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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Read-across to cetrimonium bromide from data on cetrimonium chloride (with data reliability value of 2). Read-across justifications are provided in the endpoint summary.

Data source

Referenceopen allclose all

Reference Type:
other: SCCS opinion document
Title:
Unnamed
Year:
2009
Report Date:
2009
Reference Type:
other: Assessment report for American Chemistry Council, Fatty Nitrogen Derivatives Panel, Cationics Task Group
Title:
Unnamed
Year:
2001

Materials and methods

Principles of method if other than guideline:
No guideline stated
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid - liquid: aqueous solution
Details on test material:
The SCCS opinion document refers to a study with cetrimonium chloride.
- Name of test material (as cited in study report): cetrimonium chloride
- Molecular formula (if other than submission substance): C19H42N.Cl
- Molecular weight (if other than submission substance): 320.0

Test animals

Species:
rabbit
Strain:
New Zealand White

Administration / exposure

Route of administration:
dermal
Vehicle:
water
Details on exposure:
Animals were exposed to 2.0 ml/kg of the test substance topically at concentrations of 0, 0.5, 1.0, or 2.0%. These doses corresponded to daily exposures of 0, 10, 20 and 40 mg/kg/day, respectively. The control group was treated with deionized water only. Prior to initial treatment, the dorsal area of each animal was shaved and any skin lesions were documented. At the time of treatment, the animals were fitted with a collar to prevent oral ingestion of the test substance. After the 2-hour exposure period, the collars were removed and the application site was rinsed with water and dried.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
2 hours
Frequency of treatment:
Daily for days 7 to 18 of gestation.
Duration of test:
29 days - days 0-29 of gestation
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 10, 20 and 40 mg/kg bw/day
Basis:
other: dermal treatment
No. of animals per sex per dose:
20 mated female per dose
Control animals:
yes
Details on study design:
Prior to initial treatment, the dorsal area of each animal was shaved and any skin lesions were documented. After the 2-hour exposure period, the application site was rinsed with water and dried.

Examinations

Maternal examinations:
Animals were observed twice daily for signs of toxicity, including skin irritation from days 7 through 29. Body weights were taken on gestation
days 0, 3, 6, 9, 12, 15, 18, 21, 24, 27 and 29. Individual food consumption was measured daily. A gross necropsy was conducted on animals that died in an attempt to determine the cause of death.

Following removal of the foetuses, the abdominal and thoracic cavities and
organs of the dams were examined.
Ovaries and uterine content:
All surviving dams were sacrificed at study termination on gestation day 29 using sodium pentobarbital. An examination of the uterus (including the number and location of live and dead foetuses, early and late resorptions, and implantation sites), and ovaries (including the number of corpora lutea), was conducted. Uteri from females that appeared non-gravid were placed in 10% ammonium sulfide solution for confirmation of pregnancy.
Fetal examinations:
Foetuses less than 28 days old were fixed in buffered neutral formalin and those 28 days or older were cleared and stained. At sacrifice foetuses were identified, weighed, and examined externally for defects. Gross dissection and examination of viscera, and internal sex determination also were conducted on each foetus. Finally, an examination of the skeleton for anomalies and ossification variations was conducted after clearing and alizarin
red staining of the foetuses.
Statistics:
Body weight changes and food consumption and number of early and late resorptions, dead fetuses, total implantations, corpora lutea, skeletal abnormalities, and mean fetal body weight were compared by analysis of variance (Bartlette’s). If variance was not significant, then treatment-control comparisons were made using the least significant difference (LSD) criterion. If variance was significant, then comparisons were made using the t-test for unequal variances and the Wilcoxon, Mann-Whitney rank sum test. Additionally, a regression and lack of fit were performed on each of these parameters. The number of pregnancies per group, the percentage of skeletal abnormalities and soft tissue malformations were compared in each treated group to the control group by Fisher’s exact test. A 5% two-sided risk was used.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Skin irritation was observed at all doses with dose-related severity and duration, and included erythema, oedema, desquamation, atonia and coriaceousness. Marked to moderate irritation was observed primarily in the mid and high dose groups. No treatment-related maternal body weight or food intake effects were noted. A slight increase in congested lungs was observed in the high dose group at necropsy.

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
The incidence of foetal malformation and genetic and developmental variation in the treated groups was comparable to that of the control group. No other treatment-related effects were noted.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Two control, one intermediate and one high dose pregnant females died during the study. The cause of death could not be determined. Two of the animals that died aborted prior to death (one control and one intermediate dose group animal). Two additional abortions occurred, one each in the intermediate and high dose groups. None of these deaths or abortions were considered related to test substance toxicity.

Applicant's summary and conclusion

Conclusions:
Under the test conditions used, cetrimonium chloride was found to be non-foetotoxic and non-teratogenic. The NOEL for maternal systemic toxicity and embryo-foetal toxicity appeared to be 40 mg cetrimonium chloride/kg bw/day.
Executive summary:

20 mated female New Zealand albino white rabbits per group were exposed daily for days 7 to 18 of gestation to cetrimonium chloride at dermal dosage levels of 0, 10, 20 and 40 mg/kg bw/day.

Maternal toxic effects: Skin irritation was observed at all doses with dose-related severity and duration, and included erythema, oedema, desquamation, atonia and coriaceousness. Marked to moderate irritation was observed primarily in the mid and high dose groups. No treatment-related maternal body weight or food intake effects were noted. A slight increase in congested lungs was observed in the high dose group at necropsy.

Embryotoxic effects: The incidence of foetal malformation and genetic and developmental variation in the treated groups was comparable to that of the control group. No other treatment-related effects were noted.

Under the test conditions used, cetrimonium chloride was found to be non-foetotoxic and non-teratogenic. The NOEL for maternal systemic toxicity and embryo-foetal toxicity appeared to be 40 mg cetrimonium chloride/kg bw/day.