Butanedioic acid, 1-[2-[(1-oxo-2-propen-1-yl)oxy]ethyl] ester

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

150 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The study was considered as reliable without restriction and performed under GLP.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Oral (Gavage) Reproduction/Devlopmental Toxicity Screening Test in the Rat

Introduction

The study was performed to screen for potential adverse effects of the test item on reproduction including offspring development and provides an initial hazard assessment for effect on reproduction. The study is compatible with the recommendations of the OECD Guidelines for Testing of Chemicals No. 421 “Reproduction/Developmental Toxicity Screening Test” (adopted 27 July 1995). 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 ten male and ten female Wistar Han™:RccHan™:WIST strain rats, for up to eight weeks (including a two week maturation phase, pairing, gestation and early lactation for females), at dose levels of 15, 50 and 150 mg/kg/day. A control group of ten males and ten females was dosed with vehicle alone (Polyethylene glycol 400). Clinical signs, body weight change, dietary intake and water consumption were monitored during the study. Pairing of 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. Adult males were terminated on Day 43, and all females with offspring on Day 5 post partum. All animals were subjected to a gross necropsy examination and histopathological evaluation of reproductive tissues was performed.

Results

Adult Responses:

Mortality: There were no unscheduled deaths.

Clinical Observations; No clinical signs of toxicity or indications of treatment-related behavioural change were observed.

Animals of either sex treated with 150 mg/kg/day showed transient episodes of increased salivation around the time of dosing from Day 2 onwards. A similar finding was evident intermittently in males treated with 50 mg/kg/day from Week 2 onwards. Sporadic instances of staining around the mouth, noisy respiration and sneezing were also observed in test and control group animals during the study. Observations of this nature are often reported following oral administration of an unpalatable or slightly irritant test item formulation and in the absence of supporting evidence of toxicity are considered not to be indicative of systemic toxicity.

Body Weight: Males treated with 150 mg/kg/day showed a statistically significant decrease in body weight gain at Week 2 only in comparison with the concurrent controls. No such effects were detected in females treated with 150 mg/kg/day or in animals of either sex treated with 15 and 50 mg/kg/day.

Food Consumption and Food Efficiency: No adverse effects on food consumption or food efficiency were detected for treated animals when compared with controls.

Water Consumption; No intergroup differences were detected.

Reproductive Screening:

Mating: There were no treatment-related effects on mating in males or females treated with 15, 50 or 150 mg/kg/day.

Fertility: There were no treatment-related effects detected in conception rates. No treatment-related effects on fertility were detected between treated animals when compared to controls.

Gestation Lengths: No treatment-related effects were detected for the length of gestation between control and treated groups. The length of gestation ranged between 22 to 24 days for control and test animals. Statistical analysis of the data did not reveal any significant intergroup differences.

Pathology:

Necropsy: No treatment-related macroscopic findings were observed in the reproductive organs.Treatment-related gastric inflammation identified as a raised limiting ridge and thickening of the glandular gastric epithelium were identified in three males and one female at 15 mg/kg/day, five males and one female at 50 mg/kg/day and in nine males and two females at 150 mg/kg/day. In addition the glandular region of the stomach of two 150-mg/kg/day males showed reddened patches.

Organ Weights: No treatment-related effects were detected in the organ weights measured.

Histopathology: There were no treatment related histopathological changes detected in the reproductive organs. However, treatment-related findings characterized by minimal to slight gastric irritation were detected in the stomach of three males and one female at 15 mg/kg/day, five males and one female at 50 mg/kg/day and nine males and two females at 150 mg/kg/day.

Conclusion

The oral administration of MAES to rats by gavage at dose levels of 15, 50 and 150 mg/kg/day resulted in treatment-related effects associated with the locally irritant properties of the test item and on this basis a “No Observed Adverse Effect Level” (NOAEL) for systemic toxicity, was not established in this study. The above findings under the conditions of this study were shown to have no adverse impact on reproductive performance and for this reason the No Observed Effect Level' (NOEL) for reproductive toxicity was considered to be 150 mg/kg/day.

Short description of key information:

Oral administration of MAES to rats by gavage at dose levels of 15, 50 and 150 mg/kg/day resulted in treatment-related effects associated with the locally irritant properties of the test item. However, none of the dosages applied had any adverse impact on reproductive performance.

Justification for selection of Effect on fertility via oral route:

Compatible with OECD Guidelines for Testing of Chemicals No. 421.

Effects on developmental toxicity

Description of key information

Oral administration of MAES to rats by gavage at dose levels of 15, 50 and 150 mg/kg/day resulted in treatment-related effects associated with the locally irritant properties of the test item. However, none of the dosages applied had any adverse impact on litter size, viability, sex ratio, body weights behaviour or physical development.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

150 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The study was considered as reliable without restriction and performed under GLP.

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

Oral (Gavage) Reproduction/Devlopmental Toxicity Screening Test in the Rat

Results

Litter Responses:

Offspring Litter Size, Sex Ratio and Viability: No significant differences in litter size, viability or sex ratio were evident for offspring from treated litters when compared to those from the controls.

Offspring Growth and Development: Offspring body weight gain and litter weights at birth and subsequently on Day 1 and Day 4 post partum were comparable to controls. No adverse effects were detected in surface righting reflex on Day 1.

Offspring Observations: No clinical signs of toxicity or indications of treatment-related behavioural change were observed for offspring from all treatment groups.

Justification for selection of Effect on developmental toxicity: via oral route:

Compatible with OECD Guidelines for Testing of Chemicals No. 421.

Justification for classification or non-classification

The submission substance is not considered classified with regards to reproductive toxicity.