2-Butenedioic acid, 2-methyl-, 1,4-bis(2-ethylhexyl) ester, (2Z)-

Repeated dose toxicity: other routes

Administrative data

Endpoint:

repeated dose toxicity: other route

Remarks:

other: DEREK Nexus 3.0.1

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Study period:

2013

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: DEREK QSAR Modelling

Justification for type of information:

QSAR prediction: migrated from IUCLID 5.6

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2013

Report date:

2014

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: ECHA Guidance R.6 on QSARs and grouping of substances, May 2008

Principles of method if other than guideline:

Derek Nexus v. 3.0.1, knowledge base Derek KB 2012 v. 1.0, last modified 29. November 2012.
Please see the description of the DEREK model in section 13, Attachment 5.
The test was conduted in accordance with the instructions from LHASA UK, the software supplier by a trained and experienced user.
The Derek method is in the ECHA Guidance R.6 Guidance on QSARs and grouping of substances, R.6.1.8.5.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

1,4-bis(2-ethylhexyl) (2Z)-2-methylbut-2-enedioate

EC Number:

807-715-4

Cas Number:

1354569-12-2

Molecular formula:

C21 H38 O4

IUPAC Name:

1,4-bis(2-ethylhexyl) (2Z)-2-methylbut-2-enedioate

Constituent 2

Reference substance name:

CC(C(=O)(OCC(CC)CCCC))=CC(=O)(OCC(CC)CCCC)

IUPAC Name:

CC(C(=O)(OCC(CC)CCCC))=CC(=O)(OCC(CC)CCCC)

Test material form:

other: in silico

Details on test material:

Input data used: molecular structure of the parent compound, MW 354.52, log Kp 0.97 (Potts & Guy), log P 8.24 (BioByte Corp., version 4.0)

Test animals

Species:

other: none

Strain:

other: none

Details on test animals or test system and environmental conditions:

Species in the knowledge base: bacterium Escherichia coli, Salmonella typhimurium, all mammalian species
Hydrogen options: perceive implicit and explicit hydrogens.
Settings: evaluations were made on all DEREK endpoints including in vitro non-mammalian and mammalian cell systems. (A list of the endpoints is attached in section 13 as attachment 5.)

Results and discussion

Effect levels

Dose descriptor:

other: peroxisome proliferation in mammal

Effect level:

other: Alert 258 DOUBTED

Based on:

other: Alkylalkane carboxylic acid or precursor

Sex:

male/female

Basis for effect level:

other: Alert 258 - 2-Alkylalkane carboxylic acid or precursor. Peroxisome proliferation in mammal: DOUBTED.

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Comments (please see details in attachment 2):

Peroxisome proliferation induced by these compounds is likely to be weak.

Examples of active compounds which fire the alert:

2-Ethylhexanoic acid

Di-(2-ethylhexyl)sebacate

2-Propylhexanoic acid

Mono-(2-ethylhexyl)phthalate

2-Ethylhexanol

Di-(2-ethylhexyl)phosphate

Di-(2-ethylhexyl)adipate

The alert also covers ester, amide, aldehyde and alcohol precursors of the acid, and carbon and phosphorus ester derivatives of alcohol precursors.

Repeated oral dosing or feeding of mice or rats with peroxisome proliferators produces liver hyperplasia and hypertrophy. Histology shows the hypertrophy to be characterised by proliferation of the peroxisomes and the smooth endoplasmic reticulum. Such effects are not seen in higher mammals, including man.

The peroxisome proliferation is accompanied by selective increases in the specific activities of certain peroxisomal enzymes, particularly those involved in the beta-oxidation of fatty acids (e.g. acyl CoA oxidase). The proliferation of the endoplasmic reticulum is accompanied by specific induction of cytochrome P450 4A which exhibits high specificity for the omega-oxidation of fatty acids (e.g. lauric acid hydroxylation).

Chronic oral administration of many peroxisome proliferators, including clofibrate and ciprofibrate, has produced liver carcinomas considered to be directly related to peroxisome proliferation in mice and rats, but not in man.

Peroxisome proliferation appears to be related to resistance to beta-oxidation by liver peroxisomes, and requires a long alkyl chain, e.g. as in tetradecylthioacetic acid, or an aryl or heteroaryl group, e.g. as in Wy-14643. Peroxisome proliferators have been shown to activate one or more nuclear steroid hormone-like receptors (PPARs) which induce increases in the oxidative enzyme activity associated with peroxisome proliferators.

The strength of the binding with the PPAR sites is expected to be a factor in determining the potency of peroxisome proliferators. Both hydrophilic groups (e.g. carboxylic acid or carboxylate groups) and lipophilic groups (e.g. long chain alkyl groups) are required. The high potency of Wy-14643, for example, may be related to the presence of two aromatic rings in the substituent on the acid-linked group, giving strong receptor binding. The structural similarity to thyroxine, which interacts with a steroid-type receptor, is notable, and may reflect a similar structural requirement.

The type and the level of expression of PPARs strongly influence differences in species responses

Applicant's summary and conclusion

Conclusions:

The peroxisome proliferator alert refers to a hepatic effect only seen in rats, so it has no human health consequences. Chemicals that cause this effect it rats are seen to cause liver enlargement, with characteristic changes at the cellular level.

Executive summary:

Bis-(2-ethylhexyl)-citraconate had DEREK alert for Peroxisome proliferation (Alkylalkane carboxylic acid or precursor) as doubted. The expert assessment concludes that the peroxisome proliferator alert refers to a hepatic effect only seen in rats, so it has no human health consequences. Chemicals that cause this effect it rats are seen to cause liver enlargement, with characteristic changes at the cellular level. The reliablility of the modelling result is not assignable (Klimisch 4).