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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:
key study
Study period:
February - March 1990
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1991
Report date:
1991

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
EPA OPP 83-3 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
DDAC
IUPAC Name:
DDAC
Constituent 2
Chemical structure
Reference substance name:
Didecyldimethylammonium chloride
EC Number:
230-525-2
EC Name:
Didecyldimethylammonium chloride
Cas Number:
7173-51-5
Molecular formula:
C22 H48 N.Cl
IUPAC Name:
N-decyl-N,N-dimethyldecan-1-aminium chloride
Constituent 3
Reference substance name:
N,N-Didecyl-N,N-dimethylammonium Chloride
IUPAC Name:
N,N-Didecyl-N,N-dimethylammonium Chloride
Constituent 4
Reference substance name:
1-Decanaminium, N-decyl-N,N-dimethyl-, chloride
IUPAC Name:
1-Decanaminium, N-decyl-N,N-dimethyl-, chloride
Constituent 5
Reference substance name:
Bardac 2280
IUPAC Name:
Bardac 2280
Details on test material:
The test material was Bardac 2280 (Didecyldimethylammonium Chloride; DDAC, in aqueous/alcohol solution), supplied by Lonza Inc. The substance was described as a very viscous honey coloured liquid.
DDAC is hydrolytically and photolytically stable under the conditions of this study and has been shown to be stable in aqueous, alcohol and alcohol/aqueous solutions for extended periods, e.g. at least seven years under standard laboratory conditions.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
The test animals were 10-week old female Sprague-Dawley (Crl:CD BR) rats, obtained from Charles River Breeding Laboratories, MI, USA. The animals were quarantined for approximately 2 weeks. Representative animals were subject to faecal screening, serum viral antibody analysis and histological examination of selected organs. Rats were housed in same-sex pairs in stainless steel wire mesh cages during acclimatisation. Rats were housed singly thereafter (except during mating). Food (Purina Certified Ground Rodent Chow) and municipal water were provided ad libitum. Temperature was maintained at 66-77°F, and relative humidity 40-70%, with a 12 hour light/dark cycle.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Remarks:
Millipore water
Details on exposure:
The test substance (in deionised water) was administered by gavage to timed pregnant dams (GD 6-15). The concentration of the test substance in the vehicle was 0, 0.2, 2.0 and 4.0 mg/ml. Dose preparations were corrected for percent active ingredient. Solutions were prepared twice during the study. Dose volume was maintained at 5 ml/kg bw. Administered volumes were adjusted on the basis of the most recent body weight of each animal.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Stability and homogeneity studies were conducted, and solutions were analysed for test substance concentration using gas-chromatography with Nitrogen-Phosphorous detection. The dosing solutions were demonstrated to be homogenous, stable for at least 12 days when stored at room temperature, and within 97.0 to 103.85 of nominal.
Details on mating procedure:
Rats were mated 1:1 in stainless steel wire mesh cages. Females were checked daily in the morning for copulatory plugs, and cage boards were checked twice daily for dropped copulatory plugs. The date a plug was found was designated gestational day 0. Plug-positive females were singly housed.
Duration of treatment / exposure:
Days 6 - 15 of gestation
Frequency of treatment:
Once daily during exposure period
Duration of test:
Until Day 21 of gestation
No. of animals per sex per dose:
25 females/group
Control animals:
yes, concurrent vehicle
Details on study design:
25 plug-positive females were assigned to each treatment group by a computer-generated randomisation procedure stratified by body weight on GD 0, so that all groups were equivalent in mean body weight and body weight range. Dose levels for the study were chosen based on a previous range-finding study.

Examinations

Maternal examinations:
The rats were observed twice daily for clinical signs and mortality during dosing, and daily thereafter. Bodyweights were recorded on GD 0, 6, 9, 12, 15, 18 and 21 of gestation. Food consumption was determined at 3 day intervals throughout gestation.
Gross necropsy was performed on all rats at terminal sacrifice (GD 21). The gravid uterus, ovaries (including corpora lutea), cervix, vagina, and abdominal and thoracic organs were examined grossly. The lumen of the oesophagus, stomach and trachea were examined for any signs of irritation from the dosing solution. The uterus was examined externally for signs of haemorrhage before removal. Organ weights were obtained for the liver and gravid uterus.
Ovaries and uterine content:
The number of corpora lutea and the number and status of implantation sites were recorded. All live and dead foetuses and resorption sites were noted and recorded. Uteri from females that appeared nongravid were placed in 10% ammonium sulphide solution for detection of early resorptions
Fetal examinations:
All live foetuses were weighed, sexed and examined for external malformations. Half the foetuses were used for skeletal examinations using alizarin red S staining, and half were used for visceral examinations. These foetuses were decapitated and their heads fixed in Bouin's solutions for examination of craniofacial features.
Statistics:
Levene’s test for equal variances, analysis of variance, and t-tests with Bonferroni probabilities for pairwise comparisons. Nonparametric data were analyzed with Kruskal-Wallis test followed by Mann-Whitney U test when appropriate. Incidence data were compared using Fisher’s Exact Test.
Indices:
No information available.
Historical control data:
No information available.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Audible respiration and gasping was observed at 20 mg a.s./kg bw/d. Audible respiration was observed at 10 mg a.s./kg bw/d.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Reduced body weight gain was observed at 20 mg a.s./kg bw/d.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Reduced food consumption was observed at 20 mg a.s./kg bw/d.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not examined
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
There were no treatment-related effects on gravid uterine weight or liver weights.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Ulceration of the stomach and gas filled intestines were observed in 20 mg a.s./kg bw/d females at gross necropsy.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not examined
Other effects:
not specified

Maternal developmental toxicity

Number of abortions:
no effects observed
Description (incidence and severity):
There were no abortions or early births.
Pre- and post-implantation loss:
not specified
Total litter losses by resorption:
not specified
Early or late resorptions:
not specified
Dead fetuses:
not specified
Changes in pregnancy duration:
not specified
Changes in number of pregnant:
effects observed, treatment-related
Description (incidence and severity):
One dam each at 1 and 10 mg/kg bw/d and two dams at 20 mg/kg bw/d were not pregnant.
Other effects:
not specified
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
There were no maternal mortalities. Audible respiration and gasping was observed at 20 mg a.s./kg bw/d. Audible respiration was observed at 10 mg a.s./kg bw/d. Reduced body weight gain and food consumption were observed at 20 mg a.s./kg bw/d. Ulceration of the stomach and gas filled intestines were observed in 20 mg a.s./kg bw/d females at gross necropsy. There were no treatment-related effects on gravid uterine weight or liver weights. There were no abortions or early births.

Effect levels (maternal animals)

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
1 mg/kg bw/day
Based on:
act. ingr.
Basis for effect level:
clinical signs
Dose descriptor:
NOEL
Effect level:
20 mg/kg bw/day
Based on:
act. ingr.
Basis for effect level:
other: developmental toxicity

Maternal abnormalities

Key result
Abnormalities:
effects observed, treatment-related
Localisation:
other: quivalent to ca. 1.2 mg test substance/kg bw/d. Based on clinical signs (audible breathing) observed at 10 mg a.s./kg bw/d

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
There were no treatment-related effects on foetal body weight.
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
All pregnant dams had one or more live foetuses at scheduled sacrifice.
Changes in sex ratio:
not specified
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not specified
External malformations:
no effects observed
Description (incidence and severity):
No malformations were noted at gross necropsy.
Skeletal malformations:
no effects observed
Description (incidence and severity):
There were no treatment-related skeletal or visceral variations or malformations.
Visceral malformations:
no effects observed
Description (incidence and severity):
There were no treatment-related visceral malformations.
Other effects:
not specified
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
One dam each at 1 and 10 mg/kg bw/d and two dams at 20 mg/kg bw/d were not pregnant. All pregnant dams had one or more live foetuses at scheduled sacrifice. There were no treatment-related effects on foetal body weight, and no malformations were noted at gross necropsy. There were no treatment-related skeletal or visceral variations or malformations.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
> 20 mg/kg bw/day
Based on:
test mat.
Sex:
male
Basis for effect level:
other: no developmental toxicity observed at the highest dose level
Remarks on result:
not determinable due to absence of adverse toxic effects

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Any other information on results incl. tables

No developmental toxicity including teratogenicity was observed at any dosage employed.

Applicant's summary and conclusion

Conclusions:
Maternal toxicity was evident at 10 and 20 mg a.s./kg bw/d. No developmental toxicity including teratogenicity was observed at any dose.
Executive summary:

The teratogenic potential of the test item was evaluated in female Sprague-Dawley rats according to OECD 414. The test substance was administered by gavage to pregnant rats on gestation days 6 -15, at concentrations of 0, 1, 10 and 20 mg a.s./kg/d. The dams were sacrificed at gestation day 21 and the foetuses were examined for visceral and skeletal variations and malformations.

Pregnant rats treated with 20 mg a.s./kg bw/d showed reduced body weight gain and reduced food consumption. Audible respiration and gasping occurred at 20 mg a.s./kg bw/d and audible breathing also occurred at 10 mg a.s./kg bw/d. Ulceration of the stomach and gas filled intestines were observed at 20 mg a.s./kg bw/d. All other dams and all foetuses remained unaffected. There were no treatment-related effects on foetal body weight or visceral/skeletal findings. The NOAEL for maternal toxicity was 1 mg a.s./kg/day (equivalent to ca. 1.2 mg test substance/kg bw/d); the NOEL for developmental toxicity was at least 20 mg a.s./kg/day (equivalent to ca. 24.8 mg test substance/kg bw/d).