Dioctyl maleate, branched

Endpoint summary

Description of key information

A read-across and weight of evidence approach has been taken to fulfill the acute toxicity endpoints. Data was not available on the registered substance, and testing cannot be conducted as the substance is solely used as a cosmetic ingredient. Existing data on similar substances has been used to fulfill the endpoint requirements.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

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

Reference 2

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.

Reason / purpose for cross-reference:

read-across: supporting information

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

Species:

rat

Strain:

other: albino

Sex:

male/female

Details on test animals or test system and environmental conditions:

Not detailed

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

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

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.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 000 mg/kg bw

Quality of whole database:

2

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: dermal

Type of information:

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

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Justification for type of information:

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

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

no guideline followed

Principles of method if other than guideline:

No information on the methodology is reported by the chemical review.

GLP compliance:

not specified

Remarks:

Study performed prior to GLP adoption

Test type:

other: Not reported by the chemical review

Species:

rabbit

Strain:

not specified

Sex:

not specified

Type of coverage:

not specified

Vehicle:

not specified

Sex:

not specified

Dose descriptor:

LD50

Effect level:

2 620 mg/kg bw

Based on:

not specified

Interpretation of results:

Category 5 based on GHS criteria

Conclusions:

The acute dermal LD50 of the registered substance to rabbits was reported to be 2620 mg/kg bw in the chemical review.

Reference 2

Endpoint:

acute toxicity: dermal

Type of information:

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

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

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

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

no guideline followed

Principles of method if other than guideline:

The testing guideline and methodology is not reported by the handbook.

GLP compliance:

not specified

Remarks:

The GLP status of the result is not reported by the handbook.

Test type:

other: The test type is not reported by the handbook.

Specific details on test material used for the study:

No details on the test material are reported by the handbook.

Species:

rabbit

Strain:

not specified

Sex:

not specified

Type of coverage:

not specified

Vehicle:

not specified

Control animals:

not specified

Sex:

not specified

Dose descriptor:

LD50

Effect level:

1 560 mg/kg bw

Based on:

not specified

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The acute dermal LD50 of maleic anhydride to rabbits was reported as 1650 mg/kg bw in the handbook.

Reference 3

Endpoint:

acute toxicity: dermal

Type of information:

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

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

secondary literature

Justification for type of information:

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

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

Test conducted prior to adoption of guideline.

Deviations:

not specified

Principles of method if other than guideline:

The review article does not include full test methodology for this entry.

GLP compliance:

not specified

Remarks:

The review article was published prior to GLP adoption.

Test type:

other: The review article does not include test methodology for this entry.

Specific details on test material used for the study:

The review article does not provide information on the test material.

Species:

rabbit

Strain:

New Zealand White

Sex:

female

Type of coverage:

occlusive

Vehicle:

not specified

No. of animals per sex per dose:

3 female

Control animals:

not specified

Details on study design:

The method used for skin absorption toxicity was essentially that of Smyth et al (1962), except that three female albino New Zealand rabbits were used per dose and the doses were kept in place by 8-ply gauze patches under a latex rubber film.

Sex:

female

Dose descriptor:

LD50

Effect level:

2 620 mg/kg bw

Based on:

test mat.

95% CL:

>= 1 930 - <= 3 550

Interpretation of results:

Category 5 based on GHS criteria

Conclusions:

The acute dermal LD50 of the registered substance to rabbits was reported to be 2620 (2620 - 3550) mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 620 mg/kg bw

Quality of whole database:

2

Additional information

A weight of evidence approach and read-across to a metabolically similar substance was taken to fulfil the dermal route endpoint. The available data provide acute dermal LD50 values of between 1650 -2620 mg/kg bw. The registered substance is much larger in size than the read-across substance and has a lower dermal absorption coefficient. A higher acute toxicity value for the dermal route is therefore expected. To allow the greatest margin of safety possible the LD50 of the registered substance by the dermal route is expected to be ca. 2620 mg/kg bw.

Justification for classification or non-classification

Based upon the information presented in the weight of evidence approach on similar substances, the registered substance does not fulfill the criteria for classification as acutely toxic of the Classification, Labelling, and Packaging (CLP) regulation (1272/2008).