Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

No study.

Effects on developmental toxicity

Description of key information

Under the conditions of this study, the no observed adverse effect level (NOAEL) was established as 300 mg/kg/day for dams and foetuses.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
subacute
Species:
rat
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 study was conducted to determine the effects of the test material on the embryonic and foetal development of the rat in accordance with the standardised guidelines OECD 414, US EPA OPPTS 870.3700 and exceeds the current requirements of the European Council and Japanese Ministry of Agriculture, Forestry, and Fisheries. The study was carried out under GLP conditions.

Four groups of 20 female time-mated Sprague Dawley Crl:CD(SD) rats were administered 0 (vehicle), 100, 300 or 1000 mg/kg/day of the test material once daily by oral gavage from Gestation Day (GD) 6 to 20, inclusive, at a dose volume of 10 mL/kg. The control material was Polyethylene glycol 400 (PEG 400).

Assessment of toxicity was based on clinical observations, body weight and food consumption. On GD 21, females were sacrificed and the progress and outcome of pregnancy was evaluated. Complete necropsies were performed on all animals, with a recording of macroscopic abnormalities for all tissues. Foetuses were evaluated for external, visceral, and skeletal malformations and variations.

No test material-related unscheduled deaths occurred. 18, 15, 17, and 17 pregnant females administered 0, 100, 300 or 1000 mg/kg/day, respectively, had live foetuses on GD 21.

For females administered 1000 mg/kg/day, clinical observations consisted of isolated instances of a convulsive episode, hunched posture, thin appearance, red tears in the eye and raised fur. Paddling behaviour and salivation were noted immediately post-dose for a few animals.

Initial reductions in body weight gains (30 % between GD 6 and 9) compared with controls and lower food consumption were evident following administration of 1000 mg/kg/day.

No macroscopic abnormalities were evident following 1000 mg/kg/day, however, lower placenta weights and lower mean foetal weights were evident and foetal evaluations showed ocular malformations (small and misshapen lens) in two foetuses from two litters. Furthermore, variations only observed at this dose level were noted in the skull (sutral bone) and tail (fleshy tab) and higher incidences of misshapen scapula and supernumerary liver lobe were also evident.

For animals administered 300 or 100 mg/kg/day, test material-related clinical observations included instances of mouth rubbing noted immediately post-dose (with isolated instances of paddling behaviour also noted for animals administered 100 mg/kg/day) and an initial reduction in body weight gain and food consumption. No macroscopic abnormalities or implantation or uterine changes were evident, and foetal weights were essentially similar to controls. Furthermore, no test material-related malformations were noted. The only possible foetal variations noted were higher incidences of misshapen scapula at these dose levels, compared with controls.

In conclusion, the oral administration of 0, 100, 300 or 1000 mg/kg/day to the pregnant Sprague Dawley rat caused test material-related effects in the maternal animal, resulting in lower placenta and foetal weights, and ocular malformations noted in two foetuses following administration of 1000 mg/kg/day.

Maternal effects noted following administration of 300 or 100 mg/kg/day did not result in foetal effects; as such, the no observed adverse effect level (NOAEL) was established as 300 mg/kg/day for dams and foetuses.

Mode of Action Analysis / Human Relevance Framework

Dose levels for this study were set on the basis of an existing 28 day study in rats in which some effects on the red blood cells, and organ weight increases, including increased spleen weights (often associated with blood effects) in females. There was no microscopic pathology seen at 1000 mg/kg bw/day (the limit dose).  As such, a limit dose of 1000 mg/kg was selected as the top dose for the current study.

The dose level selection proved to be tolerated by the mothers and there were no maternal deaths.  Apart from isolated incidences of hunched posture, thin appearance, red tears in the eye, and raised fur, there were some consistent clinical signs in the mothers related to the unpleasant taste of the test material.    Initial reductions in body weight gains (30% between GD 6 and 9), compared with controls, and lower food consumption were evident following administration of 1000 mg/kg/day.

Effects in the 28 day study indicated that decreased red blood cell count, haemoglobin concentration and haematocrit would have occurred at 1000 mg/kg in the mothers in this study along with increase spleen weights, and potentially exacerbated by pregnancy.   Some foetal developmental effects might be  expected as a consequence, as these are often associated with maternal blood effects.

General litter production was not affected (there was no reduction in live pups, increased pre- or post implantation loss), and no macroscopic abnormalities were evident at any dose.

However, lower placenta weights and lower mean foetal weights were evident, and foetal evaluations showed ocular malformations (small and misshapen lens) in two foetuses from two litters, which is a significant finding because it is very uncommon (zero incidence in the historical control data).

Some increased variations (less serious than malformations) were observed at this dose level: skull (sutral bone) and tail (fleshy tab), and higher incidences of misshapen scapula and supernumerary liver lobes.

The indications are that these malformations and variations are unlikely to have arisen as a direct effect (extreme dose required, similar effects seen in anaemic/ iron deficient rats  see e.g. http://onlinelibrary.wiley.com/doi/10.1002/tera.1420220310/abstract), and are related to the anaemia, if they are not exacerbation of a common back ground findings.

Justification for classification or non-classification

No classification for reproduction is proposed based on the available data. There were no adverse effects on reproduction as examined in the OECD 414 study with rats, and developmental effects seen at the limit dose are secondary to haematological effects.