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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1983
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1983

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Trimethyloctadecylammonium chloride
EC Number:
203-929-1
EC Name:
Trimethyloctadecylammonium chloride
Cas Number:
112-03-8
Molecular formula:
C21H46NCl
IUPAC Name:
N,N,N-trimethyloctadecan-1-aminium chloride
Test material form:
not specified

Test animals

Species:
rat
Strain:
other: Strain: CFY
Details on test animals or test system and environmental conditions:
- Four groups (caged individually)
- Temperature: 20°C +/- 2°C, Relative humidity: 55 +/- 10%
- 12/12 hours dark/light
-Free access to food (Spratts Laboratory Animals Diet No 1) and tp water

Administration / exposure

Route of administration:
dermal
Vehicle:
other: distilled water
Details on exposure:
On Days 4 or 5 of pregnancy, an area (4x4 cm) of fur in the scapular region was removed by electric clippers. (Shaving was repeated when necessary but no depilatory agents were used). Dosing started on Day 6 and continued up to and including Day 15 of gestation. On each day, the test substance was applied to the shaved area at the rate of 0.5 mL/rat, and at a speed minimising 'run off' into surrounding fur. The exposed area was neither washed nor occluded at any time.
Analytical verification of doses or concentrations:
yes
Remarks:
no further details
Duration of treatment / exposure:
From Gestation Day 6 to 15
Frequency of treatment:
each day
Doses / concentrationsopen allclose all
Dose / conc.:
0 other: %
Remarks:
corresponding to 0 mg/kg bw/day
Dose / conc.:
0.9 other: %
Remarks:
corresponding to 18 mg/kg bw/day
Dose / conc.:
1.5 other: %
Remarks:
corresponding to 30 mg/kg bw/day
Dose / conc.:
2.5 other: %
Remarks:
corresponding to 50 mg/kg bw/day
No. of animals per sex per dose:
20
Control animals:
yes, concurrent vehicle
Details on study design:
Concentrations: 0.0, 0.9, 1.5, and 2.5% in distilled water administered per 0.5 mL/rat/day (2 mL/kg bw/day for a weight of ca. 250g).

Examinations

Maternal examinations:
Signs of systemic reaction and local reaction of the exposed area of skin (scores: 1-4): daily.
Body weights: on Days 1, 3, 6, 10, 17, and 20 of pregnancy.
Food and water consumption: at regular intervals throughout the study.
Ovaries and uterine content:
On Day 20 of pregnancy:
- congenital abnormalities and macroscopic pathological changes in maternal organs
- ovaries and uteri: number of corpora lutea, number/distribution of live young and embryo/foetal deaths (early and late, stages of implantation) and post implantation loss ((No. of implantations - No. of live young) x 100 / No. of implantations)
Fetal examinations:
On Day 20 of pregnancy:
- litter weight from which the mean pup weight was calculated, foetal abnormalities (external and internal + classification) and post implantation loss ((No. of implantations - No. of live young) x 100 / No. of implantations)
- sex determination
Statistics:
- Group mean values were calculated from individual litter values and, where expressed as a percentage, were calculated as the mean of the percentages within individual litters (and not from group totals for foetuses)
- Non-parametric methods (analysis of litter and abnormalities), analysis of variance (body weight, food or water consumption), and Kruskal-Wallis test (where significant heterogenicity was recorded)

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
No systemic signs of reaction
Dermal irritation (if dermal study):
effects observed, treatment-related
Description (incidence and severity):
- In terms of incidence of animals affected, and degree of reaction.
- In all cases, initial reaction was evident within a day of the first administration. It reached a peak of severity around the mid point of the dosing period, and stabilized or showed a decline thereafter. This phenomenon was frequently associated with scab formation.
- Local reactions (erythema and oedema).
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 examined
Water consumption and compound intake (if drinking water study):
no effects observed
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:
not examined
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
no macroscopic pathological changes in internal organs
Histopathological findings: neoplastic:
not examined

Maternal developmental toxicity

Number of abortions:
no effects observed
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
Changes in number of pregnant:
not examined
Other effects:
no effects observed
Description (incidence and severity):
No differences in the number of corpora lutea were recorded.
Details on maternal toxic effects:
Only dermal irritation was observed

Effect levels (maternal animals)

open allclose all
Key result
Dose descriptor:
NOAEL
Remarks:
systemic effect
Effect level:
50 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: overall no systemic toxicity except "dermal irritation"
Key result
Dose descriptor:
NOAEL
Remarks:
local effect
Effect level:
18 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
dermal irritation

Maternal abnormalities

Key result
Abnormalities:
effects observed, treatment-related
Localisation:
other: dermal
Description (incidence and severity):
- In terms of incidence of animals affected, and degree of reaction.
- In all cases, initial reaction was evident within a day of the first administration. It reached a peak of severity around the mid point of the dosing period, and stabilized or showed a decline thereafter. This phenomenon was frequently associated with scab formation.
- Local reactions (erythema and oedema).

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
The mean foetal weight was not modified by the treatment
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
not examined
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
The litter weight was not modified by the treatment
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:
In all groups, the incidence of affected litters and foetuses was within the limits of historical control values. The types of malformations or anomaly observed were compatible with the types of abnormality recorded among concurrent or historical control vlaues and there was no unusual clustering of a particular type of abnormality in any one test group.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: no effects

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
Under the study conditions, a dermal application of the test substance did not induce toxic effects on dams or foetuses, except for a local irritation (erythema and oedema) on the skin of pregnant animals. The maternal NOAELs (systemic and local) were therefore established at 50 and 18 mg/kg bw/day, respectively. The developmental NOAEL was determined at 50 mg/kg bw/day.
Executive summary:

A study was conducted to determine the developmental toxicity of the test substance, C18 TMAC (98.8% purity), according to a method similar to OECD Guideline 414. Pregnants rats were exposed dermally to the test substance from Day 6 to Day 15 of gestation. Volumes of 0.5 mL were applied on shaved skin. The concentrations of the test substance ranged from 0.0 to 2.5% (i.e., corresponding to 0, 18, 30 and 50 mg/kg bw/day). Signs of systemic reaction and local reaction of the exposed area of skin were assessed on a daily basis. Body weights were recorded on Days 1, 3, 6, 10, 17, and 20 of pregnancy. Food and water consumption were measured at regular intervals throughout the study. On Day 20 of pregnancy, congenital abnormalities and macroscopic pathological changes in maternal organs as well as in ovaries and uteri (number of corpora lutea, number/distribution of live young and embryo/foetal deaths (early and late, stages of implantation)) and post implantation loss were evaluated. Litter weights (from which the mean pup weight was calculated), foetal abnormalities (external and internal), and sex determination were also recorded on Gestation Day 20. Under the study conditions, a dermal application of the test substance did not induce toxic effects on dams or foetuses, except for a local irritation (erythema and oedema) on the skin of pregnant animals. The maternal NOAELs (systemic and local) were therefore established at 50 and 18 mg/kg bw/day, respectively. The developmental NOAEL was determined at 50 mg/kg bw/day (Palmer, 1983).