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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Additional information

A screening test for reproductive/developmental toxicity (OECD 422) was performed on Fyrolflex Sol-DPto provide information on the potential systemic, reproductive, developmental and neuro-toxicity of the product.The test material was orally administeredby gavageto 4 groups of ten male and ten female rats at concentrations of 0, 50, 250, 1000mg/kg/day.The control and high dose groups each contained 5 additional rats/ sex for the same duration but were not mated. These rats were designated as recovery animals and were held for at least 14 days after treatment termination to evaluate the recovery potential from any adverse treatment related effects.

The parental rats were administered with the test material for 14 days prior to mating.  Then, one male was housed with one female from the same concentration group. Each couple was allowed to mate for up to 2 weeks while the administration of the test substance continued. During the mating period, daily vaginal smears were taken from each of the female rats and were evaluated for the presence of sperm, as well as the stage of the estrus cycle. Standard evaluations including body weight, food consumption, clinical pathology, organ weights, histopathology, mating performance, liter viability, and neurotoxicity (FOB and automated motor activity assessments) were included in the study. All parental males were dosed for a minimum of 35 consecutive days prior to sacrifice. Females were treated through gestation and lactation periods, until necropsy.

At termination of the study, a complete gross necropsy was performed on all animals that included examination of the external surface of the body, all orifices, the cranial, thoracic, and peritoneal cavities, and their contents. The uterus of each rat was examined for evidence of implantation sites and the number of sites was recorded. In addition, the corpora lutea were counted. In addition, a bone marrow smear was collected and fixed for possible future evaluation. Testes and epididymides were fixed in Bouin's solution and the eyes and associated tissues (e.g., optic nerve) were fixed in Davidson's solution. All other tissues were fixed in 10% neutral buffered formalin. Rat pups (F1 generation) were sexed and given a gross external physical examination on postnatal day 0. Dead or still born pups were examined for gross external anomalies and, when feasible, a visceral exam was performed. Off springs postmortem examinations: Hematology, Organ weight, Neurotoxicity, Gross pathology and Histopathology.

Some randomly selected tissues, obtained from the vehicle control and high dose groups were subjected to histopathological evaluation. Protocol-specified necropsy procedures included examination of the external surface of the body, all orifices, the cranial, thoracic, and peritoneal cavities and their contents.

Results: Overall, mating, pregnancy, litter survival, and pup body weights were unaffected by treatment with E-AF98T. The number of sperm-positive breeding pairs was similar across groups (10/10 in all groups except for 250mg/kg group 9/10). Successful pregnancy was 100% in all groups except for 50mg/kg group). The length of gestation was similar in all groups and averaged 22 days. The number of dams undergoing successful parturition was similar. However, one dam treated with 50mg/kg delivered a non-viable litter. Litter survival was similar across all groups on postnatal days 0 and 4.

No treatment- related deaths or adverse clinical signs of toxicity were observed during the study. No adverse treatment- related alteration in food consumption, body weights, organ weights, clinical pathology, motor activity or functional observational battery were noted. Additionally, no effects on mating, pregnancy, litter viability or pup body weights were observed in groups treated with the test substance. No treatment-related gross lesions or microscopic findings were noted in this study. The NOAEL is therefore determined to be greater than 1000mg/kg/day (highest dose tested).


Short description of key information:
Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test of E-AF098T in Rats.

Effects on developmental toxicity

Description of key information
The information is available from two stiudies: 
Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test of E-AF098T in Rats.
Sol-DP: Study for effects on embryo-fetal development in the New Zealand White rabbit by oral gavage administration
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Additional information

A screening test for reproductive/developmental toxicity (OECD 422) was performed on Fyrolflex Sol-DPto provide information on the potential systemic, reproductive, developmental and neuro-toxicity of the product.The test material was orally administeredby gavageto 4 groups of ten male and ten female rats at concentrations of 0, 50, 250, 1000mg/kg/day.The control and high dose groups each contained 5 additional rats/ sex for the same duration but were not mated. These rats were designated as recovery animals and were held for at least 14 days after treatment termination to evaluate the recovery potential from any adverse treatment related effects.

The parental rats were administered with the test material for 14 days prior to mating.  Then, one male was housed with one female from the same concentration group. Each couple was allowed to mate for up to 2 weeks while the administration of the test substance continued. During the mating period, daily vaginal smears were taken from each of the female rats and were evaluated for the presence of sperm, as well as the stage of the estrus cycle. Standard evaluations including body weight, food consumption, clinical pathology, organ weights, histopathology, mating performance, liter viability, and neurotoxicity (FOB and automated motor activity assessments) were included in the study. All parental males were dosed for a minimum of 35 consecutive days prior to sacrifice. Females were treated through gestation and lactation periods, until necropsy.

At termination of the study, a complete gross necropsy was performed on all animals that included examination of the external surface of the body, all orifices, the cranial, thoraic, and peritoneal cavities, and their contents. The uterus of each rat was examined for evidence of implantation sites and the number of sites was recorded. In addition, the corpora lutea were counted. In addition, a bone marrow smear was collected and fixed for possible future evaluation. Testes and epididymides were fixed in Bouin's solution and the eyes and associated tissues (e.g., optic nerve) were fixed in Davidson's solution. All other tissues were fixed in 10% neutral buffered formalin. Rat pups (F1 generation) were sexed and given a gross external ohysical examination on postnatal day 0. Dead or still born pups were examined for gross external anomalies and, when feasible, a visceral exam was performed. Offsprings postmortem examinations: Hematology, Organ weight, Neurotoxicity, Gross pathology and Histopathology.

Some randomly selected tissues, obtained from the vehicle control and high dose groups were subjected to histopathological evaluation. Protocol-specified necropsy procedures included examination of the external surface of the body, all orifices, the cranial, thoracic, and peritoneal cavities and their contents.

Results: Overall, mating, pregnancy, litter survival, and pup body weights were unaffected by treatment with E-AF98T. The number of sperm-positive breeding pairs was similar across groups (10/10 in all groups except for 250mg/kg group 9/10). Successful pregnancy was 100% in all groups except for 50mg/kg group). The length of gestation was similar in all groups and averaged 22 days. The number of dams undergoing successful parturition was similar. However, one dam treated with 50mg/kg delivered a non-viable litter. Litter survival was similar across all groups on postnatal days 0 and 4.

No treatment- related deaths or adverse clinical signs of toxicity were observed during the study. No adverse treatment- related alteration in food consumption, body weights, organ weights, clinical pathology, motor activity or functional observational battery were noted. Additionally, no effects on mating, pregnancy, litter viability or pup body weights were observed in groups treated with the test substance. No treatment-related gross lesions or microscopic findings were noted in this study. The NOAEL is therefore determined to be greater than 1000mg/kg/day (highest dose tested).

 

  The influence of SOL-DP on embryo-fetal survival and development in New Zealand White rabbits was assessed following oral administration from implantation (Day 6 after mating) until Day 28 after mating (shortly before the end of pregnancy).

Initially a preliminary phase of three groups, each comprising six female rabbits, received SOL-DP by gavage at doses of 100, 300 or 1000 mg/kg/day from Day 6 to 28 after mating. A similarly constituted Control group received the vehicle 1% MC (methylcellulose, in water for formulation), at the same volume-dose throughout the same period. Animals were killed on Day 29 after mating for reproductive assessment and fetal examination. This preliminary phase of the study was designed to initially investigate the effects of treatment in a small number of animals. As no adverse effects of treatment were observed, an additional 16 animals were allocated to each group to form the main phase of the study in order to form the full complement of 22 females at each dose level.

The main phase females followed the same treatment regime as the preliminary phase. For each phase, clinical observations, bodyweight and food consumption were monitored. Adult females were examined macroscopically at necropsy on Day 29 after mating and all fetuses were examined macroscopically at necropsy and subsequently by detailed internal visceral examination of the head or skeletal examination. For reporting purposes, data for the two phases were combined.

Administration of SOL-DP by oral gavage at dose levels of 100, 300 or 1000 mg/kg/day was well tolerated by pregnant New Zealand White rabbits, with no treatment-related mortalities observed. One Control female was killed for reasons of animal welfare on Day 17 of gestation due to signs of abortion and subsequent respiratory distress but this was related to the low implantation count and not to treatment with SOL-DP. There were no dosing signs observed and no clinical signs or macroscopic necropsy findings that were related to treatment. Maternal bodyweight (including bodyweight adjusted for the contribution of the gravid uterus) and food consumption were unaffected by treatment. Embryo-fetal survival was unaffected by treatment with no effects upon litter data and placental, litter and fetal weight, and there were no fetal findings observed that were considered to represent any adverse effect upon fetal development.

In conclusion, based on the results of this study it is concluded that daily oral gavage administration of SOL-DP to female New Zealand White rabbits up to and including 1000 mg/kg/day did not cause adverse effects upon maternal parameters or embryo-fetal survival, growth and development. The highest dose of 1000 mg/kg/day is therefore the No Observed Adverse Effect Level (NOAEL) in this study.

Justification for classification or non-classification

Based on the information available for Fyrolflex SOL-DP from the screening test, this substance should not be classified for reproduction/ developmental toxicity according to the EEC criteria for classification and labelling for Dangerous Substances and Preparations (67/548/EEC) and the CLP Regulation (EC No 1272/2008).