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The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

In accordance with column 2 of REACH Annex IX, a study with toxicity to reproduction does not need to be conducted if repeat-dose studies do not indicate adverse effects on reproductive organs. Furthermore, no concern for reproductive toxicity is evident based on the available developmental studies.

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

No data on fertility are available. In accordance with column 2 of REACH Annex IX, a study with toxicity to reproduction does not need to be conducted if repeat-dose studies do not indicate adverse effects on reproductive organs.

Effects on developmental toxicity

Description of key information

No developmental effects were reported in a OECD414 compliant study performed with rabbits. The NOAEL was derived at the highest dose level of 2000 mg/kg body weight.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
(1981-05-12)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Cheshire Rabbit Farms (Dudden Lodge, Nr. Tarporley, Cheshire), Ranch Rabbits (Crawley Down, Sussex), Buxted Rabbit Co. Ltd. (Gt. Totease Fram, Buxted, Sussex)
- Weight at study initiation: 3.5 to 4.6 kg (pretest); 2.8 to 3.6 kg (females only, main study)
- Age at study initiation: 12 - 20 weeks
- Housing: individual housing in metal cages equipped with sheet stainless steel sides, stainless steel wire front and an aluminated perforated floor panel. Individual undercage plastic trays were lined with absorbent paper.
- Diet (e.g. ad libitum): SDS rabbit diet SQC, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: at least 10 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 ± 3
- Humidity (%): 55 ± 15
- Photoperiod (hrs dark / hrs light): 10/14
Route of administration:
oral: gavage
Vehicle:
other: methylcellulose (1%)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The highest required concentration of suspension was prepared by trituration of weighed compound with vehicle using a mortar and pestle to form a smooth mixture, then addition of further vehicle to required volume. Further mixing was carried out using a "Silverson" Laboratory mixer. The lower concentrations were prepared by serial dilution with the vehicle.

VEHICLE
- Concentration in vehicle: 5 % (dose: 500 mg/kg bw/d), 10% (dose: 1000 mg/kg bw/d), 20% (dose: 2000 mg/kg bw/d)
- Amount of vehicle (if gavage): 10mL/kg bw
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1
- Length of cohabitation: at least 1 hour after coitus was observed
Duration of treatment / exposure:
day 7-19 of gestation
Frequency of treatment:
daily, 7 days/week
Duration of test:
29 days after gestation
Dose / conc.:
500 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
Dose / conc.:
2 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
18 (female rabbits)
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Dosages were based on a prior preliminary study in which animals were orally exposed to test substance with doses of 500, 1000 and 2000 mg/kg bw over a period of 13 days and sacrifice after 21 days. At 2000 mg/kg bw/d majority of animals showed pale discoloration of the faeces during the treatment period.

- Rationale for animal assignment (if not random):
rabbits were weighed and 24 within the bodyweight range 3.5 to 4.6 kg allocated to four groups, such that mean bodyweight and source of animals were similar for all groups.
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: day 1, 7, 9, 11, 15, 20, 24 and 29 of gestation

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes (g/rabbit/day)
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes

Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of pre-implantation loss: Yes
- Number of post-implantation loss: Yes
- Other:
- number and distribution of live young
- number and distribution of embryonic/foetal deaths
- individual foetal weights
- foetal abnormalities
- Embryonic/foetal deaths were classified as:
- Early: only placenta visible at termination
- Late: both placenta and embryonic remnants visible at termination
Abortion: only implantation site scars visible at termination
Fetal examinations:
- External examinations: Yes [all per litter]
- Soft tissue examinations: Yes [all per litter]
- Skeletal examinations: Yes: [all per litter]
- Head examinations: Yes: [all per litter ]

OTHER:
Live young were examined externally then killed by intrathoracic injection of Pentobarbitone Sodium. They were weighed; dissected and examined for visceral abnormalities, and sexed. Where appropriate young showing suspected abnormalities were examined by alternative procedures (eg. micro-dissection, histopathology) to clarify initial observations. Young were skinned, eviscerated and fixed in 740P industrial methylated spirit; after fixation the heads were sliced through the line of the frontoparietal suture and the brain examined for visible abnormalities (eg.hydrocephaly, hydranencephaly) prior to clearing and staining (modified Dawson technique) of the carcasses for skeletal examination.
Statistics:
Statistical analyses were performed routinely on litter data and incidences of skeletal anomalies and skeletal variants using the litter as the basic sample unit. Non-parametric methods (Kruskal-Wallis and Jonckheere tests) were employed since these values rarely follow a normal distribution.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
The majority of animals at 2000 mg/kg/day showed pale discolouration of faeces throughout the treatment period. At 1000 mg/kg/day approximately half of the animals occasionally showed pale discolouration of faeces during the treatment period. There were no other signs of reaction considered attributable to treatment.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Single dosed animals at 500 and 2000 mg/kg/day, and one in the control group died or were killed. No treatment relationship was considered to be indicated.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Intergroup variation in bodyweight gain generally appeared unrelated to dosage, although at all dosages mean gain during the first two days of treatment was slightly lower than among control animals. Overall weight gain at 1000 and at 2000 mg/kg/day was greater than that of control animals. At 1000 mg/kg/day weight gain was higher than in the high dose group.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
At all dosages mean food consumption during the first four days of the dosing period was similar to that of control animals. Thereafter individual mean test group values tended to be higher than, or similar to, those of control animals.
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
Description (incidence and severity):
There were no macroscopic findings at terminal autopsy that were considered attributable to treatment.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Details on maternal toxic effects:
Pregnancy rate as judged by the numbers of animals pregnant at termination, was high in all groups.
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: no effects at this dose level
Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
body weight and weight gain
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Mean foetal weights were essentially similar for all groups and intergroup differences- among mean values for litter weight were not statistically significant (P >0.05).
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
Intergroup differences among mean values for litter size,and pre- and post implantation loss were not statistically significant (p >0.05).
Changes in postnatal survival:
effects observed, non-treatment-related
Description (incidence and severity):
A single animal, from the control group, showed total litter loss. For the following intergroup comparisons control values calculated excluding this animal (i.e. Mean B values) were employed.
External malformations:
no effects observed
Description (incidence and severity):
The incidence of malformed foetuses appeared unaffected by treatment; although the incidence at 500 mg/kg/day was higher than in the control group, the incidence at 1000 mg/kg/day was lower, and at 2000 mg/kg/day no malformations were observed.
Skeletal malformations:
no effects observed
Description (incidence and severity):
Incidences of skeletal anomalies were not adversely affected at any dosage and the only differences to be statistically significantly (P <0.05) related to lower incidences of skeletal anomalies at 500 and 2000 mg/kg/day. At all dosages the incidence of foetuses with extra thoracolumbar rib and of foetuses with variant sternebrae tended to be similar to the control incidence; there were no statistically significant differences (p >0.05).
Visceral malformations:
no effects observed
Description (incidence and severity):
Incidences of visceral anomalies were not adversely affected at any dosage.
Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: no adverse effects observed
Abnormalities:
not specified
Developmental effects observed:
not specified
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
2 000 mg/kg bw/day
Species:
rabbit
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

In a GLP-compliant developmental toxicity study the test substance (5, 10, 20 % in aqueous methylcellulose (1 %)) was administered orally to 18 female New Zealand white rabbit/dose by gavage at dose levels of 0, 500, 1000, 2000 mg/kg bw/day from days 7 through 19 of gestation. The only treatment-related clinical signs observed were pale discoloration of the feces at 1000 and 2000 mg/kg bw. There were no treatment-related effects in mortality, body weight, food consumption, or cesarean parameters. The maternal NOEL is 1000 mg/kg bw/day. There were no treatment-related effects in malformations, visceral and skeletal anomalies. The developmental NOAEL is 2000 mg/kg bw/day.

The experimental results were supported by a second developmental toxicity study. The test substance in 2 % aqueous Carboxymethylcellulose was administered orally to 25 of females Tif: RAIf (SPF) rats/dose by gavage at dose levels of 0, 100, 1000 and 3000 mg/kg bw/day from days 6 through 15 of gestation. A dose-related increase in food consumption (for the last 4 days only) and a slight reduced body-weight gain for the high dose group was seen. There were no treatment-related effects in mortality, further clinical signs, body weight, food consumption, or cesarean parameters. There were no treatment-related effects in malformations, visceral and skeletal anomalies.

In a further supporting developmental toxicity study the test substance in 2 % aqueous Carboxymethylcellulose was as administered orally to 30 Tif:MAGf mice/ dose by gavage at dose levels of 100, 500, 1500 mg/kg bw/day from days 6 through 15 of gestation. Apart from a slight reduced food intake at low and high dose group no further clinicals signs were seen in dams. There were no treatment-related effects in mortality, body weight, food consumption, or cesarean parameters. No significant increase in embryolethality was noticed. A slight delay of the physiological growth, indicated by a diminished body weight increase, was seen. Four instances of cleft palate were found in the intermediate and high dose group. Other effects occurred like dilated renal pelvic cavitation (1 instance in the intermediate group), irregularly ossified sternum observed (1 fetus in the intermediate dose and 1 in the vehicle control group), and the partial costal fusion (1 fetus of the high-dose group). All these effects were considered as spontaneous and not substance related.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance is not considered to be classified for reproductive toxicity under Regulation (EC) No. 1272/2008.

Additional information