Hexyl hexanoate

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

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:

weight of evidence

Justification for type of information:

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The target substance will breakdown in the body into chemical groups substantially similar to the source substances. The source substance and target substances have similar molecular weight ranges, low to moderate water solubility, low partition coefficient, and are in the physical form of a liquid. The source and target substances meet Lipinski’s rule of five, indicating that the substances are likely to be similarly orally active. The potential for acute oral toxicity is therefore likely to be the same in both source and target substances.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Both the source substances and the target substance are esters with different chain lengths but similar overall size. In particular, octyl acetate has the same molecular formula as the target substance hexyl butyrate. Both the octyl acetate and hexyl acetate would break down to form acetic acid and an alcohol (octanol and hexanol, respectively).The target substance would breakdown to form butanoic acid and a straight chain alcohol (hexanol). Note that the alcohols formed are all straight chain. The Butyl lactate source substance also breaks down to form similar products: a straight chain alcohol (butanol) and 2-hydroxypropanoic acid.
Both the source and target substances have similar physico-chemical properties (see appended full justification). A summary of the relevant properties for oral toxicity is shown below.
• All substances are liquids at room temperature with boiling points of >160 °C
• All substances have a low to moderate solubility in water (0.02-4 g/L)
• All substances have similar partition coefficients (Log Pow <4)
Both the source and target substances pass Lipinski’s rule of five with no violations.

3. ANALOGUE APPROACH JUSTIFICATION
Due to the similarities of the source and target substance with regards to physico-chemical properties, Lipinski’s rule of 5, and the fact that the target substance is expected to breakdown into structurally similar molecules in the body, 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 an acute oral toxicity 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 full justification document.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Interpretation of results:

GHS criteria not met

Data source

Reference

Reference Type:

review article or handbook

Title:

Safety Assessment of Lactate Esters

Author:

Clary J J, Feron V J and van Velthuijsen J A

Year:

1996

Bibliographic source:

Regulatory Toxicology & Pharmacology 27, 88–97 (1998); Article No. Rt971175

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

not specified

Remarks:

GLP compliance data is not presented in the review article.

Test type:

standard acute method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isoamyl, 2-Ethylhexyl, Isodecyl and Benzyl lactate

IUPAC Name:

Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isoamyl, 2-Ethylhexyl, Isodecyl and Benzyl lactate

Test animals

Species:

rat

Strain:

not specified

Sex:

male/female

Details on test animals or test system and environmental conditions:

no data

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

The test substance diluted with water (20% w/v) was given by gavage at a dose of 10 ml/kg bw.

Doses:

10 ml/kg bw.

No. of animals per sex per dose:

5

Control animals:

not specified

Details on study design:

Clinical observations, mortality, body weights, and gross pathological changes were recorded during a 14-day observation period.

Statistics:

Not applicable

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks:

Various lactates

Mortality:

No

Clinical signs:

other: Piloerection in most tests, diarrhea in one (n-butyl lactate), sluggishness in one (n-propyl lactate).

Gross pathology:

No effects reported.

Any other information on results incl. tables

Acute Oral Toxicity of L-Lactate Esters in Rats:

Lactate	LD50(mg/kg/bw)	Observations
Methyl	>2000	Piloerection up to 24 h	No gross necropsy changes
Ethyl	>2000	Piloerection up to 24 h	No gross necropsy changes
Propyl	>2000	Sluggishness up to 4 h	No gross necropsy changes
Isopropyl	>2000	Piloerection up to 24 h	No gross necropsy changes
Butyl	>2000	Piloerection up to 24 h, diarrhea,	No gross necropsy changes
Isoamyl	>2000	Piloerection up to 24 h	No gross necropsy changes
2-Ethylhexyl	>2000	Piloerection up to 4 h	No gross necropsy changes
Isodecyl	>2000	Piloerection up to 4 h	No gross necropsy changes
Benzyl	>2000	Piloerection up to 24 h	No gross necropsy changes

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

In acute oral limit tests no mortality was seen for any of a range of lactate esters at 2000 mg/kg body wt, the highest concentration tested in rats.