9-Octadecenoic acid (Z)-, zinc salt, basic

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

one screening study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Introduction

The study was designed to investigate the systemic toxicity and potential adverse effects of the test item on reproduction (including offspring development), to assess the ability of the animals to recover from any toxicity following the withdrawal of treatment and is designed to be compatible with the requirements of the OECD Guidelines for Testing of Chemicals No. 422 “Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test” (adopted 22 March 1996). This study was also designed to be compatible with Commission Regulation (EC) No 440/2008 of 30 May 2008 laying down test methods pursuant to Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH).

 

Methods

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 seven weeks (including a two week pre-pairing phase, pairing, gestation and early lactation for females), at dose levels of 100, 300 or 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 during the final week of treatment, and for five selected parental females from each dose group on Day 4post partum. Urinalysis was performed on five non-recovery males per dose group during the final week of treatment and five non-recovery males and females from each dose group were selected for hematology and blood chemistry assessments prior to termination.

 

Adult non-recovery males were terminated on Days 43 or 44, followed by the termination of all females and offspring on Day 5post partum. Any female which did not produce a pregnancy was terminated on Day 26post 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. Urinalysis was performed on all recovery group males during the final week of the treatment period. In addition, hematological and blood chemical assessments were performed on all recovery group animals at the end of the treatment-free period. These animals were then subjected to a gross necropsy, but as there were no treatment-related histopathology findings, histopathological examinations of tissues from these animals was not performed.

 

Results

Adult Responses

Mortality: There were no unscheduled deaths on the study.

Clinical Observations: Throughout the study, there were no clinical signs considered to be related to the toxicity of the test item.

Behavioral Assessment: There were no treatment-related changes in the behavioral parameters measured.

Functional Performance Tests: There was no effect of treatment with the test item at any dose level on functional performance in animals of either sex.

Sensory Reactivity Assessments: Sensory reactivity scores across all treated groups were similar to controls.

Body Weight: Body weight development for animals of either sex remained unaffected throughout the treatment and recovery period.

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. Dietary intake and food efficiency in recovery animals of both sexes was also unaffected.

Water Consumption: Visual inspection of water bottles did not indicate any differences in water intake for treated animals of either sex in comparison with controls.

Reproductive Performance

Mating: There was no effect of treatment with the test item on mating performance.

Fertility: There were no treatment-related effects in conception rates for treated animals.

Gestation Lengths: There were no differences in gestation lengths in treated animals when compared with controls.

Litter Responses

Offspring Litter Size, Sex Ratio and Viability: Of the litters born, litter size at birth and subsequently on Days 1 and 4post partumwere comparable with controls. A total litter loss was observed for one female treated with 1000 mg/kg bw/day, however, this was considered unlikely to be of any toxicological significance. There were no inter-group differences in sex ratio (percentage male offspring) or viability indices for litters from treated groups when compared with controls.

Offspring Growth and Development: Clinical signs for all pups from one litter from the high dose group included small size; due to the isolated nature of this incidence, however, this finding was considered to be of no toxicological significance. Offspring growth and development from the remaining litters from treated groups was similar to controls.

Laboratory Investigations

Hematology: No toxicologically significant effects were detected in animals of either sex receiving the test item at any dose level.

Blood Chemistry: No toxicologically significant effects were detected in animals of either sex receiving the test item at any dose level.

Urinalysis: No toxicologically significant effects were detected in animals of either sex receiving the test item at any dose level.

Pathology

Necropsy: No treatment-related macroscopic observations were detected at any dose level.

Organ Weights: At the end of the dosing period, group mean absolute and body weight-related liver weights in males given the test item at 1000 mg/kg bw/day were slightly but statistically significantly higher than controls. Group mean absolute and body weight-related thyroid weights in the females from this dose group were slightly but statistically significantly lower than controls at the end of the treatment and recovery periods. There were no histopathology correlates, and these observations along with any other statistically significant differences were considered to be of no toxicological relevance.

Histopathology: Microscopic examination of tissues from the control and high dose groups did not reveal any treatment-related findings.

Conclusion

The oral administration of the test item to rats by gavage, at dose levels of 100, 300 and 1000 mg/kg bw/day was well tolerated. The ‘No Observed Adverse Effect Level’ (NOAEL) for systemic toxicity was considered to be 1000 mg/kg bw/day, based on the absence of toxicologically significant or treatment-related findings. The ‘No Observed Effect Level’ (NOEL) for reproductive toxicity was considered to be 1000 mg/kg bw/day.

Short description of key information:
Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test. The NOAEL for systemic toxicity was found to be 1000 mg/kg bw/day (OECD 422).

Justification for selection of Effect on fertility via oral route:
Guideline GLP study performed on the substance itself

Effects on developmental toxicity

Description of key information

Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test. The NOAEL for systemic toxicity was found to be 1000 mg/kg bw/day (OECD 422).

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

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

Introduction

The study was designed to investigate the systemic toxicity and potential adverse effects of the test item on reproduction (including offspring development), to assess the ability of the animals to recover from any toxicity following the withdrawal of treatment and is designed to be compatible with the requirements of the OECD Guidelines for Testing of Chemicals No. 422 “Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test” (adopted 22 March 1996). This study was also designed to be compatible with Commission Regulation (EC) No 440/2008 of 30 May 2008 laying down test methods pursuant to Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH).

 

Methods

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 seven weeks (including a two week pre-pairing phase, pairing, gestation and early lactation for females), at dose levels of 100, 300 or 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 during the final week of treatment, and for five selected parental females from each dose group on Day 4post partum. Urinalysis was performed on five non-recovery males per dose group during the final week of treatment and five non-recovery males and females from each dose group were selected for hematology and blood chemistry assessments prior to termination.

 

Adult non-recovery males were terminated on Days 43 or 44, followed by the termination of all females and offspring on Day 5post partum. Any female which did not produce a pregnancy was terminated on Day 26post 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. Urinalysis was performed on all recovery group males during the final week of the treatment period. In addition, hematological and blood chemical assessments were performed on all recovery group animals at the end of the treatment-free period. These animals were then subjected to a gross necropsy, but as there were no treatment-related histopathology findings, histopathological examinations of tissues from these animals was not performed.

 

Results

Adult Responses

Mortality: There were no unscheduled deaths on the study.

Clinical Observations: Throughout the study, there were no clinical signs considered to be related to the toxicity of the test item.

Behavioral Assessment: There were no treatment-related changes in the behavioral parameters measured.

Functional Performance Tests: There was no effect of treatment with the test item at any dose level on functional performance in animals of either sex.

Sensory Reactivity Assessments: Sensory reactivity scores across all treated groups were similar to controls.

Body Weight: Body weight development for animals of either sex remained unaffected throughout the treatment and recovery period.

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. Dietary intake and food efficiency in recovery animals of both sexes was also unaffected.

Water Consumption: Visual inspection of water bottles did not indicate any differences in water intake for treated animals of either sex in comparison with controls.

Reproductive Performance

Mating: There was no effect of treatment with the test item on mating performance.

Fertility: There were no treatment-related effects in conception rates for treated animals.

Gestation Lengths: There were no differences in gestation lengths in treated animals when compared with controls.

Litter Responses

Offspring Litter Size, Sex Ratio and Viability: Of the litters born, litter size at birth and subsequently on Days 1 and 4post partumwere comparable with controls. A total litter loss was observed for one female treated with 1000 mg/kg bw/day, however, this was considered unlikely to be of any toxicological significance. There were no inter-group differences in sex ratio (percentage male offspring) or viability indices for litters from treated groups when compared with controls.

Offspring Growth and Development: Clinical signs for all pups from one litter from the high dose group included small size; due to the isolated nature of this incidence, however, this finding was considered to be of no toxicological significance. Offspring growth and development from the remaining litters from treated groups was similar to controls.

Laboratory Investigations

Hematology: No toxicologically significant effects were detected in animals of either sex receiving the test item at any dose level.

Blood Chemistry: No toxicologically significant effects were detected in animals of either sex receiving the test item at any dose level.

Urinalysis: No toxicologically significant effects were detected in animals of either sex receiving the test item at any dose level.

Pathology

Necropsy: No treatment-related macroscopic observations were detected at any dose level.

Organ Weights: At the end of the dosing period, group mean absolute and body weight-related liver weights in males given the test item at 1000 mg/kg bw/day were slightly but statistically significantly higher than controls. Group mean absolute and body weight-related thyroid weights in the females from this dose group were slightly but statistically significantly lower than controls at the end of the treatment and recovery periods. There were no histopathology correlates, and these observations along with any other statistically significant differences were considered to be of no toxicological relevance.

Histopathology: Microscopic examination of tissues from the control and high dose groups did not reveal any treatment-related findings.

Conclusion

The oral administration of the test item to rats by gavage, at dose levels of 100, 300 and 1000 mg/kg bw/day was well tolerated. The ‘No Observed Adverse Effect Level’ (NOAEL) for systemic toxicity was considered to be 1000 mg/kg bw/day, based on the absence of toxicologically significant or treatment-related findings. The ‘No Observed Effect Level’ (NOEL) for reproductive toxicity was considered to be 1000 mg/kg bw/day.

Justification for classification or non-classification

No classification for reproductive or developmental toxicity is required as there were no adverse effects up to and including the maximum recommended dose leverl of 1000 mg/kg bw/day.