Reaction mass of 2,2-bis(hydroxymethyl)propane-1,3-diyl bis(2-ethylhexanoate) and 3-[(2-ethylhexanoyl)oxy]-2-{[(2-ethylhexanoyl)oxy]methyl}-2-(hydroxymethyl)propyl 2-ethylhexanoate and 3-[(2-ethylhexanoyl)oxy]-2,2-bis{[(2-ethylhexanoyl)oxy]methyl}propyl 2-ethylhexanoate

Endpoint summary

Description of key information

An OECD 422 study (MHWL, 2005) with the surrogate pentaerythritol esters with 2-ethylhexanoic acid 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 study (Klimisch score 2 due to read-across) from a reference substance with similar structure and intrinsic properties. Read-across is justified based on common precursors/breakdown products (refer to endpoint discussion for further details). The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, in accordance with Annex XI, 1.5, 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 on the repeated dose toxicity of Multi constituent ester of pentaerythritol 2-ethylhexanoate. In order to fulfil the standard information requirements set out in Annex VII-IX 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 physicochemical, toxicological and ecotoxicological properties may be predicted from data for reference substance(s) by interpolation to other substances on the basis of structural similarity, Hexanoic acid, 2-ethyl-, 2,2-bis [ [(2-ethyl-1-oxohexyl)oxy] methyl] -1,3-propanediyl ester (CAS 7299-99-2) is selected as source substance for assessment of repeated dose toxicity.

Repeated dose toxicity

CAS	-- (a)	7299-99-2 (b)
Chemical name	Multi constituent ester of pentaerythritol 2-ethylhexanoate	Hexanoic acid, 2-ethyl-, 2,2-bis [ [(2-ethyl-1-oxohexyl)oxy] methyl] -1,3-propanediyl ester
MW	388.5 - 640.9g/mol	640.9 g/mol
Repeated dose toxicity, oral	RA: CAS 7299-99-2	Experimental result: NOAEL: ≥ 1000 mg/kg bw/day (OECD 422)
Repeated dose toxicity, inhalation	--	--
Repeated dose toxicity, dermal	--	--

(a) The substance subject to the REACh Phase-in registration deadline of 31 May 2013 is indicated in bold font. Only for this substance a full set of experimental results and/or read-across is given.

(b) Reference (read-across) substances are indicated in normal font. Lack of data for a given endpoint is indicated by “--“.

The above mentioned substances are considered to be similar on the basis of same precursers/breakdown products. The available endpoint information is used to predict the same endpoint for Multi constituent ester of pentaerythritol 2-ethylhexanoate.

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. A substance-tailored exposure-driven testing was followed for the hazard assessment of repeated dose toxicity. No significant exposure is expected throughout all relevant exposure scenarios according to Annex XI, section 3.2(a) (i), therefore testing for toxicity to reproduction is omitted in accordance with Annex VIII column 2 section 8.6.1. The justification is based on an exposure assessment in accordance with section 5 of Annex I.

Further details are given in the endpoint itself, as well as in the chapter "Toxicological information" and in chapter 9 and 10 of the CSR.

Discussion

A combined repeated dose toxicity study with the reproduction/developmental toxicity screening test was performed according to OECD 422 and in compliance with GLP (MHWL, 2005). Twelve male and 12 female Crj: CD(SD) rats per dose were treated by gavage with 100, 300, and 1000 mg/kg bw/day of Hexanoic acid, 2-ethyl-, 2,2-bis [ [(2-ethyl-1-oxohexyl)oxy] methyl] -1,3-propanediyl ester. Male rats and additional 5 female rats (recovery animals of control and 1000 mg/kg bw/day dose group) were dosed once daily for 42 days. The other females were treated from day 14 before mating to day 4 of lactation. There was no substance-related mortality and no clinical signs that were related to treatment were observed during the study period. No adverse effect on body weight gain was observed. Males of the 100 mg/kg group showed body weight loss compared to the control group, but this was not statistically significant. There was no difference in female groups and satellite groups compared with control groups. Females of the satellite 1000 mg/kg group showed significantly more food consumption during days 29 - 30 compared to the control group. However, this change was considered as not compound-related as no difference in other groups was found, both within the treatment period as well as in the recovery period. No treatment-related effects were observed regarding organ weights, clinical chemistry and pathology. At the end of dosing period, a significantly increase of absolute weight of brain was found in females (300 mg/kg), but the change of relative weight was not significant. No significant differences in males between treatment group and the control group were observed.

At the end of dosing period, a significantly increase of relative liver weight in females of the 1000 mg/kg group was noted, while no differences in males were found. The change was not considered as compound-related, since no corresponding abnormalities were observed in the livers. Histopathology revealed fatty change in periportal hepatocytes and microgranuloma, extramedullary haematopoiesis and brown deposits in the spleen, focal degeneration/fibrosis in myocardium, mineralization on arterial wall of lung and atrophy in thymus. These effects occurred in both the control and high dose groups and were evaluated as accidental. In conclusion, the NOAEL was ≥ 1000 mg/kg bw/day.

Conclusion

The results of the OECD 422 study with the surrogate substance Hexanoic acid, 2-ethyl-, 2,2-bis [ [(2-ethyl-1-oxohexyl)oxy] methyl] -1,3-propanediyl ester indicate that no repeated dose toxicity is anticipated for Multi constituent ester of pentaerythritol 2-ethylhexanoate. Thus, a NOAEL of ≥ 1000 mg/kg bw/day was concluded for Multi constituent ester of pentaerythritol 2-ethylhexanoate.

 

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Hazard assessment is conducted by means of read-across from a surrogate. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall assessment of quality, duration and dose descriptor level (refer to the endpoint discussion for further details).

Justification for classification or non-classification

The available data on toxicity after repeated exposure of the substance do not meet the criteria for classification according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.