Bis(2-ethylhexyl) maleate

Endpoint summary

Description of key information

In the absence of significant data with dioctyl maleate itself, a weight of evidence approach was applied. Because of the chemical similarities of dioctyl maleate to n-butyl maleate and dibutyl maleate, the available repeated-dose toxicity data should be sufficient for read-across assessment. Animal studies showed that the main target organs were the kidneys. A 90-day oral study in rats with dibutyl maleate revealed the most severe systemic effects (CPN). Therefore, the LOAEL of 30 mg/kg/day was selected for the derivation of the DNEL for long systemic effects.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

LOAEL

30 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Additional information

In the absence of significant data with dioctyl maleate itself, a weight of evidence approach was applied to assess the substance for repeated-dose systemic toxicity. N-butyl maleate and dibutyl maleate are close analogues of dioctyl maleate and all are associated to maleic acid. Because of the chemical similarity of these alkyl diesters, the available repeated dose toxicity data should be sufficient for read-across assessment.

The only available study with dioctyl maleate regarding this endpoint was a 28-day combined repeated-dose and toxicity study with reproductive/developmental toxicity screening test which showed low toxicity. The main target organs were the kidneys and liver. The parental NOAEL was 300 mg/kg bw/day and the reproductive/developmental NOAEL was 1000 mg/kg/day.

For the purpose of the read cross assessment, a two-week study with n-butyl maleate was evaluated. This study was conducted to evaluate the potential renal toxicity of n-butyl maleate due to its association to maleic acid which is known to induce nephrotoxicity in the rat. Based on the results, n-butyl maleate showed mild renal toxicity. The NOAEL was determined to be 30 mg/kg/day.

In addition, a 90-day oral subchronic toxicity study with dibutyl maleate was evaluated. This study showed increased kidney weights in males and females at 300 mg/kg/day on Day 91 and was persisted in the males at 300 mg/kg/day on Day 105 (recovery). These increased kidney weights correlated histologically to chronic progressive nephropathy (CPN) as well as tubular basophilia within the renal cortex. The renal lesions included CPN, mineralization at the corticomedullary junction and/or medulla, tubular basophilia within the cortex, and tubular ectasia in the cortex and/or medulla. Overall, oral administration of DBM to rats for 90 days was associated with persistent kidney findings at all doses during the recovery phase. Due to these persistent findings, the LOAEL was established at 30 mg/kg/day.

Collectively, the 90-day study in rats with dibutyl maleate revealed the most severe systemic effects (CPN). Therefore, the LOAEL of 30 mg/kg/day was selected for the derivation of the DNEL for long systemic effects.

Justification for classification or non-classification

According to Regulation (EC) No 1272/2008 and based on the read across assessment with dibutyl maleate which exhibited chronic progressive nephropathy (CPN) and mineralization in the kidneys in the 90-day oral subchronic toxicity study in rats, dioctyl maleate is classified category 2 for STOT-RE.