahology of limited organs was performed.

Justification for type of information:

Information on the category justification can be found in the Quaternary ammonium salts (QAS) category and section 13.2 of IUCLID.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2001

Report date:

2001

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Quaternary ammonium compounds, (C16-18 and C18-unsatd. alkyl)trimethyl, chlorides

EC Number:

268-074-9

EC Name:

Quaternary ammonium compounds, (C16-18 and C18-unsatd. alkyl)trimethyl, chlorides

Cas Number:

68002-61-9

Molecular formula:

Representative molecular formula of the major constituents, as the substance is an UVCB: C16 TMAC: C19H42CL1N1 C18 TMAC: C21H46CL1N1 C18-unsatd. TMAC: C21H44CL1N1

IUPAC Name:

Quaternary ammonium compounds, (C16-18 and C18-unsatd. alkyl) trimethyl, chlorides

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

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

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

Key result

Dose descriptor:

NOAEL

Effect level:

10 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

dermal irritation

other: see 'Remark'

Target system / organ toxicity

Key result

Critical effects observed:

no

Applicant's summary and conclusion

Conclusions:

Under the study conditions, the NOAEL for the target substance is considered to be 10 mg/kg bw/day.

Executive summary:

A 28-day study was conducted to determine the repeated dose dermal toxicity of the source substance, TMAC C16 (54.5% active in aqueous isopropanol), in New Zealand albino rabbits (both sexes) according to a method similar to OECD Guideline 410. The purity was not specified and the study included a lower than recommended number of animals (i.e., 10/group rather than 20/group as per guideline) and histopathology was performed only on limited organs. The source substance (0 and 10 mg/kg bw/day) was applied to the shaved, intact skin of groups of 5 New Zealand albino rabbits/sex/group for 6.5 to 7 h, 5 days/week for 4 weeks. 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 and limited histopathology was conducted. There were no systemic treatment-related effects on 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 study conditions, the 28d NOAEL for male and female rabbits were determined to be 10 mg/kg bw/day (TRS-HPV, 2001). Based on the results of the source study, similar absence of systemic effects can be expected for the target substance.