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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
90 mg/kg bw/day
Additional information

A Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test (Adamska, 2011, K) was conducted with the substance according to the OECD Guideline No. 422 and in compliance with GLP. The substance was dosed once daily by gavage at dose levels of 0, 30, 60 and 90 mg/kg bw/f (dose volume of 4 mL/kg bw in corn oil) to Han Wistar rats. Male rats were administered for at least 28 days and female rats for 14 days prior to pairing, through the pairing and gestation periods until the F1 generation reached day 4 post-partum.

During the treatment ten animals were found dead before scheduled necropsy: four males at the dose level of 90 mg/kg bw/day, four males and one female at the dose level of 60 mg/kg bw/day and one male at the dose level of 30 mg/kg bw/day. Some of these animals had reduced food consumption and reduced body weight gain. Because of breathing noises observed in these animals a penetration of the test item into the airways was assumed. During histopathological examination necrosis of the trachea was found in all these animals and this pathological change was identified as a cause for the deaths.

Treatment with the test item caused bedding in mouth, salivation and breathing noises in several males and females at the dose levels of 90 and 60 mg/kg bw/day, at the dose level of 30 mg/kg bw/day breathing noises were observed in one male. These clinical signs indicated irritative properties of the test item.

During functional observational battery test item-related effects on number of rearings and locomotor activity were recorded in males at the dose levels of 90, 60 and 30 mg/kg bw/day and in females at the dose level of 90 mg/kg bw/day.

Food consumption, body weights and body weight gain were adversely reduced in males treated at the dose level of 90 and 60 mg/kg bw/day. In females reduction of food consumption was observed at the dose level of 90 mg/kg bw/day. Because no test item-related effects on body weights or body weight gain were observed, reduction of food consumption in females was considered not to be adverse.

As established during macroscopical and microscopical examinations treatment with the test item induced lesions in the forestomach of males treated at the dose levels of 30, 60 and 90 mg/kg bw/day and in females treated at the dose level of 90 mg/kg bw/day. These inflammatory, degenerative and reactive changes were caused by irritative or corrosive properties of the test item. Residual microdroplets of the dose formulations remaining on intubation cannula during removal after administration could irritate esophagus, cause an opening of the epiglottis and aspiration of the test item. This was assumed to be the reason for the macroscopical and microscopical changes found in the respiratory tract of the animals.

 

With the exception for mean precoital time, the relevant reproduction parameters (duration of gestation, number of corpora lutea, implantation sites, pre- and post implantation losses, number of pups) were not affected by the treatment with the test item. The litter size at first litter check and on day 4 post-partum was also not affected.

A prolongation of mean precoital time was recorded at the dose level of 90 mg/kg bw/day. In the absence of any test item-related pathological changes in reproductive organs in males and in females, prolongation of the precoital time was considered to be secondary to the bad condition of males and females during the pairing period and not to be a sign of test item-related toxicity to reproduction. Because this effect did not result in lower number of offspring, this effect was considered not to be adverse.

No effects on body weights and body weight gain of pups during the first four days post-partum were observed.

External and visceral examination of pups did not give any indication of test item-related effects on development.

During skeletal examination, an increase of incompletely ossified os frontal was observed at the dose level of 90 mg/kg bw/day.

The authors considered that this effect was test item-related. However, the delayed of ossification observed in the fetuses from the dams treated at the highest dose were likely secondary to the maternal toxicity. Furthermore, in the absence of any further signs of a delay in pup development and because a delay in the ossification is expected to recover during the post natal life and not impact the later development and animal life, this effect was not considered as adverse.

In conclusion, findings in parental animals observed during the in live-phase and recorded upon termination of the study were considered to result from irritative or corrosive properties of the test item. Under the conditions of this study no indications of systemic toxicity of the test item were observed.

Consequently, because of one case of death at the low dose level due to the irritative/corrosive effects resulting from gavage administration, no NOAEL (No Observed Adverse Effect Level) could be established for general toxicity for parental animals.

Based on a prolongation of mean precoital time that was related to the poor general physical condition of the animals induced by the irritative properties of the test material, the dose level of 90 mg/kg bw/day was considered to be the NOAEL for reproduction and breeding.

Based on a delay in the ossification state of cranial bones observed in pups at the dose level of 90 mg/kg bw/day, the NOAEL for pup development was considered to be 90 mg/kg bw/day. However, the slight ossification retardation observed at the highest dose levels in this study is considered to be of low level of concern as nonlethal and not detrimental to postnatal survival variations which are generally reversible or transitory. In fact, the delays in ossification resolve in time as the growth of the individual reaches a comparable stage to that of the control group to which it is being compared.


Short description of key information:
Based on a prolongation of mean precoital time that was related to the poor general physical condition of the animals induced by the irritative properties of the test material, the dose level of 90 mg/kg bw/day was considered to be the NOAEL for reproduction and breeding.

Effects on developmental toxicity

Description of key information
Based on a delay in the ossification state of cranial bones observed in pups at the dose level of 90 mg/kg bw/day, the NOAEL for pup development was considered to be 90 mg/kg bw/day even if this effect is considered to be of low level of concern.
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
90 mg/kg bw/day
Additional information

See above summary.

Justification for classification or non-classification

Based on the results of the key study, the substance is not classified for reprotoxicity according to the criteria of the Regulation (EC) No. 1272/2008 (CLP) and the Council Directive 67/548/EEC (and subsequent adaptations).