Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

- NOAEL for general toxicity in parents was considered to be 100 mg/kg/day (i.e. 133 mg/kg/day in terms of test item as registered) based on clinical findings in males

- NOEL for reproductive performance was considered to be 300 mg/kg/day (i.e. 398 mg/kg/day as registered substance) in the absence of any treatment-related effect on mating and fertility at this dose-level,

- NOAEL for toxic effects on progeny was considered to be 300 mg/kg/day (i.e. 398 mg/kg/day as registered substance) based on equivocal reduced pup survival at this dose-level which can be considered as secondary effect to the general toxicity in parents

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
100 mg/kg bw/day
Study duration:
subacute
Species:
rat
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

The lowest NOAEL available for the selected study is 10 mg/kg bw/day based on maternal toxicity.

NOAEL developmental toxicity: 60 mg/kg bw day


Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
10 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

The developmental toxicity potential of the substance to rats was evaluated. Wistar rats were exposed to the substance, via the oral route, daily from day 6 to day 15 p.c. The following parameters of maternal toxicity were impaired:

the body weight gain in the 60 and 360 mg/kg group dams and the feed intake in the 360 mg/kg group (60 mg/kg marginally) were reduced during the treatment period. Decreased water consumption and reduced faeces excretion were observed in some dams of the 360 mg/kg group.  

The following parameters on intrauterine development were affected:

In the 360 mg/kg group increased numbers of placentas with necrotic border and slightly reduced placental weights were observed. In the 360 mg/kg group increased numbers of fetuses with skeletal variations and retardations were observed. St the dosed of 360 mg/kg b.w. increased incidences of vertebral and multiple malformations that may occur spontaneously were evident, while the overall incidence of malformations was comparable between control and 360 mg/kg group. A treatment related effect for this slightly different distribution cannot be excluded.

However, primary developmental toxicity was not evident, since all embryotoxic findings observed at the dose of 360 mg/kg appeared in a maternally toxic dose range.

NOAEL maternal toxicity: 10 mg/kg bw day

NOAEL developmental toxicity: 60 mg/kg bw day

Toxicity to reproduction: other studies

Description of key information

- NOAEL for general toxicity in parents was considered to be 100 mg/kg/day (i.e. 133 mg/kg/day in terms of test item as registered) based on clinical findings in males

- NOEL for reproductive performance was considered to be 300 mg/kg/day (i.e. 398 mg/kg/day as registered substance) in the absence of any treatment-related effect on mating and fertility at this dose-level,

- NOAEL for toxic effects on progeny was considered to be 300 mg/kg/day (i.e. 398 mg/kg/day as registered substance) based on equivocal reduced pup survival at this dose-level which can be considered as secondary effect to the general toxicity in parents

Additional information

In a combined repeated dose toxicity study with the reproductive/developmental toxicity screening test by oral route performed in compliance with the GLP and in accordance with the OECD 422 test guideline, the test item diluted in water was administered daily by gavage to Sprague Dawley rats (10 animals/sex/dose) at doses of 0; 30; 100 and 300 mg/kg bw/d (corresponding to 0; 39.8; 133 and 398 mg/kg bw/d in terms of active subsatnce). Males were exposed 2 weeks before pairing, during pairing and until sacrifice (at least 5 weeks in total) whereas females were exposed 2 weeks before pairing, during pairing, during gestation and during lactation until day 5 post-partum (6-7 weeks in total). The animals were paired for mating after 2 weeks of treatment and the dams were allowed to litter and rear their progeny until day 5 p.p.

Animals were checked daily for clinical signs, mortality, and detailed clinical observations were conducted weekly. Body weight was recorded weekly until sacrifice and then at designated intervals throughout gestation and lactation for the females. Female estrous cycle stage was determined each morning during the pairing period, until the females are mated. Prior to sacrifice, blood samples were also taken from these animals for analysis of hematology and blood biochemistry parameters. At sacrifice body weights and selected organs weights were recorded and a complete macroscopic post-mortem examination performed with particular attention paid to the reproductive organs. A microscopic examination was also conducted on selected organs from the first five animals in the control group and the high-dose group. Microscopic examination was conducted on all macroscopic lesions from all groups.

The total litter sizes and numbers of pups of each sex were recorded after birth. The pups were observed daily for clinical signs of toxicity and pup body weights were recorded on days 1 and 5 p.p.

Pups showing relevant external abormalities at scheduled sacrifice and those found dead before study termination, were submitted for a macroscopic post-mortem examination.

The test item concentrations in the administered dose formulations analyzed in weeks 1, 3 and 5 remained within an acceptable range of -3.7 % to +4.4 % when compared to the nominal values. SUPRAGIL WP was not detected in control samples.

 

With regards to reproductive and developmental parameters, the following observations were made: there were no treatment related effects on mating and fertility data. No relevant differences between control and test item-treated groups were observed regarding the mean duration of gestation, the mean number of corpora lutea, the mean number of implantations, the mean pre-implantation loss, the mean number of pups delivered and the mean post-implantation loss. In the 300 mg/kg bw/d group, there were increases in the number of found dead and cannibalizedpups: one litter had four found dead pups and three cannibalized pups. While not dose-related, a test item treatment-related effect cannot be excluded. There were no obvious treatment-related effects on live birth, viability and lactation indexes with the exception of a trend towards decreased viability and lactation indexes at 300 mg/kg bw/d. There were no effects on the mean body weight of pup during the lactation period (day 1 or day 5p.p.). While not statistically significant, there was a dose-related decrease in sex-ratio (% of male pups) both on day 1 and 5p.p.. At 300 mg/kg bw/d, a test item treatment-related effect cannot be excluded. There were no obvious treatment-related findings at necropsy of found dead pups or scheduled sacrifice pups.

In conclusion, based on the experimental conditions of this study:

- NOEL for reproductive performance was considered to be 398 mg/kg/day (highest dose tested) in the absence of any treatment-related effect on mating and fertility at this dose-level,

- NOAEL for toxic effects on progeny was considered to be 398 mg/kg/day based on equivocal reduced pup survival at this dose-level which can be considered as secondary effect to the general toxicity in parents.

The findings of the reproductive/developmental toxicity studies reported effects, mainly in presence of maternal toxicity, for which a hazard classification is not foreseen.

Justification for classification or non-classification

Based on the available information, retrieved from a combined repeated dose toxicity study with the reproductive/developmental toxicity screening test and a developmental toxicity,the substance is not classified for reproductive toxicity according to the CLP Regulation (EC) No.1272/2008