Registration Dossier

Administrative data

Description of key information

An OECD 422 screening study (MHWL, 2005) with the structural analogue Pentaerythritol tetra(2-ethylhexanoate) is available, where no adverse effects were found revealing a NOAEL of 1000 mg/kg bw (highest dose tested).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises an adequate and reliable subacute toxicity study (Klimisch score 2), and is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.6, of Regulation (EC) No 1907/2006.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for grouping of substances and read-across

There are no data available for repeated dose toxicity of 2,2-dimethylpropane-1,3-diyl 2-ethylhexanoate (CAS No. 28510-23-8). In order to fulfil the standard information requirements set out in Annex IX, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from structurally related substances was conducted.

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across).

Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, 1.5, of Regulation (EC) No 1907/2006, whereby substances may be predicted as similar provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity.

Repeated dose toxicity

CAS

28510-23-8

7299-99-2

Chemical name

2,2-dimethylpropane-1,3-diyl 2-ethylhexanoate

Hexanoic acid, 2-ethyl-, 2,2-bis [ [(2-ethyl-1-oxohexyl)oxy] methyl] -1,3-propanediyl ester

MW

356.55 g/mol

640.95 g/mol

Repeated dose toxicity, oral

RA: CAS 7299-99-2

NOAEL: 1000 mg/kg bw

Repeated dose toxicity, inhalation

-

-

Repeated dose toxicity, dermal

-

-

 

The above mentioned substances are considered to be similar on the basis of the structural similar properties and/or activities. The available endpoint information is used to predict the same endpoints for 2,2-dimethylpropane-1,3-diyl 2-ethylhexanoate (CAS No. 28510-23-8).

A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

Furthermore, based on exposure considerations no further data for the endpoints “Repeated dose toxicity” and “Toxicity to reproduction” were included in the dossier. In order to put the main focus on human health, a very conservative approach was followed. The exposure assessment is based on the reproductive toxicity of 2 -ethylhexanoic acid, which is assumed to be the most sensitive endpoint (LOEL = 100 mg/kg bw/day for reproductive toxicity). No further adverse effects after repeated exposure of the test substance itself is supposed. This is supported by a OECD 422 study (MHWL, 2005) with the structural analogue Pentaerythritol tetra(2-ethylhexanoate) (CAS 7299 -99 -2), where no adverse effects were found revealing a NOAEL of 1000 mg/kg bw (highest dose tested).

 

Discussion

A subacute study is available for assessment of repeated dose toxicity with the analogue substance Hexanoic acid, 2-ethyl-, 2,2-bis [ [(2-ethyl-1-oxohexyl)oxy] methyl] -1,3-propanediyl ester. The study was performed according to OECD guideline 422 and in accordance with GLP (Ohta, 2005). Male and female Crj: CD(SD) rats were dosed up to 42 days with Hexanoic acid, 2-ethyl-, 2,2-bis [ [(2-ethyl-1-oxohexyl)oxy] methyl] -1,3-propanediyl ester (100, 300, and 1000 mg/kg bw; diluted in corn oil) once daily by oral gavage. Rats were allocated to main control and treatment (12 female rats per group; 7-12 male rats per group) as well as satellite control and treatment (5 rats per group; control and 1000 mg/kg bw) groups. The male and female rats of the main study were sacrificed at day 43 of treatment and day 5 of lactation, respectively. The offspring was sacrificed 4 days after birth, and the satellite group animals were sacrificed 15 days after exposure ended.

There was no substance-related mortality and no clinical signs were observed during the study period. No effect on body weight gain was observed. Food and water consumption were similar in the control and treatment groups. No substance-related differences between control and treatment group were observed regarding haematology and clinical chemistry parameters. No neurobehavioral abnormalities were observed. At the end of recovery period, a significant increase of relative liver weight in females of the 1000 mg/kg bw group was noted, while no differences in males were found. The change was not considered as biologically significant. The statistical significance may be due to narrow variations of the organ and body weights at all (relative liver weight for control group: 2.69 ± 0.08 g (%); high dose group: 2.83 ± 0.09). This assumption was supported by the fact that no effect on absolute organ weights was observed. In addition no findings in the liver were observed after gross pathology and histopathology examination. In conclusion, based on the lack of systemic toxicity in general and the absence of adverse findings after pathology and histopathology evaluation a NOAEL of 1000 mg/kg bw was deduced, which was the highest dose tested.

 

 


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
There is only one study available.

Justification for classification or non-classification

According to DSD (67/548/EEC) or CLP (1272/2008/EC) classification criteria for repeated dose toxicity, no classification is warranted.