Registration Dossier

Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Study initiated October 2019, Dose Range Finding (DRF) Study October 2019, Necropsy November 2019.
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2019
Report date:
2019

Materials and methods

Principles of method if other than guideline:
Draft DRF study for “Combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening of FeF cetyl trimethyl ammonium bromide (CTAB) USP/NF by oral gavage in rats” to follow OECD Guideline 422. Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, July 2016 and EPA Health Effects Test Guideline OPPTS 870.3650: Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, July 2000
GLP compliance:
yes
Remarks:
DRF study perfomed according to GLP, draft report will be signed and GLP approved in the report on main study 20212915

Test material

Constituent 1
Chemical structure
Reference substance name:
Cetrimonium bromide
EC Number:
200-311-3
EC Name:
Cetrimonium bromide
Cas Number:
57-09-0
Molecular formula:
C19H42N.Br
IUPAC Name:
hexadecyltrimethylazanium bromide
Test material form:
solid
Specific details on test material used for the study:
White powder
Batch (Lot) Number: GX0B433
Expiry date: 31 December 2022
Purity: 100% according to certificate of analysis

Test animals

Species:
rat
Strain:
Wistar
Sex:
female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
Dose levels: 0, 50, 100, 200, 300 mg/kg bw/day
Duration of treatment / exposure:
14 days
Frequency of treatment:
daily
No. of animals per sex per dose:
3 female rats/ group

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
All rats treated at 100, 200 and 300 mg/kg/day were sacrificed moribund at Day 5, 4 and 3 respectively. Cause of moribundity were considered test item-related forestomach lesions in all rats in the form of the macroscopic finding irregular surface with the microscopic correlate ulceration/erosion of the forestomach up to marked degree. This was accompanied by (sub) mucosal edema (up to moderate) and lymphogranulocytic inflammation (up to marked) and/or squamous cell hyperplasia (minimal).
Furthermore, findings in the glandular stomach were noted which consisted of a focal ulcer at 300 mg/kg/day (minimal) and from 200 mg/kg/day onward a slightly increased incidence of granulocytic infiltrate (minimal). Although these findings can be seen as spontaneous background findings, a relationship with treatment with the test item for these latter two findings cannot be excluded.
Minor findings were noted for the intestines which included a minor increase in incidence and/or severity of inflammatory cell infiltrate (up to slight) at 200 and/or 300 mg/kg/day and epithelial necrosis in the duodenum of one rat treated at 300 mg/kg/day (minimal). A test item-relationship cannot be excluded.
There was no microscopic correlate for the macroscopic finding gelatinous contents (considered test item-related) noted in the stomach of all 300 mg/kg/day treated rats and in the intestinal tract of all rats treated at 100, 200 and 300 mg/kg/day.
There were no test item-related morphologic alterations in rats treated at 50 mg/kg/day for 14 consecutive days.
Dermal irritation (if dermal study):
not specified
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Effect levels (P0)

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 50 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
gross pathology
Key result
Dose descriptor:
LOAEL
Effect level:
ca. 100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
gross pathology

Results: F1 generation

Effect levels (F1)

Remarks on result:
not determinable because of methodological limitations

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Adverse test item-related morphologic alterations following the administration of FeF Cetyl Trimethyl Ammonium Bromide (CTAB) USP/NF were noted at 100, 200 and 300 mg/kg/day in the form of an early onset of moribundity related with marked forestomach ulceration/erosion and concomitant findings, as edema, inflammation and squamous cell hyperplasia.

Treatment for 14 days at 50 mg/kg/day was well tolerated.
Due to the observed steep dose-reponse relationship for forestomach ulceration/erosion and because of longer exposure period in the main study, the maximum dose in the main study should be no higher than 50 mg/kg bw/day.