Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
LOAEL
30 mg/kg bw/day
Additional information

In a 28-day combined repeated-dose and reproductive/developmental toxicity screening test (RL1), hyperthrophy of the liver, increased kidney weights and kidney to body weight ratios were noted in males and females at 1000 mg/kg but not supported by histopathological or clinical biochemistry parameters. At 300 mg/kg, higher liver and kidney weights were noted in males without histopathological correlates. However, no adverse effect on reproductive performance was found. The parental NOEL was determined to be 300 mg/kg bw/day. The reproduction NOAEL was determined at 1000 mg/kg/day and developmental NOAEL was determined at 1000 mg.kg.day. In another OECD 422 study but with dibutyl maleate, no adverse effect on reproductive performance was found. The NOAEL was determined at 95 mg/kg/day based on increased liver and kidney weights in high dose animal of both sexes.

Also, a 90-day subchronic toxicity study with dibutyl maleate was conducted. The test substance was administered via oral gavage to rats at 30, 95 and 300 mg/kg bw/day. No effects were seen on the reproductive organs. In this study, the LOAEL was determined to be 30 mg/kg bw/day based on chronic progressive nephropathy and mineralization in the kidneys but no adverse effects were seem in the histopathological examination of reproductive organs. Based on the adverse kidney effects seen in the 90 -day subchronic toxicity study with dibutyl maleate, the LOAEL of 30 mg/kg/day was selected for the chemical safety assessment.


Short description of key information:
A 28-day combined repeated-dose and reproductive/developmental toxicity screening test in rats was performed according to OECD 422 guidelines with dioctyl maleate. In this study, the NOAEL for reproductive and developmental toxicity was 1000 mg/kg bw/day. Based on the read across assessment with dibutyl maleate, the LOAEL of 30 mg/kg/day from the 90-day subchronic toxicity study in rats was selected for the chemical safety assessment.

Another OECD 422 study with dibutyl maleate, a structural similar substance, was performed. The NOAEL for reproductive and developmental toxicity was 95 mg/kg/day. In addition, results from a 90-day subchronic toxicity with dibutyl maleate did not show adverse effects in the reproductive organs.

Based on the physico-chemical and structural commonalities between dioctyl maleate and dibutyl maleate, it can be concluded that dioctyl maleate is neither a developmental nor reproductive toxicant. However, as a result of the read across approach, the LOAEL of 30 mg/kg bw/day was selected for the chemical safety assessment.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
28 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on developmental toxicity: via inhalation route
Dose descriptor:
NOAEC
850 mg/m³
Effect on developmental toxicity: via dermal route
Dose descriptor:
NOAEL
840 mg/kg bw/day
Additional information

Justification for selection of Effect on developmental toxicity: via oral route:
In the absence of a developmental study for the substance of record, the Lead Registrant presents developmental data from a number of structurally-related substances. The detailed read across rationale has been attached in IUCLID Section 13. Of the three read across substances presented, the selected NOAEL is from the structurally-related subtance bis(2-ethylhexyl) adipate. This substance was selected as it has the lowest NOAEL value, and therefore represents the most conservative choice in the overall substance assessment.

Justification for selection of Effect on developmental toxicity: via inhalation route:
In the absence of a developmental study for the substance of record, the Lead Registrant presents developmental data from a number of structurally-related substances. The detailed read across rationale has been attached in IUCLID Section 13. The selected NOAEL is from the structurally-related subtance 2-ethyl-1-hexanol.

Justification for selection of Effect on developmental toxicity: via dermal route:
In the absence of a developmental study for the substance of record, the Lead Registrant presents developmental data from a number of structurally-related substances. The detailed read across rationale has been attached in IUCLID Section 13. The selected NOAEL is from the structurally-related subtance 2-ethyl-1-hexanol.

Toxicity to reproduction: other studies

Additional information

Celanese Chemicals Europe GmbH acknowledges the information gap for pre-natal developmental toxicity (information requirement of Annex IX, Section 8.7.2) in the bis(2-ethylhexyl) maleate dossier, identified by ECHA in the draft decision issued on April 11, 2014.

Annex IX states that:

"Before new tests are carried out to determine the properties listed in this Annex, all available in vitro data, in vivo data, historical human data, data from valid (Q)SARs and data from structurally related substances (read-across approach) shall be assessed first."

Annex IX also allows adaptations of the specific rules for information requirements according to the general rules contained in Annex XI:

"In addition to these specific rules, a registrant may propose to adapt the required standard information set out in column 1 of this Annex according to the general rules contained in Annex XI. In this case as well, he shall clearly state the reasons for any decision to propose adaptations to the standard information under the appropriate headings in the registration dossier referring to the appropriate specific rule(s) in column 2 or in Annex XI."

In order to close data gaps, while avoiding unnecessary testing and taking into consideration animal welfare, REACH Annex XI " General Rules for Adaptation of the Standard Testing Regime set out in Annexes VII to X", Section1.5. Grouping of substances and read-across approach, Celanese Chemicals Europe GmbH believes that the identified information gap for pre-natal developmental toxicity (information requirement of Annex IX, Section 8.7.2) in the bis(2-ethylhexyl) maleate dossier can be appropriately closed by applying a read across approach.   This is in line with REACH Annex IX as well as REACH Title III “Data Sharing and Avoidance of Unnecessary Testing” Art. 25 “Objectives and general rules” of the REACH regulation [(EC) No 1907/2006]:

1. In order to avoid animal testing, testing on vertebrate animals for the purposes of this Regulation shall be undertaken only as a last resort. It is also necessary to take measures limiting duplication of other tests

Endpoint recrods on pre-natal developmental toxicity (information requirement of Annex IX, Section 8.7.2)

have been entered for three read across substances, with three routes of exposure presented for one of those substances. The detailed read across rationale has been attached in IUCLID Section 13.

Justification for classification or non-classification

According to criteria in Regulation (EC) No. 1272/2008, dioctyl maleate does not have to be classified for reproductive effects.

Additional information