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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

Oral: OECD 414, rabbit. No developmental toxicity was observed at any doses up to 2000 mg/kg (highest dose tested) with the read-across substance. Reliability = 2.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Justification for type of information:
Additional documentation, provided within the IUCLID Assessment Reports (Section 13), supports the read-across approach.
Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes
Limit test:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Cheshire Rabbit Farms, Ranch Rabbits, and Buxted Rabbit Co. Ltd.
- Weight at study initiation: 3.5 to 4.6 kg (preliminary study), 2.8 to 3.6 kg (teratogenicity study)
- Housing: Housed individually in metal cages equipped with sheet stainless steel sides, back and top, a stainless steel wire front and an aluminium perforated floor panel. Individual undercage plastic trays were lined with absorbent paper, which was inspected and changed daily.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: At least 10 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 ± 3
- Humidity (%): 55 ± 15
- Photoperiod: Natural lighting in the room was supplemented by artificial light between 7.00 am and 9.00 pm
Route of administration:
oral: gavage
Vehicle:
other: 1% methylcellulose
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. The suspensions were prepared freshly each day.

VEHICLE
- Concentration in vehicle: 5, 10, 20% w/v
- Amount of vehicle: 10 mL/kg
Analytical verification of doses or concentrations:
no
Details on mating procedure:
Does were mated with males of proven fertility; once coitus had been observed, each female was allowed to remain with the male for at least one hour. Seventy-two of those dams which successfully completed coitus were each injected intravenously with 25 i.u. of Chorulon® (luteinizing hormone) to promote ovulation. The day of mating was considered as Day 0 of pregnancy. Mating was phased over consecutive week days ensuring that no more than 16 animals were mated on any one day.
Duration of treatment / exposure:
GD 7 to 19
Frequency of treatment:
Once daily
Dose / conc.:
500 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Dose / conc.:
2 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
Control, 500 mg/kg groups: 18
1000 mg/kg group: 19
2000 mg/kg group: 17
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Dosages were based on a prior preliminary study (0, 100, 500, and 2000 mg/kg/day).
Results from preliminary study: At the maximum practical dosage of 2000 mg/kg/day animals showed pale discolouration of faeces and slightly lower mean bodyweight gain. There were no other signs of reaction considered attributable to treatment. No treatment related deaths were observed. Mean food consumption at 2000 mg/kg/day was consistently marginally lower than among control animals. There were no macroscopic findings at terminal autopsy that appeared attributable to treatment.
- Rationale for animal assignment: Mating was phased over consecutive week days ensuring that no more than 16 animals were mated on any one day. On each of these days, mated does were allocated to four groups equalising distribution as far as possible, as to number allocated, source of animals and male to which they were mated. Following allocation, does were re-assigned to cages in the experimental room.
Maternal examinations:
CAGE SIDE OBSERVATIONS:
- Time schedule: All animals were regularly handled and observed daily. Obvious changes or signs of reaction to treatment were recorded. Any animals that died or were killed for reasons of animal welfare were weighed and subjected to post mortem.

BODY WEIGHT:
- Time schedule for examinations: All rabits were weighed on Days 1, 7, 9, 11, 15, 20, 24, and 29 of gestation.

FOOD CONSUMPTION: The food intake of all rabbits was measured from weigh-day to weigh-day.
Ovaries and uterine content:
On Day 29 of pregnancy the animals were killed by cervical dislocation, dissected and examined for congenital abnormalities and macroscopic pathological changes in maternal organs; the ovaries and uteri were examined immediately to determine:
(a) number of corpora lutea
(b) number and distribution of live young
(c) number and distribution of embryonic/foetal deaths
(d) individual foetal weights
(e) foetal abnormalities
Fetal examinations:
- External examinations: Yes
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
- Head examinations: Yes
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.
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:
effects observed, non-treatment-related
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 to a lesser extent 2000 mg/kg/day was greater than that of control animals.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
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.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
There were no macroscopic findings at terminal autopsy that were considered attributable to treatment.
Details on results:
Pregnancy rate, as judged by the numbers of animals pregnant at termination, was high in all groups.
Number of abortions:
no effects observed
Pre- and post-implantation loss:
effects observed, non-treatment-related
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).
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Description (incidence and severity):
A single animal, from the control group, showed total litter loss.
Dead fetuses:
no effects observed
Changes in number of pregnant:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: no adverse effects at highest dose tested
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Changes in litter size and weights:
no effects observed
External malformations:
effects observed, non-treatment-related
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:
effects observed, non-treatment-related
Description (incidence and severity):
Incidences 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
Key result
Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: no adverse effects at highest dose tested
Key result
Abnormalities:
no effects observed
Developmental effects observed:
no
Conclusions:
There were no adverse effects on maternal toxicity, litter parameters, incidences of malformations, visceral and skeletal anomalies, and skeletal variants up to the highest dose tested.
Executive summary:

In this assessment of the effect of the test substance on pregnancy of the rabbit, daily dosages of 0, 500, 1000 and 2000 mg/kg were administered by intragastric intubation during Days 7 to 19 inclusive of pregnancy. This study was conducted following OECD Guideline 414. On Day 29, animals were killed, litter values determined and fetuses examined for visceral and skeletal abnormality.

Dosages were based on a prior preliminary study in which at the maximum practical dosage of 2000 mg/kg/day animals showed pale discolouration of faeces and slightly lower mean bodyweight gain. In the main study, animals dosed at 2000 mg/kg/day, and to a lesser extent at 1000 mg/kg/day, showed pale discolouration of the faeces during the treatment period. There were no adverse effect on mean food consumption or weight gain that was clearly attributable to treatment and overall weight gain at 1000 mg/kg/day, and to a lesser extent at 2000 mg/kg/day, was greater than for control animals. There was no adverse effect on litter parameters as assessed by mean values for litter size, pre- and post implantation loss, and litter and mean foetal weight. Incidences of malformations, visceral and skeletal anomalies and skeletal variants were not adversely affected by treatment.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
2 000 mg/kg bw/day
Study duration:
subacute
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

The developmental toxicity potential of the test substance was examined in rabbits in accordance with OECD guideline 414. Daily dosages of 0, 500, 1000 and 2000 mg/kg were administered by intragastric intubation during Days 7 to 19 inclusive of pregnancy. In the main study, animals dosed at 2000 mg/kg/day, and to a lesser extent at 1000 mg/kg/day, showed pale discolouration of the faeces during the treatment period. There was no adverse effect on mean food consumption or weight gain that were clearly attributable to treatment and overall weight gain at 1000 mg/kg/day, and to a lesser extent at 2000 mg/kg/day, was greater than for control animals.

There was no adverse effect on litter parameters as assessed by mean values for litter size, pre- and post-implantation loss, and litter and mean foetal weight. Incidences of malformations, visceral and skeletal anomalies and skeletal variants were not adversely affected by treatment. The NOAEL for maternal and developmental toxicity was 2000 mg/kg (highest dose tested).

Justification for classification or non-classification

The test substance was not uniquely toxic to the developing foetus using a read-across material. As no reproductive toxicity study is available for the test substance or read-across substance, no classification for the test substance can be determined according the EU Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.

Additional information