Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
75 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The study has been conducted according to OECD Guideline 422 and GLP and is adequately reported. The study has been assigned a reliability 1.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Summary of Reproductive Performance:

Mating. There was no adverse effect of treatment on mating performance.

Fertility. Fertility, as assessed by the number of pregnant females, was unaffected by treatment.

Gestation Lengths. There was a tendency towards a longer gestation length at 75 and 150/100 mg/kg bw/day in comparison to control females and those receiving 30 mg/kg bw/day.

Discussion on Reproductive Performance and Litter Responses:

Mating performance was unaffected by treatment at all dosages and fertility, a s assessed by the number of pregnant females, was similarly unaffected. 

Gestation lengths for the majority of control and 30 mg/kg bw/day females were twenty three days or less; only two females showed a longer gestation period and both subsequently showed total litter loss post partum. At 75 and 150/100 mg/kg bw/day the majority of females delivered on Day 23 ½ or later. However, despite the comparatively later delivery times for females at these dosages, only one female at 150/ 100 mg/kg bw/day subsequently showed total litter loss post partum.

Corpora lutea counts, pre-implantation loss and implantation counts were similar at all dosages, however subsequent post partum litter size at birth/Day 1 for females at 150/100 mg/kg bw/day was lower than control and other treated groups due to higher post-implantation loss. The lower litter size at 150/100 mg/kg bw/day may have been expected to lead to an improvement in post partum survival due to the comparatively lower demand on the nursing females; however there was no evidence of this as offspring survival to Day 4 at this dosage was slightly inferior to control and other treatment groups.

Although there were clear adverse effects on the overall survival of offspring at 150/100 mg/kg bw/day, there was no adverse effect on post partum body weight of the offspring on Day 1 or subsequent body weight gain to Day 4 of age at any of the dosages investigated. At 150/100 mg/kg bw/day litter weight was lower than Control on Day 1 and Day 4 but these differences were a consequence of the lower litter size at this dosage. Clinical signs and surface righting performance did not indicate any obvious adverse effect of treatment at any of the dosages investigated. Necropsy findings for offspring, including decedents, did not indicate any adverse effect of treatment.

Within the confines of this screening study it is not possible to establish at the exact stage of the study the increase in post-implantation loss which lead to the reduction in litter size observed at 150/100 mg/kg bw/day actually occurred. Losses may have occurred in utero prior to delivery or in the immediate period around the time of parturition. The majority of females would have delivered their young at night and it is quite possible that decedent offspring may have been eaten by the dam by the time they were observed by technical staff. As such the litter size at birth may represent an under-estimation of the actual number of offspring delivered.    

 

It is not unusual for litters belonging to females that have shown an extended gestation length to exhibit increased offspring mortality. Within this study this appears to have been demonstrated by one control and one 30 mg/kg bw/day female, who both showed total litter loss post partum after a gestation length of 23½ days or more. As previously discussed, at both 75 and 150/100 mg/kg bw/day the majority of females had a gestation length of Day 23 ½ or later although the only female that subsequently showed post partum total litter loss had a gestation length of 23 days. However, if the increased post-implantation loss observed at 150/100 mg/kg bw/day was a result of increased offspring loss at birth, it is possible that offspring mortality may have been influenced to some extent by the comparative delay in parturition.

At 150/100 mg/kg bw/day, longer gestation length, increased post implantation loss and lower litter size at birth/Day 1 were observed. At 75 mg/kg bw/day, a tendency towards longer gestation length was observed but, in the absence of any post-implantation loss or litter size at birth/Day 1, this dosage can be classified as a NOAEL for reproduction.

No effects were apparent on offspring body weights and survival at 75 mg/kg bw/day and therefore this dosage can be classified as a NOEL for offspring growth and development.  


Short description of key information:
At 75 mg/kg bw/day, a tendency towards longer gestation length was observed but, in the absence of any adverse effect on post-implantation loss or litter size at birth/Day 1, this dosage is classified as a NOAEL for reproduction.

Justification for selection of Effect on fertility via oral route:
The available OECD 422 study is assigned as reliability study 1 and is the reproduction/developmental study available on the substance itself.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
75 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Two studies have been conducted according to OECD Guideline 422 and 414 and GLP and are adequately reported.
The studies have been assigned a reliability 1.
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

Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test: Key study (41101249)

Summary of Litter Responses:

Offspring Litter Size and Viability.

At 150 mg/kg bw/day litter size at birth/Day 1 was lower than control due to higher post-implantation loss and, despite this lower litter size, survival to Day 4 was slightly inferior to control. One female showed total litter loss post partum and, although a similar incidence was observed for control and 30 mg/kg bw/day, an association with treatment at this higher dosage could not be discounted.

Offspring Growth and Development.

There was no adverse effect of treatment on offspring body weight on Day 1 or body weight gain to Day 4 of age, although at 150/100 mg/kg/day litter weight was lower than control as a consequence of the lower litter size at this dosage.

Clinical signs and assessment of surface righting did not indicate any obvious adverse effect of treatment.

Discussion on Reproductive Performance and Litter Responses:

Refer to discussion in fertility section.

Prenatal Development Toxicity Study: Key study (41303258)

Summary & Discussion of Litter Responses:

Litter Responses

There was no effect of maternal treatment on litter data as assessed by numbers of implantations, in-utero offspring survival (as assessed by the mean numbers of early or late resorptions), live litter size, fetus weight, sex ratio and pre and post-implantation losses at 30, 75 and 100 mg/kg bw/day.

Fetal Examination

For all dose groups, there were no significant treatment-related trends in the proportion of fetuses (or litters) with evidence of external, visceral or skeletal anomalies. The type of external, visceral and skeletal anomalies, were those commonly observed for this type of study. There were no findings that were considered to represent any known malformations. Females treated with 100 and 75 mg/kg bw/day showed a statistically significant increase in the percent of fetuses showing incomplete ossification of thoracic centrum. Females treated with 100 mg/kg bw/day also showed a statistically significant increase in the percent of fetuses showing incomplete ossification of sternebra and less than four ossified caudal vertebrae. A statistically significant reduction was evident in the percent of fetuses showing incomplete ossification of hyoid and sacral (neural) arch from females treated with 100 mg/kg bw/day. Females treated with 75 mg/kg bw/day also showed a statistically significant reduction in the percent of fetuses showing a partially split xiphoid cartilage. The observations of isolated variants at a higher incidence compared with controls is not significant when evaluated in isolation. The distribution of the changes seen indicates a lack of specificity of affected ossification centers which suggests the differences seen are of a random pattern. The number of parameters routinely evaluated makes it highly likely that one or more finding will be seen at a higher level in dosed groups compared with controls. A true developmental effect is only seen when a number of variants or a syndrome of variants is observed, therefore the intergroup difference is considered of no biological significance. A dose related increase in the total number of fetuses with visceral findings was evident in all treatment groups. A slight dose related response was evident in all treated females showing an increase in the percent of fetuses having a kinked ureter. Female treated with 100 and 75 mg/kg bw/day also showed a slight dose related increase in the percent of fetuses having a dilated ureter. Statistical analysis of the data did not reveal any significant intergroup differences therefore these slight increases were considered not to be of toxicological importance.

Justification for classification or non-classification

In an OECD 422 study effects were observed on reproductive performance (tendency towards longer gestation) at 150/100 mg/kg bw/day in the absence of any adverse effects on mating performance and fertility (number of pregnant females). Furthermore effects on offspring litter size and viability (increased post implantation loss and lower litter size at birth/Day 1) were observed at the top dose of 150/100 mg/kg bw/day.

As an association between litter loss and treatment this dosage could not be discounted, a definitive study, a full pre-natal developmental study (OECD 414) was proposed and conducted.

In the OECD 414, there was no effect of maternal treatment on litter data as assessed by number of implantations, in-utero offspring survival, live litter size, fetus weight, sex ratio and pre and post implantation losses at 30, 75 and 100 mg/kg bw/day. Furthermore, there were no significant treatment-related trends in the proportion of fetuses (or litters) with evidence of external, visceral or skeletal anomalies. The type of external, visceral and skeletal anomalies, were those commonly observed for this type of study. There were no findings that were considered to represent any known malformations.

In the absence of any effects on the development of the litter in the OECD 414 at 30, 75 and 100 mg/kg bw/day and in the absence of any adverse effects on reproductive performance in the OECD 422 at 75 mg/kg bw/day, it is considered that the substance does not meet the criteria for classification as reproductive toxicant.