Registration Dossier

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

Administrative data

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The published study is well described. Read-across to tetradonium bromide from data on cetrimonium bromide.
Cross-reference
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1976

Materials and methods

Principles of method if other than guideline:
No guideline is given.
GLP compliance:
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): N-cetyl-N,N,N-trimethylammonium bromide (CTAB)
- 99% pure

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
3-4 weeks old housed in groups of 5 animals with free access to food and water

Administration / exposure

Route of administration:
oral: drinking water
Details on oral exposure:
The rats were given CTAB in drinking water in concentrations calculated to deliver doses of approximately 10, 20, and 45 mg/kg/day. The concentrations of CTAB in drinking water were increased during the study so that the intake of test substance per bodyweight was approximately constant throughout the experimental period. When the animals attained maturity (6-7 weeks on test) the concentrations of CTAB in drinking water were 0.007, 0.014, and 0.032%.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
56-60 weeks
Frequency of treatment:
Daily
Doses / concentrations
Remarks:
Doses / Concentrations:
10, 20, 45 mg/kg/day
Basis:
nominal in water
No. of animals per sex per dose:
10
Control animals:
yes
Details on study design:
Animals were distributed in 4 experimental groups of 10 males and 10 females each, balanced with respect to body weights.

Examinations

Observations and examinations performed and frequency:
The body weight, the length of the tail of each animal, and food and water consumption collectively for groups of 5 animals were recorded weekly during the first two months, biweekly during months 3 and 4 and monthly thereafter. Regular observations were made of the appearance and behavior of the animals.
Sacrifice and pathology:
The animals were killed 50-60 weeks after the beginning of the experiment. Blood was collected by heart puncture. Differential counts, haemoglobin determinations, quantitative determinations of serum protein, electrophoretic separation of serum proteins and determination of Na+ and K+ contents in serum were carried out. The liver, kidneys, heart, sleen, stomach, caecum, and submaxillary salivary glands were weighed. Specimens of the stomach and small intestine were fixed in buffered formalin, embedded in paraffin wax, and stained with Heidenhain's azan or kernechtrot.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Wetting and discoloration of ventral fur of 50% of the animals in the 45 mg/kg/day dosage group
Mortality:
mortality observed, treatment-related
Description (incidence):
Wetting and discoloration of ventral fur of 50% of the animals in the 45 mg/kg/day dosage group
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Reduced weight of the 45 mg/kg/day dosage group, males throughout the test period, females up to week 9 of the study
Food efficiency:
effects observed, treatment-related
Description (incidence and severity):
Decreased food efficiency of males in the 45 mg/kg/day dosage group up to week 8 of the study
Haematological findings:
no effects observed
Urinalysis findings:
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Reduced relative liver weight in males and increased relative caecum weight in both sexes in the 45 mg/kg/day dosage group. Increased relative caecum weight in males in the 20 mg/kg/day dosage group
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Reduced skeletal growth in the 45 mg/kg/day dosage group

Effect levels

Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Clinical signs; body weight; food efficiency; haematology; gross pathology; organ weights; histopathology

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Based on the results from the reported study it is concluded that cetrimonium bromide, when continuously administered in large doses, may potentially prevent proper nutrition by increasing the rate of gastric emptying and intestinal transit and/or by interfering with the absorption of nutritional substances. A NOAEL of 10 mg/kg/day is derived.
Executive summary:

A publication from 1976 reports the adverse effects observed in groups of 10 male and 10 female Sprague Dawley rats when treated orally for one year with 10, 20 and 45 mg cetrimonium bromide/kg bw/day. The following effects were noted:

10 mg/kg bw/day: - no statistically significant effects were observed

20 mg/kg bw/day: - increased relative caecum weight in males

45 mg/kg bw/day: - significantly reduced mean body weights in both sexes after

3 weeks, persisting till end of study in males and for 9 weeks in

females

- males: significantly decreased efficiency of food conversion

- significantly reduced skeletal growth (judged by the growth of the

tail) in both sexes

- wetting and discoloration of ventral fur, often associated with a

brown discoloration of the fur

- males: reduced relative liver weight

- increased relative caecum weight in both sexes

No compound related changes were observed in haematological and clinical laboratory analyses of blood and urine. No gross necropsy changes were seen, and no microscopic alterations were found in the wall of stomach and small intestine of treated rats. No other tissues were subjected to histopathological examination.

Based on the results from the reported study it is concluded that cetrimonium bromide, when continuously administered in large doses, may potentially prevent proper nutrition by increasing the rate of gastric emptying and intestinal transit and/or by interfering with the absorption of nutritional substances. A NOAEL of 10 mg/kg/day is derived.