Dioctyl maleate, branched

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1982

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study without detailed documentation

Justification for type of information:

Study conducted outside the EU over 10 years before the EU cosmetic testing ban came into effect.

Cross-reference

Reason / purpose for cross-reference:

read-across: supporting information

Reference

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Full read-across information is appended.

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The source and target substances are composed of two esters and two branched alkoxy component of the diesters. The source substance and target substances have similar molecular weight ranges, low water solubility, high partition coefficient, and are in the physical form of a liquid. The source substance meets Lipinski’s rule of five, indicating that the substance is orally active. The target substance also meets Lipinski’s rule of five, indicating that the substance is likely to be similarly orally active. The potential for acute oral toxicity is therefore the same in both substances.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Both substances are diesters, with the ester groups separated by two carbons in the centre. The only difference in the central section is that the source substance, bis(2-ethylhexyl) malate, has saturated carbons and a hydroxy group, whereas the target substance bis(1-methylheptyl) maleate has unsaturated carbons (i.e. they share a double bond).
In both substances there are two branched chains on the alcohol part of the ester, and in both cases, this is made of eight carbons, however the difference is that in the source substance the branching occurs two carbons away from the O, whereas in the target substance the branching occurs on the first carbon after the O. In addition, the branching in the source substance is made up of an ethyl and a butyl chain (both even branching), whereas in the target substance the branching is a methyl group (odd branching) and a hexyl group (even branching).
The source and target substances contain low levels of structurally similar impurities to the source and target substances themselves. These impurities are considered to be substantially similar to the source and target substances, and are likely to possess substantially similar properties.
The impact of “impurities” is therefore considered not to affect the reliability of the read-across prediction.

3. ANALOGUE APPROACH JUSTIFICATION
Due to the similarities of the source and target substance with regards to chemical structure, physico-chemical properties, and Lipinski’s rule of 5, the target substance is expected to behave in a substantially similar manner in vivo.
The target substance is therefore predicted to fail to induce acute oral toxicity in the CFR 16: 1500.3 study when conducted in the rat. By extension, the target substance is considered not to fulfil the criteria for acute oral toxicity under the Classification, Labelling, and Packaging (CLP) regulation (1272/2008).

4. DATA MATRIX
See appended pdf document.

Reason / purpose for cross-reference:

read-across source

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Interpretation of results:

GHS criteria not met

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1982

Report date:

1982

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: Code of Federal Regulations 16, Part 1500.3 (USA)

GLP compliance:

no

Test type:

fixed dose procedure

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Bis(2-ethylhexyl) malate

EC Number:

260-070-5

EC Name:

Bis(2-ethylhexyl) malate

Cas Number:

56235-92-8

Molecular formula:

C20H38O5

IUPAC Name:

bis(2-ethylhexyl) malate

Test material form:

liquid

Details on test material:

Identification: Dermol DOM
Appearance: Clear colourless to pale yellow liquid
Batch: P7677
Purity/Composition: >95%
Test item storage: At room temperature
Stable under storage conditions until: 31 December 2018 (retest date)
Additional information
Test Facility test item number: 209081/A
Purity/Composition correction factor: No correction factor required
Test item handling: No specific handling conditions required
Molecular structure: Not indicated
Molecular formula: C20H38O5
Molecular weight: 358.5

Test animals

Species:

rat

Strain:

other: albino

Sex:

male/female

Details on test animals or test system and environmental conditions:

Not detailed

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

Animals were observed for pharmacologic activity and drug toxicity 1,3,6 and 24 hours after treatment, and daily thereafter for a total of 14 days.

Doses:

5 grams per kg

No. of animals per sex per dose:

5

Control animals:

no

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 other: g/kg

Mortality:

two animals died during the study

Clinical signs:

other: not reported

Gross pathology:

Not reported

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

20% of the animals used at the dose level of 5g/kg died. LD50 is greater than 5ml/kg

Executive summary:

In this guideline (CFR 1500.3) study the LD50 of the test material was determined to be 5g/kg bw. 5 male and 5 female rats were dosed orally by gavage at 5g/kg and observed for 2 weeks post-dose. 2 deaths were observed.