Quaternary ammonium compounds, C12-14-alkyltrimethyl, Me sulfates

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because a pre-natal developmental toxicity study is available

Cross-reference

Reason / purpose for cross-reference:

data waiving: supporting information

Reference

Endpoint:

developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

1985

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

Refer to section 13 for details on the read-across justification. The study with the read across substance is considered sufficient to fulfil the information requirements as further explained in the provided endpoint summary.

Reason / purpose for cross-reference:

read-across source

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

short exposure time i.e., on gestation Days 7-18 only

GLP compliance:

yes

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Route of administration:

dermal

Vehicle:

water

Details on exposure:

TEST SITE:
Shaved dorsal area.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Rinsed with water and dried.
- Time after start of exposure: 2 h.

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2 mL/kg
- Concentration (if solution): 0, 0.5, 1.0 and 2.0%

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Days 7 - 18 of gestation.

Frequency of treatment:

Once daily (2 hours).

Duration of test:

Days 0 - 29 of gestation.

Remarks:

Concentrations: 0, 0.5, 1.0, or 2.0% (i.e., equivalent to 0, 10, 20 and 40 mg/kg bw/day, respectively)

No. of animals per sex per dose:

20 pregnant females per dose.

Control animals:

yes, concurrent vehicle

Maternal examinations:

Dams 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 dams that died in an attempt to determine the cause of death. All surviving dams were sacrificed at study termination on gestation Day 29. 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. Following removal of the foetuses the abdominal and thoracic cavities and organs of the dams were examined. Uteri from females that appeared non-gravid were placed in 10% ammonium sulphide solution for confirmation of pregnancy.

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes

Fetal examinations:

- External examinations: Yes
- Soft tissue examinations: Yes
- Skeletal examinations: Yes

Statistics:

Body weight changes and food consumption and number of early and late resorptions, dead foetuses, 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 comparison was 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 analysed by Fisher's exact test.

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

effects observed, treatment-related

Description (incidence and severity):

Skin irritation was observed at all doses with the severity and duration of erythema, oedema, desquamation, atonia and coriaceousness increased in a dose-dependent manner.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

Two control, one intermediate and one high dose doe died during the study. The cause of death could not be determined. Two of the does that died aborted prior to death (one control and one intermediate dose group animal).

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

A slight increase in congested lungs was observed for the high dose group at necropsy.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Number of abortions:

effects observed, non-treatment-related

Description (incidence and severity):

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.

Pre- and post-implantation loss:

no effects observed

Total litter losses by resorption:

no effects observed

Early or late resorptions:

no effects observed

Dead fetuses:

no effects observed

Changes in pregnancy duration:

not examined

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not examined

Changes in number of pregnant:

not examined

Details on maternal toxic effects:

Maternal toxic effects: no test substance related significant effects.

Key result

Dose descriptor:

NOAEL

Remarks:

systemic toxicity

Effect level:

40 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Basis for effect level:

other: no significant treatment-related maternal toxic effects were observed up to the highest tested dose.

Key result

Dose descriptor:

NOAEL

Remarks:

developmental toxicity

Effect level:

40 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Basis for effect level:

other: no significant treatment-related foetal development effects were observed up to the highest tested dose.

Key result

Abnormalities:

no effects observed

Fetal body weight changes:

not examined

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

not examined

Changes in litter size and weights:

no effects observed

Changes in postnatal survival:

not examined

External malformations:

no effects observed

Skeletal malformations:

no effects observed

Visceral malformations:

no effects observed

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects: no effects

Details on embryotoxic / teratogenic effects:
The incidence of foetal malformations, as well as genetic and developmental variations in the treated groups were comparable to that of the control group.

Key result

Dose descriptor:

NOAEL

Remarks:

general toxicity

Effect level:

40 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: no effects observed up to the highest dose tested

Key result

Dose descriptor:

NOAEL

Remarks:

developmental toxicity

Effect level:

40 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: no developmental effects observed up to the highest dose tested

Key result

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

Conclusions:

Based on the results of the read across study, the NOAEL of the test substance, C12-14 TMAC, for maternal as well as developmental toxicity can be considered to be 40 mg/kg bw/d in rabbits.

Executive summary:

A study was conducted to determine the developmental toxicity / teratogenicity of the read across substance, C16 TMAC, according to a method similar to OECD Guideline 414, in compliance with GLP. This experiment was performed in New Zealand White rabbits. Twenty mated female rabbits per group were exposed topically (daily for 2 h) from Days 7 to 18 of gestation at concentrations of 0, 0.5, 1.0, or 2.0% (equivalent to 0, 10, 20 and 40 mg a.i./kg bw/day, respectively). The control group was treated with deionised water only. Clinical condition and reactions to treatment were recorded at least once daily. Body weights were recorded on Days 0, 3, 6, 9, 12, 15, 18, 21, 24, 27 and 29 of gestation. All surviving females were sacrificed on Day 29 of gestation and the foetuses were removed by caesarean section. At necropsy the females were examined macroscopically. Live foetuses were weighed, sexed and were examined for visceral and skeletal abnormalities. No treatment-related maternal body weight or food intake were affected due to the treatment. The incidence of foetal malformations, as well as genetic and developmental variations in the treated groups was comparable to that of the control group. No other treatment-related effects were noted. Under the study conditions, the NOAEL for maternal as well as developmental toxicity was established at 40 mg a.i./kg bw/day in rabbits (Albridge, 1985).