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Repeated dose toxicity: oral

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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

Constituent 1
Chemical structure
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
Chemical structure
Reference substance name:
Water
EC Number:
231-791-2
EC Name:
Water
Cas Number:
7732-18-5
Molecular formula:
H2O
IUPAC Name:
water
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).