Quaternary ammonium compounds, C12-18-alkyltrimethyl, chlorides

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1991

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1991

Report date:

1991

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Version / remarks:

see 'Principles of method if other than guideline'

Deviations:

no

Principles of method if other than guideline:

Groups of 10 male and 10 female rats received test substance by oral gavage at the dose levels of 0, 30, 100 and 300 mg/kg bw/day for 28d. In addition, 5 male and 5 female animals were included in control and high dose group (recovery group). Animals were observed for clinical signs of toxicity, body weight changes, food and water consumption, haematological and biochemical parameters. Animals were necropsied and analysed for any visible abnormalities. Several tissues/organs were subjected to histopathological investigations in control and high dose group. Ophthalmological examination was also performed.

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Cetrimonium chloride

EC Number:

203-928-6

EC Name:

Cetrimonium chloride

Cas Number:

112-02-7

Molecular formula:

C19H42N.Cl

IUPAC Name:

N,N,N-trimethylhexadecan-1-aminium chloride

additive 1

Test material form:

liquid

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

28 days

Frequency of treatment:

Once daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 30, 100 and 300 mg/kg bw/day
Basis: other: The test substance used was a 24-26% aqueous solution but it is not clear if the doses mentioned are corrected for undiluted test substance.

No. of animals per sex per dose:

10 per sex per dose in main groups; 5 per sex in recovery groups (vehicle and highest dose group)

Control animals:

yes, concurrent vehicle

Details on study design:

- Rationale for selecting satellite groups: To check the reversibility of the effects, if any
- Post-exposure recovery period in satellite groups: at least 27d

Examinations

Observations and examinations performed and frequency:

Animals were observed for clinical signs of toxicity. Body weight, food and water consumption were recorded. Haematological and biochemical parameters were analysed. All animals were necropsied and checked for macroscopically visible abnormalities. Several tissues/organs were preserved and processed for histopathological investigations in control and high dose group. Additionally, eyes were examined with slit lamp microscope for any treatment-related abnormality.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Other examinations:

Animals in the recovery groups were observed for at least 27d after termination of the treatment.

Statistics:

Yes, no detail available in the summary.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Description (incidence and severity):

Symptoms of local irritation were observed in the high dose group during the last week of treatment.

Mortality:

no mortality observed

Description (incidence):

No deaths occurred throughout the study.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Total body weight gain was comparable to control in test groups.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

The mean food consumption in all treated groups was comparable to the control.

Food efficiency:

not specified

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

effects observed, treatment-related

Description (incidence and severity):

Water consumption was significantly increased in all animals of the high dose group.

Ophthalmological findings:

no effects observed

Description (incidence and severity):

The examination of the eyes by slit lamp microscope showed no treatment-related effects.

Haematological findings:

no effects observed

Description (incidence and severity):

The haematological examinations revealed no substance related variation from the control values.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

The highly significant increase in ALT-activity in the high dose group. The observed increase of the ALT-activity is considered to be an isolated finding as no other parameter is correlated with this deviation. Therefore, this finding is interpreted as incidental.

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

The absolute and relative organ weights such as spleen and adrenals showed some substance related changes in the males of high dose group.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

The macroscopical examination of the organs displayed substance related effects such as oedema of the mucosa of the forestomach, thickening of the mucosa and indication of ulceration in the animals of high dose group. Some additional observations like hydronephrosis, hydrometra and discolouration of the thymus showed no dose dependence and were therefore considered to be spontaneous. The observed irritative effects at the mucosa of the forestomach have been disappeared in the male and female animals of the recovery group 27d after termination of the treatment.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

The forestomach of the male and female animals of the high dose group showed effects indicating local irritation like inflammatory oedema of the submucosa, sporadic ulceration and acanthosis of the mucosa up to papillomatous hyperplasia. These observations were considered to be due to the irritating properties of test substance and were considered not to be symptoms of a systemic toxicity. The animals of the recovery group of high dose showed a complete and regular regeneration of the forestomach mucosa.

Histopathological findings: neoplastic:

not examined

Effect levels

Key result

Dose descriptor:

NOEL

Effect level:

ca. 100 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: based on increase in water consumption, changes in the absolute and relative weights of the adrenals and spleens (in males) without corresponding effects on haematology, clinical chemistry and histology

Remarks on result:

other: corrected to 25 mg a.i./kg bw/day (as it was unclear from the study report if it was already corrected for the undiluted test substance)

Target system / organ toxicity

Key result

Critical effects observed:

no

Applicant's summary and conclusion

Conclusions:

Under the study conditions, the rat 28 d NOEL for systemic effects was considered to be at 100 mg/kg bw/day, which is corrected to 25 mg a.i./kg bw/day (assuming its not been done in the study report)

Executive summary:

A study was conducted to determine the oral repeated dose toxicity of the test substance, C16 TMAC (24 -26% active in water), according to a method similar to OECD Guideline 407, in compliance with GLP. Groups of 10 male and female rats were administered 0, 30, 100 and 300 mg/kg bw/day of test substance by oral gavage for 28 days. The test substance used was a 24-26% aqueous solution but it is not clear if the doses mentioned were corrected. There were no treatment-related changes at the 30 and 100 mg/kg bw/day. In the high-dose group there was an increase in water consumption, changes in the absolute and relative weights of the adrenals and spleens (in males) without corresponding effects on haematology, clinical chemistry and histology. The forestomach of the high-dose group showed few microscopic changes, however animals in the high-dose recovery group showed a complete and regular regeneration of the forestomach mucosa. Hence, the forestomach effects were considered to be due to the irritating properties of the test substance rather than symptoms of systemic toxicity. Under the study conditions, the rat 28 d NOEL for systemic effects was considered to be at 100 mg/kg bw/day, which is corrected to 25 mg a.i./kg bw/day (assuming its not been done in the study report) (Potokar, 1991).