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Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Waiving with regard to OECD 421/422 testing on Annex VIII level and further reproductive toxicity testing on ANNEX IX level :

In a dermal developmental toxicity study with rats dosed to cetrimonium chloride at 0, 10, 20 and 40 mg/kg bw/d (using test solutions of 0, 0.5, 1.0 and 2.0 %) no maternal systemic effects were observed even at the highest at a dose level up to NOAEL of 40 mg/kg. However, skin irritation was observed at all dose levels increasing to marked irritation at highest dose level.

In an 28D oral gavage study with cetrimonium chloride dosed to rats at 7.5, 25 and 75 mg/kg bw/d no clear systemic effects were noted at the highest dose level of 75 mg/kg bw/d. However, severe local effect in the forestomach was noted. The rats were dosed with 10 ml water test solution/kg bw/ d. Thus the concentration in the test solution at the highest dose level was 75 mg/10 ml or 0.75% .

In a 1 year oral study with rats dosed with cetrimonium bromide via drinking water at concentrations of 0; 007%; 0.014% and 0.032% corresponding to 0; 10; 20 and 45 mg/kg bw/d no gross pathological effects were seen. A significant and persistent decrease in body weight were seen in males at 45 mg/kg bw/d. a dose level that also resulted in wetting of the anterior ventral region of the animals and brown discoloration of the fur. The authors concluded the decrease in body weight to be a follow of a decrease in feed efficiency due to local effects in the gastrointestinal tract inducing increased emptying and possible decreased absorption of the nutrients.

The lack of systemic effects in these studies may be explained by the very low dermal and oral absorption rate as indicated by the toxicokinetic studies where absorption rates of about 3 and 6%, respectively, were found .

Thus if an oral dose level at about 75 mg/kg bw/d should be used as an upper tolerable dose level in an oral OECD 421 or 422 reproductive screening study a systemic dose at about 5 mg /kg bw/d can be expected. Given the lack of specific alerts for reproductive effects for the substance it is very unbelievable that such a low systemic dose level in a screening study would result in adverse effects leading to concern for reproductive effects.

Due to the potent local toxicity of the substance and due to the given scientific reasons (as well as animal wellfare reasons) it is not considered justified to perform the OECD 421 or 422 reproductive toxicity screening study for cetrimonium bromide.

Effects on developmental toxicity

Link to relevant study records
Reference
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.
Principles of method if other than guideline:
No guideline stated
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
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
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.
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.
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.
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.
Abnormalities:
not specified
Developmental effects observed:
not specified

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.

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.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no adverse effect observed
Additional information

20 mated female New Zealand rabbits were dermally dosed with 0; 10; 20 and 40 mg/kg bw /d of cetrimonium chloride (concentrations in solutions used: 0.5; 1; and 2%) during the gestation days 7-18. No compound related foetotoxic or developmental effects were noted .The NOEL for maternal systemic toxicity and embryo-foetal toxicity appeared to be 40 mg cetrimonium chloride/kg bw/day. Skin irritation was observed at all doses with dose-related severity and duration.

These data on cetrimonium chloride are considered relevant for read-across to cetrimonium bromide.

Justification for classification or non-classification

The available data on cetrimonium chloride does not support any classification for reproductive toxicity for cetrimonium bromide.