Hexyl propionate

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 source and target substances are composed of similar chemical groups, will breakdown in the body into substantially similar 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)
The source substances and the target substance are esters, with both the alcohol component and the acid component being straight chained. The difference in the carboxylic acid parts is the length, which is only two carbons in the source substances (i.e. acetic acid was used to make these substances), whereas there is a three-carbon chain in the target substance (i.e. propanoic acid was used to make this substance).

The alcohol parts of the esters share some similarities – as mentioned above, they are all straight-chain (i.e. a straight chain alcohol was used as a reactant in the synthesis of each). The source substance hexyl acetate and the target substance hexyl propionate have the same alcohol chain – hexan-1-ol. Octyl acetate is synthesised from a larger alcohol (octan-1-ol).

As the source and target substances are esters, the breakdown products are the same as the reactants used to synthesise the esters. The target substance is expected to metabolise to produce similar breakdown products to that of hexyl acetate, both breakdown to form hexanol. The only difference is that hexyl propionate will breakdown to form propanoic acid, whereas hexyl acetate will form acetic acid. This means that when ingested, the substances are expected to be absorbed and metabolise in a similar way, as a straight chain acid and a straight chain alcohol is formed. The potential for absorption is further confirmed by the similar results of the Lipinski’s rule of 5.

3. ANALOGUE APPROACH JUSTIFICATION
The target substance breakdown products contain substantially similar chemical groups as the source structures. As the chemical groups are so similar they are predicted to act upon the body in a substantially similar manner, which in turn is predicted to give rise to similar toxicological effects.
The source and target substances have a similar molecular weight range (see Table 2 in the attached justification) and similar ranges for water solubility and n-octanol/water partition coefficient (Log Pow) (see Table 9 in the attached justification). The source and target substances both pass Lipinski’s rule of 5. It is therefore inferred that the source and target substances are both expected to be absorbed at approximately the same rate.

While detailed information on the test method is not available, acute oral toxicity for the source substances was all determined in the rat. The underlying scientific principal for acute oral toxicity is relatively simple, and has changed little since the first standardisation of scientific methods.
Given that the chemical structures of the source and target substances are substantially similar, and the rate of absorption of expected to be substantially similar, the effect levels for acute toxicity in the test model (rat) are expected to be substantially similar for both the source and target substances.

4. DATA MATRIX
See attached 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

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.