Registration Dossier

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 tetradonium bromide.

Effects on developmental toxicity

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1979
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Read-across to tetradonium bromide from data on dodecyltrimethylammonium chloride (with data reliability value of 2). R
Principles of method if other than guideline:
No guideline stated.
GLP compliance:
no
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Route of administration:
oral: gavage
Details on exposure:
Definitive study: Thirteen or 14 mated female rabbits per group were exposed to the test substance orally at doses of 0, 2, 8 and 24 mg/kg/day for days 6 through 18 of gestation. The control group was treated with deionized water only.
Range-Finding Study: Three mated female rabbits per group were exposed to the test substance orally at doses of 0, 25, 50, 100, 200 or 400 mg/kg/day for days 6 through 18 of pregnancy.
Duration of treatment / exposure:
Days 6 - 18 of gestation
Frequency of treatment:
Daily
Duration of test:
Days 6 - 18 of gestation
Remarks:
Doses / Concentrations:
2, 8, 24 mg/kg/day - definitive study
Basis:

Remarks:
Doses / Concentrations:
25, 50, 100, 200, 400 mg/kg/day – range-finding study
Basis:

No. of animals per sex per dose:
13 or 14
Control animals:
yes, concurrent vehicle
Maternal examinations:
Definitive study: Animals were observed daily for signs of toxicity. Body weights were taken every three days during pregnancy. Food consumption was measured daily. All surviving dams were sacrificed at study termination on gestation day 29 using sodium pentobarbital.
Range-finding study: Body weights were determined on days 0, 6, 11, 17 and 29. Food consumption was measured daily. Animals found dead were necropsied.
Ovaries and uterine content:
Definitive study: An examination of the uterus, including the number corpora lutea, implantations, and resorptions was conducted. Uteri from females that appeared non-gravid were placed in 10% ammonium sulfide solution for confirmation of pregnancy.
Range-finding study: Uterine disposition of young was recorded, and corpora lutea and resorptions sites were counted
Fetal examinations:
Definitive study: At sacrifice fetuses were weighed, and examined externally for defects. Sex determination also was conducted on each fetus. Two thirds of the fetuses were examined for skeletal and 1/3 were examined for visceral abnormalities.
Range-finding study: Survivors were sacrificed on day 29 of gestation and fetuses were weighed and examined microscopically.
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
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 specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Details on maternal toxic effects:
Maternal toxic effects:no effects. Remark: Definitive study

Details on maternal toxic effects:
Range finding study:
Morality occurred in the dams as follows: 1/3, 1/3, 2/3, 3/3, and 3/3 for the 25, 50, 100, 200, and 400 mg/kg/day groups, respectively. A decrease in body weight was observed at 50 and 100 mg/kg/day. Apparent resorptions occurred in the two surviving females at 50 mg/kg/day but the intercurrent mortality was considered to prohibit definitive judgment on a direct effect of the test substance on maintenance of pregnancy
Key result
Dose descriptor:
NOEL
Effect level:
ca. 24 mg/kg bw/day (nominal)
Based on:
test mat.
Remarks:
35% iin Dobanol 45E7
Basis for effect level:
other: maternal toxicity
Key result
Dose descriptor:
NOEL
Effect level:
ca. 24 mg/kg bw/day (nominal)
Based on:
test mat.
Remarks:
35% in Dobanol 45E7
Basis for effect level:
other: developmental toxicity
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
no effects observed
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects. Remark: Definitive study

Details on embryotoxic / teratogenic effects:
Range-finding study:
An indirect embryotoxic effect based on fetal body weight was considered to have been exhibited at 50 mg/kg/day.
Key result
Dose descriptor:
NOEL
Effect level:
ca. 24 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
changes in sex ratio
fetal/pup body weight changes
changes in litter size and weights
changes in postnatal survival
external malformations
skeletal malformations
visceral malformations
Abnormalities:
not specified
Key result
Developmental effects observed:
no
Lowest effective dose / conc.:
24 mg/kg bw/day
Treatment related:
no
Conclusions:
Within the limitations of the experimental conditions used, C12-14 trimethylammonium chloride was not directly fetotoxic or teratogenic. The NOEL for maternal systemic toxicity and developmental toxicity appeared to be 24 mg/kg bw/day. An indirect embryotoxic effect based on fetal body weight was considered to have been exhibited at 50 mg/kg/day in the range finding test.
Executive summary:

13 -14 mated female New Zealand white rabbits per group were exposed daily for days 6 to 18 of gestation to C12 -14 trimethylammonium chloride orally (gavage) at dosage levels of 0, 2, 8 and 24 mg/kg bw/day.

Animals were observed daily for signs of toxicity. An examination of the uterus, including the number corpora lutea, implantations, and resorptions was conducted. At sacrifice fetuses were weighed, and examined externally for defects. Sex determination also was conducted on each fetus. Two thirds of the fetuses were examined for skeletal and 1/3 were examined for visceral abnormalities.

No effects related to treatment were observed at the doses used in this study. Within the limitations of the experimental conditions used,

C12 -14 trimethylammonium chloride was not directly fetotoxic or teratogenic. The NOEL for maternal systemic toxicity and developmental toxicity appeared to be 24 mg/kg bw/day.

An indirect embryotoxic effect based on fetal body weight was considered to have been exhibited at 50 mg/kg/day in the range finding test.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Read-across to tetradonium bromide from data on cetrimonium chloride (with data reliability value of 2).
Principles of method if other than guideline:
No guideline stated
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
NA
Route of administration:
dermal
Vehicle:
water
Remarks on MMAD:
NA
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.
Clinical signs:
not specified
Description (incidence and severity):
Not given
Description (incidence and severity):
Not given
Description (incidence):
Not given
Description (incidence and severity):
Not given
Description (incidence and severity):
Not given
Description (incidence and severity):
Not given
Description (incidence and severity):
Not given
Description (incidence and severity):
Not given
Description (incidence and severity):
Not given
Description (incidence and severity):
Not given
Description (incidence and severity):
Not given
Description (incidence and severity):
Not given
Description (incidence and severity):
Not given
Description (incidence and severity):
Not given
Description (incidence and severity):
Not given
Description (incidence and severity):
Not given
Description (incidence and severity):
Not given
Description (incidence and severity):
Not given
Description (incidence and severity):
Not given
Details on results:
NA
Description (incidence and severity):
Not given
Description (incidence and severity):
Not given
Description (incidence and severity):
Not given
Description (incidence and severity):
Not given
Description (incidence and severity):
Not given
Description (incidence and severity):
Not given
Migrated Data from removed field(s)
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.DescriptionIncidenceAndSeverityEffectsOnPregnancyDuration): Not given
Description (incidence and severity):
Not given
Description (incidence and severity):
Not given
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.
Key result
Dose descriptor:
NOEL
Effect level:
ca. 40 mg/kg bw/day
Based on:
not specified
Basis for effect level:
clinical signs
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Not given
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): Not given
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
Not given
Changes in sex ratio:
no effects observed
Description (incidence and severity):
Not given
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
no effects observed
Changes in postnatal survival:
no effects observed
Description (incidence and severity):
No effects observed
External malformations:
no effects observed
Description (incidence and severity):
no effects observed
Skeletal malformations:
no effects observed
Description (incidence and severity):
no effects observed
Visceral malformations:
no effects observed
Description (incidence and severity):
no effects observed
Other effects:
no effects observed
Description (incidence and severity):
no effects observed
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.
Key result
Dose descriptor:
NOEL
Effect level:
ca. 40 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
changes in sex ratio
fetal/pup body weight changes
changes in litter size and weights
changes in postnatal survival
external malformations
skeletal malformations
visceral malformations
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 adverse effect observed
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.

13 -14 mated female New Zealand rabbits were orally dosed with 0; 2; 8 and 24 mg/kg bw /d of C12 -14 trimethylammonium chloride during the gestation days 6-18. No compound related foetotoxic or developmental effects were noted .The NOEL for maternal systemic toxicity and embryo-foetal toxicity appeared to be 24 mg C12 -14 trimethylammonium chloride/kg bw/day.

Skin irritation was observed at all doses with dose-related severity and duration.

These data on C12 -14 trimethylammonium chloride and cetrimonium chloride are considered relevant for read-across to tetradonium bromide.


Justification for selection of Effect on developmental toxicity: via oral route:
Read-across to oral prenatal developmental toxicity study with C12-C14alkyltrimethylammonium chloride. No maternal or developmental effects observed at highest dose level of 24 mg/kg bw/d.

Justification for classification or non-classification

The available data on cetrimonium chloride and C12 -C14 trimethylammonium chloride do not support any classification for reproductive toxicity for tetradonium bromide.