Z-85

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Additional information

In a key study designed to investigate the systemic toxicity and potential adverse effects of the test item on reproduction (including offspring development) and performed in accordance with OECD Guideline No. 422 “Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test” the test item was administered by gavage to three groups, each of twelve male and twelve female Wistar Han™:RccHan™:WIST strain rats, for up to eight weeks (including a two week pre-pairing phase, pairing, gestation and early lactation for females), at dose levels of 100, 500 and 1000 mg/kg bw/day. A control group of twelve males and twelve females was dosed with vehicle alone (Arachis oil BP). Two recovery groups, each of five males and five females, were treated with the high dose (1000 mg/kg bw/day) or the vehicle alone for forty-two consecutive days and then maintained without treatment for a further fourteen days. Clinical signs, behavioural assessments, body weight change and food and water consumption were monitored during the study. Pairing of non-recovery animals within each dose group was undertaken on a one male: one female basis within each treatment group on Day 15 of the study, with females subsequently being allowed to litter and rear their offspring to Day 5 of lactation. During the lactation phase, daily clinical observations were performed on all surviving offspring, together with litter size and offspring weights and assessment of surface righting reflex. Extensive functional observations were performed on five selected non-recovery males from each dose group after the completion of the pairing phase, and for five selected parental females from each dose group on Day 4 post partum. Hematology and blood chemistry assessments were performed on five non-recovery males and females per dose group prior to termination. Adult non-recovery males were terminated on Day 43/44, followed by the termination of all females and offspring on Day 5 post partum. Any female which did not produce a pregnancy was terminated on or after Day 25 post coitum. All animals were subjected to a gross necropsy examination and histopathological evaluation of selected tissues was performed.

Following forty-two days of treatment, recovery group animals were maintained without treatment for a further fourteen days. Hematological and blood chemical assessments were performed on all recovery group animals at the end of the treatment-free period. Recovery animals were killed on Day 57. All animals were then subjected to a gross necropsy and histopathological examinations of selected tissues was performed.

Results

Adult Responses

Mortality

There were no unscheduled deaths.

Clinical Observations

Treatment at 1000 mg/kg bw/day was associated with increased post-dosing salivation for both sexes from Day 15 onwards, with all animals being affected at some stage of the study. At 500 mg/kg bw/day, isolated incidences of increased post-dosing salivation was observed for animals of either sex towards the end of the treatment period. No such effects were detected in animals of either sex treated with 100 mg/kg bw/day.

Body Weight

There were no treatment related effects on body weights throughout the study of either treated sex.

Food Consumption

No adverse effects on dietary intake were noted for males during the study or for females during the pre-pairing, gestation or lactation phases of the study, including the recovery phase.

Water Consumption

Visual assessment of water bottles did not reveal any significant intergroup differences.

Reproductive Performance Mating

There were no treatment-related effects on mating performance.

Fertility

There were no treatment related differences in fertility.

Gestation Lengths

Gestation lengths were between 22 and 23½ days and appeared unaffected by maternal treatment.

Litter Responses

Offspring Litter Size, Sex Ratio and Viability

There was no obvious effect of treatment on the corpora lutea count, pre-implantation loss, numbers of implantations, post-implantation loss, litter size at birth/Day 1 and subsequent offspring survival to Day 4 of age at 100, 500 or 1000 mg/kg bw/day. Sex ratio for the offspring was similar in all groups and did not indicate any selective effect of maternal treatment on survival for either sex. Offspring Growth and Development

Offspring body weight gain and litter weights at birth and subsequently on Days 1 and 4 post partum were essentially similar or slightly superior to controls and appeared unaffected by maternal treatment at 100, 500 or 1000 mg/kg bw/day. Offspring performance during assessment of surface righting appeared to be unaffected by maternal treatment.

Laboratory Investigations

Hematology

Assessment of hematology parameters did not indicate any adverse effect of treatment at 100, 500 or 1000 mg/kg bw/day for either sex.

Blood Chemistry

Males at 1000 mg/kg bw/day showed a statistically significant increase in alanine aminotransferase compared with control. Females at this dosage showed statistically significant increases in alanine aminotransferase, aspartate aminotransferase, creatinine and bile acids compared with control. No statistically significant differences from control were apparent for blood chemistry parameters in either sex at both 100 and 500 mg/kg bw/day.

Pathology

Necropsy

Neither the type, incidence or distribution of necropsy findings for adult animals indicated any adverse effects of treatment.

Organ Weights

For non-recovery males at 500 and 1000 mg/kg bw/day, higher absolute and body weight relative liver weights attained statistical significance when compared with control. No such effects were detected in females treated with 1000 or 500 mg/kg bw/day, animals of either sex treated with 100 mg/kg bw/day or recovery animals following fourteen days without treatment.

Histopathology

A treatment related microscopic abnormality was detected in the liver. Minimal centrilobular hepatocellular hypertrophy was evident in two males treated with 1000 mg/kg bw/day. This was considered to be an adaptive response to the test item and was not considered to represent an adverse effect of treatment. No such effects were detected in females treated with 1000 mg/kg bw/day.

Conclusion

The oral administration of OS282640 to rats by gavage, at dose levels of 100, 500 and 1000 mg/kg bw/day, did not result in any adverse effects of treatment. The ‘No Observed Adverse Effect Level’ (NOAEL) for systemic toxicity was therefore considered to be 1000 mg/kg bw/day. The ‘No Observed Effect Level’ (NOEL) for reproductive toxicity was considered to be 1000 mg/kg bw/day.

Short description of key information:
The oral administration of the test material to rats by gavage, at dose levels of 100, 500 and 1000 mg/kg bw/day, did not result in any adverse effects of treatment. The ‘No Observed Effect Level’ (NOEL) for reproductive toxicity was considered to be 1000 mg/kg bw/day.

Effects on developmental toxicity

Description of key information

The oral administration of the test material to rats by gavage, at dose levels of 100, 500 and 1000 mg/kg bw/day, did not result in any adverse effects of treatment. The ‘No Observed Effect Level’ (NOEL) for developmental toxicity was considered to be 1000 mg/kg bw/day. 

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Additional information

In a key study designed to investigate the systemic toxicity and potential adverse effects of the test item on reproduction (including offspring development) and performed in accordance with OECD Guideline No. 422 “Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test” the test item was administered by gavage to three groups, each of twelve male and twelve female Wistar Han™:RccHan™:WIST strain rats, for up to eight weeks (including a two week pre-pairing phase, pairing, gestation and early lactation for females), at dose levels of 100, 500 and 1000 mg/kg bw/day. A control group of twelve males and twelve females was dosed with vehicle alone (Arachis oil BP). Two recovery groups, each of five males and five females, were treated with the high dose (1000 mg/kg bw/day) or the vehicle alone for forty-two consecutive days and then maintained without treatment for a further fourteen days. Clinical signs, behavioural assessments, body weight change and food and water consumption were monitored during the study. Pairing of non-recovery animals within each dose group was undertaken on a one male: one female basis within each treatment group on Day 15 of the study, with females subsequently being allowed to litter and rear their offspring to Day 5 of lactation. During the lactation phase, daily clinical observations were performed on all surviving offspring, together with litter size and offspring weights and assessment of surface righting reflex. Extensive functional observations were performed on five selected non-recovery males from each dose group after the completion of the pairing phase, and for five selected parental females from each dose group on Day 4 post partum. Hematology and blood chemistry assessments were performed on five non-recovery males and females per dose group prior to termination. Adult non-recovery males were terminated on Day 43/44, followed by the termination of all females and offspring on Day 5 post partum. Any female which did not produce a pregnancy was terminated on or after Day 25 post coitum. All animals were subjected to a gross necropsy examination and histopathological evaluation of selected tissues was performed.

Following forty-two days of treatment, recovery group animals were maintained without treatment for a further fourteen days. Hematological and blood chemical assessments were performed on all recovery group animals at the end of the treatment-free period. Recovery animals were killed on Day 57. All animals were then subjected to a gross necropsy and histopathological examinations of selected tissues was performed.

Results

Adult Responses

Mortality

There were no unscheduled deaths.

Clinical Observations

Treatment at 1000 mg/kg bw/day was associated with increased post-dosing salivation for both sexes from Day 15 onwards, with all animals being affected at some stage of the study. At 500 mg/kg bw/day, isolated incidences of increased post-dosing salivation was observed for animals of either sex towards the end of the treatment period. No such effects were detected in animals of either sex treated with 100 mg/kg bw/day.

Body Weight

There were no treatment related effects on body weights throughout the study of either treated sex.

Food Consumption

No adverse effects on dietary intake were noted for males during the study or for females during the pre-pairing, gestation or lactation phases of the study, including the recovery phase.

Water Consumption

Visual assessment of water bottles did not reveal any significant intergroup differences.

Reproductive Performance Mating

There were no treatment-related effects on mating performance.

Fertility

There were no treatment related differences in fertility.

Gestation Lengths

Gestation lengths were between 22 and 23½ days and appeared unaffected by maternal treatment.

Litter Responses

Offspring Litter Size, Sex Ratio and Viability

There was no obvious effect of treatment on the corpora lutea count, pre-implantation loss, numbers of implantations, post-implantation loss, litter size at birth/Day 1 and subsequent offspring survival to Day 4 of age at 100, 500 or 1000 mg/kg bw/day. Sex ratio for the offspring was similar in all groups and did not indicate any selective effect of maternal treatment on survival for either sex. Offspring Growth and Development

Offspring body weight gain and litter weights at birth and subsequently on Days 1 and 4 post partum were essentially similar or slightly superior to controls and appeared unaffected by maternal treatment at 100, 500 or 1000 mg/kg bw/day. Offspring performance during assessment of surface righting appeared to be unaffected by maternal treatment.

Laboratory Investigations

Hematology

Assessment of hematology parameters did not indicate any adverse effect of treatment at 100, 500 or 1000 mg/kg bw/day for either sex.

Blood Chemistry

Males at 1000 mg/kg bw/day showed a statistically significant increase in alanine aminotransferase compared with control. Females at this dosage showed statistically significant increases in alanine aminotransferase, aspartate aminotransferase, creatinine and bile acids compared with control. No statistically significant differences from control were apparent for blood chemistry parameters in either sex at both 100 and 500 mg/kg bw/day.

Pathology

Necropsy

Neither the type, incidence or distribution of necropsy findings for adult animals indicated any adverse effects of treatment.

Organ Weights

For non-recovery males at 500 and 1000 mg/kg bw/day, higher absolute and body weight relative liver weights attained statistical significance when compared with control. No such effects were detected in females treated with 1000 or 500 mg/kg bw/day, animals of either sex treated with 100 mg/kg bw/day or recovery animals following fourteen days without treatment.

Histopathology

A treatment related microscopic abnormality was detected in the liver. Minimal centrilobular hepatocellular hypertrophy was evident in two males treated with 1000 mg/kg bw/day. This was considered to be an adaptive response to the test item and was not considered to represent an adverse effect of treatment. No such effects were detected in females treated with 1000 mg/kg bw/day.

Conclusion

The oral administration of OS282640 to rats by gavage, at dose levels of 100, 500 and 1000 mg/kg bw/day, did not result in any adverse effects of treatment. The ‘No Observed Adverse Effect Level’ (NOAEL) for systemic toxicity was therefore considered to be 1000 mg/kg bw/day. The ‘No Observed Effect Level’ (NOEL) for reproductive toxicity was considered to be 1000 mg/kg bw/day.

Justification for classification or non-classification

In the absence of adverse effects for reproductive toxicity in a 28-day screening study for repeat dose and reproduction at the classification concentration limit of 1000 mg/kg bw/day, classification of the substance for reproductive toxicity is not required.