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Diss Factsheets

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

Effects on developmental toxicity

Description of key information

Based on the available data, the test substance is not considered to have potential for developmental toxicity.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Administration from day 6 until day 15 of pregnancy.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
Administration only during day 6-15 of pregnancy
GLP compliance:
no
Remarks:
Study pre-dates GLP regulations
Limit test:
no
Specific details on test material used for the study:
- Name as used in study report: FAT 60 149/B
Species:
rat
Strain:
other: Tif: RAIf (SPF)
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: closed breeding colony (CIBA-GEIGY, WST)
- Age at study initiation: 2 months
- Weight at study initiation: approximately 200 g
- Housing: in groups of 5 in Macrolon cages
- Diet: standard cube diet (Nafag No. 890 Tox), ad libitum
- Water: ad libitum
- Acclimation period: 7-14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 1
- Humidity (%): 60 ± 5
- Photoperiod (hrs dark / hrs light): 14/10
Route of administration:
oral: gavage
Vehicle:
other: 2% aqueous solution of a sodium carboxymethylcellulose
Details on exposure:
- Preliminary study: 2 groups of 10 females were administered either vehicle control or 1000 mg/kg
- Main study: 4 groups of 25 females were administered vehicle control, 100 mg/kg, 300 mg/kg or 1000 mg/kg
The amount of fluid administered was 1 ml/100 g of body weight. The suspension of test material was freshly prepared daily by homogenizer and magnetic stirrer.
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
Females were mated over night with males of proven fertility in the ratio of 1 male: 3 females. The day on which spermatozoa were found in the vaginal smear or a vaginal plug was observed, was designated as day 0 of pregnancy.
Duration of treatment / exposure:
day 6 to 15 of gestation
Frequency of treatment:
Once per day
Duration of test:
Termination at day 21 of gestation
Dose / conc.:
0 mg/kg bw/day
Remarks:
vehicle control
Dose / conc.:
100 mg/kg bw/day
Dose / conc.:
300 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
No. of animals per sex per dose:
- preliminary study: 10 females
- main study: 25 females treated (22-25 pregnancies per group)
Control animals:
yes, concurrent vehicle
Details on study design:
Dams were killed and fetuses removed by caesarean section on day 21 of pregnancy.
Maternal examinations:
- general condition, daily
- body weight gain, daily
- symptoms, daily
- food consumption, days 6, 11, 16 and 21 of gestation
- gross examination of organs
Ovaries and uterine content:
- mucosa, amniotic fluid and placentae
- total implantations, embryonal resorptions, foetal resorptions
- examination of uteri without any visible implantation by ammonium sulfide staining
- gravid uterus weight
Fetal examinations:
- live foetuses, dead foetuses, total litter size
- foetal weight
- sex ratio
- skelet (two-thirds of foetuses)
- soft tissues (one-thirds of live foetuses)
- external malformations
Statistics:
-chi-square test, Yates correction
Historical control data:
Yes, for skeletal malformations
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
One female in the mid-dose group developed inflammation of the thoracic region, induced by an intubation error
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
The body-weight gain was generally comparable for all groups.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
The food consumption was generally comparable for all groups.
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:
not examined
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
The implantation rates were comparable for all groups
Total litter losses by resorption:
not specified
Early or late resorptions:
no effects observed
Description (incidence and severity):
By the comparison to the vehicle control, the rates of of embryolethality and foetolethality (resorptions) were not increased (chi-square test, Yates correction, P ≤ 0.01)
Dead fetuses:
no effects observed
Description (incidence and severity):
Three dead foetuses in the mid-dose group (300 mg/kg), of which two in the same litter. No dead foetuses in any other group
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 specified
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
22/25 pregnant rats in both the vehicle control group and the mid-dose group (300 mg/kg), 25 pregnant rats in the low dose group (100 mg/kg) and high dose group (1000 mg/kg).
Key result
Remarks on result:
not determinable due to absence of adverse toxic effects
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
The average weight of the live foetuses was comparable for all groups
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): The average weight of the live foetuses was comparable for all groups
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Description (incidence and severity):
The sex ratios (expressed as % male foetuses) were comparable for all groups.
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
One multiple malformation was recorded for one foetus each of the 100 mg/kg and 1000 mg/kg dose group.
- 100 mg/kg group: Multiple malformation : hydrocephaly, hypognathia, " open eyes" (unilat.) , oedema, coelosomia, oligodactyly of fore-limbs (associated with ectromelia) , "pes varus" of right hind-limb
- 1000 mg/kg group: Multiple malformation : agnathia, "open eyes", coelosomia, oedema, amelia (left fore and hind-limb), brachymelia (right fore-limb ), ectromelia (right hind-limb )
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Next to the skeletal malformations seen in the multiple malformations:
- The skeletal assessment of the foetuses revealed irregular ossification of sternebrae in one foetus each of the 100 mg/kg and 300 mg/kg dose group and two foetuses from one litter of the 1000 mg/kg dose group.
- By comparing the skeletal maturation of the foetuses of the experimental groups on the basis of the 99% confidence limits determined for the vehicle control, there was found an increase in the number of still unossified phalangeal nuclei of the hind-limb at 1000 mg/kg as well as calcaneus at 300 mg/kg and 1000 mg/kg.
Visceral malformations:
no effects observed
Description (incidence and severity):
No visceral abnormalities were noted in either the experimental groups or the vehicle control
Details on embryotoxic / teratogenic effects:
The slight delay of physiological growth encountered in the foetuses from mothers treated at doses of 300 mg/kg and 1000 mg/kg is considered to be of a non-specific nature, and of doubtful experimental significance.
Remarks on result:
not determinable due to absence of adverse toxic effects
Abnormalities:
no effects observed
Developmental effects observed:
no
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 study available
Additional information

A developmental toxicity study, similar to OECD 414, is available. In order to determine the dose levels for the main study, a preliminary experiment was carried out on 10 fertilized rats using a dose of 1000 mg/kg of body weight. The test material was suspended in a 2% aqueous solution of sodium carboxymethylcellulose (CMC) and administered orally by intubation once daily from day 6 until day 15 of pregnancy, inclusive. In comparison to the vehicle control, the dams and the progeny were not affected by the treatment. On the basis of this result the dosage for the main study was selected at 100, 300 and 1000 mg/kg of body weight. The test material was again suspended in 2% aqueous CMC and administered once daily by the oral route from day 6 until day 15 of pregnancy, inclusive. No reactions to the treatment were recorded for the dams. The progeny of the low dose group (100 mg/kg) remained unaffected by the treatment. At the intermediate and high dose (300 mg/kg and 1000 mg/kg) the skeletal assessment of the foetuses revealed a slight increase in the number of still unossified calcanei; at the high dose the number of still unossified phalangeal nuclei of the hind-limb was slightly increased, in addition. One multiple malformation was recorded for one foetus each of the low and high dose group. This finding was assumed to be of a spontaneous origin. Likewise, the one instance of irregularly ossified sternebrae each occurring in the 100 mg/kg and the 300 mg/kg dose groups and the two instances occurring in one litter of the 1000 mg/kg dose group were not considered to be related to the treatment. Sternebral anomalies were recorded to occur at the incidence of 0.16 percent in the historical (cumulative) control population of the breed of rats used for the present study. To summarize, the test substance was considered to be devoid of an embryotoxic activity and teratogenic potency in the albino rat under the conditions of the present experiment. The slight delay of physiological growth encountered in the foetuses from mothers treated at doses of 300 mg/kg and 1000 mg/kg is considered to be of a non-specific nature, and of doubtful experimental significance.

Justification for classification or non-classification

Based upon the available data, classification for developmental toxicity according to the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 is not warrented.

Additional information