Hexyl acetate

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

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

Adequacy of study:

supporting study

Study period:

Not stated, data published in 1982

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non guideline study, published results for assessment of class of compounds, with relevance to hexyl acetate by read-across

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1982

Report date:

1981

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

determination of serum triglyceride and cholesterol contents in male rats receiving diets containing plasticizers and analogues of the ester 2-ethylhexanol. Dietary administration for 3 weeks with terminal blood chemistry evaluations.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

The plasticisers in the diet were di-(2-ethylhexyl) adipate and di-(ethyl)phthalate, 2-ethylhexanol. hexanol. 2•ethylhexanoic acid. hexanoic acid, 2-ethylhexyl aldehyde, and hexyl aldehyde

IUPAC Name:

The plasticisers in the diet were di-(2-ethylhexyl) adipate and di-(ethyl)phthalate, 2-ethylhexanol. hexanol. 2•ethylhexanoic acid. hexanoic acid, 2-ethylhexyl aldehyde, and hexyl aldehyde

Test material form:

not specified

Details on test material:

- Name of test material (as cited in study report):di-(2-ethylhexyl) adipate and di-(ethyl)phthalate, 2-ethylhexanol. hexanol. 2•ethylhexanoic acid. hexanoic acid, 2-ethylhexyl aldehyde, and hexyl aldehyde
The data are used for read- across to hexyl acetate

- Physical state:
- Analytical purity:

- Purity test date:
- Lot/batch No.:

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:Simonson Labs, Gilroy, California, USA
- Age at study initiation:
- Weight at study initiation:
- Fasting period before study: none but animals were fasted for 24 h prior to termination
- Housing:housed in pairs in steel screen bottomed cages
- Diet (e.g. ad libitum):Purina Chow ad libitum. During test phase chow containing 20% (v/w) of the test compound
- Water (e.g. ad libitum):ad libitum
- Acclimation period: 3 weeks



IN-LIFE DATES: From: not stated To: not stated

Administration / exposure

Route of administration:

oral: feed

Vehicle:

not specified

Details on oral exposure:

chow containing 20% (v/w) of the test compound was administered for 3 weeks to rats.

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No information

Duration of treatment / exposure:

3 weeks

Frequency of treatment:

daily administration in diet

Doses / concentrations

Remarks:

Doses / Concentrations:
20% nominal in diet but no details of achieved dose levels given in publication
Basis:
nominal in diet

No. of animals per sex per dose:

No details provided

Control animals:

not specified

Details on study design:

Male rats were administered diets containing the plasticizers di-(2-ethylhexyl) adipate and di-(ethyl)phthalate, 2-ethylhexanol, hexanol, 2-ethylhexanoic acid, hexanoic acid, 2-ethylhexyl aldehyde, and hexyl aldehyde for 3 weeks. and serum triglyceride and cholesterol values were determined.
Animals were fasted for 24 h prior to termination and blood samples were obtained under ether anaesthesia from the abdominal aorta and triglyceride and cholesterol contents of serum preparations were determined.

Positive control:

no information

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: No data

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: terminal samples from abdominal aorta
- Animals fasted: Yes - 24 hours prior to termination
- How many animals: all
- Parameters examined. serum triglycerides and cholesterol

Sacrifice and pathology:

Animal terminated following terminal blood sample collection, no details provided for necropsy.

Other examinations:

No further details

Statistics:

No data

Results and discussion

Results of examinations

Clinical signs:

not specified

Mortality:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Details on results:

A significant decrease in both serum cholesterol and triglyceride was found in animals receiving diets containing di-(2-ethylhexyl)adipate, 2-ethylhexanol, 2-ethylhexanoic acid, 2-ethylhexyl aldehyde, and hexyl aldehyde. Animals treated with di-(ethyl)phthalate and 2%-hexanoic acid also had significantly lowered triglyceride values, but serum cholesterol was not altered. The triglyceride-lowering effect of hexanoic acid was not, however, seen in animals receiving diets containing higher concentrations.
Hexanol produced no significant effects at the 2-4% levels and induced an increase in serum triglycerides when incorporated into the diet at the 8% level. Adipate produced a slight, but significant increase in serum cholesterol with no effect on triglycerides.
compounds which caused a decrease in both serum triglyceride and cholesterol also produced a proliferation of peroxisomes and induction of the peroxisomes associated enzymes in a previous investigation (not reported here.)
The results of this study demonstrate that other plasticizers with an ester linkage to 2-ethylhexanol, 2-ethylhexanol itself, and its analogues 2-ethylhexanoic acid and 2-ethylhexyl aldehyde produce a hypolipidemic effect in association with their action of the branched-chain alcohol and carboxylic acid to that of their straight-chain analogues, both the 2-ethylhexyl aldehyde, hexanoic and hexyl aldehyde produced a decrease in serum lipids.
Primarily due to the relationship between the proliferation of peroxisomes and effect of the ensuing hypolipidemia, peroxisomes have been implicated in lipid metabolism.

At least two enzymes involved in fatty acid metabolism, carnitine acyl transferase and a fatty acyl-CoA oxidation complex, have been identified in mammalian peroxisome fractions and their activities are induced by several peroxisome-proliferating hypolipidemic agents including the plasticizer DEHP. The serum lipid lowering effect of these plasticizers may in addition be attributed to their inhibitory action on lipid biosynthesis

While the acute toxicity of DEHP and other plasticizers is extremely low, there is a concern about the chronic action of these widely distributed compounds.
reports indicate that these compounds are carcinogenic in test animals. Reports have shown that other peroxisome-proliferating hypolipidemic compounds are also carcinogenic in animals but produce negative results in conventional mutagenicity tests peroxisome-proliferating action of compounds may prove a useful screen for their potential carcinogenic action.

Effect levels

Dose descriptor:

other: Hypolipidemic effect seen as a decrease in ·serum triglycerides and cholesterol. 

Based on:

test mat.

Remarks on result:

not measured/tested

Remarks:

Effect level not specified (migrated information)

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Inclusion of the plasticizer DEHP in the diet of rats and mice results in a decrease in ·serum triglycerides and cholesterol. The hypolipidemic effect is associated with a proliferation of hepatic peroxisomes. In this manner, the action of DEHP is similar to other compounds exemplified by clofibrate, and tibric acid. the proliferation of peroxisomes also occurred following treatments with mono-(2-ethylhexyl) phthalate and 2-ethylhexanol, but not the phthalate anhydride. These findings suggested that the branched-chain 2-ethylhexanol may be the active component. Other plasticizers with an ester linkage to 2-ethylhexanol, di-(2-ethylhexyl) sebacate and di-(2-ethylhexyl)adipate, induce an increase in hepatic peroxisomes and peroxisome-associated enzymes. Only a marginal response was noted in animals treated with di-(ethyl)phthalate, and none in animals receiving adipate in their diets. The action of the branched-chain alcohol was duplicated by the carboxylic acid analogue, 2-ethylhexanoic acid, and to a lesser extent by the aldehyde, 2-ethylhexyl aldehyde, while hexanol and hexanoic acid gave negative results.

Table 1Serum cholesterol and triglyceride values for animals receiving plasticizers and analogues of the 2-ethylhexyl ester in their diet

Compound	Serum cholesterol mg/100 ml	Serum triglyceride mg/100 ml
Control	46.1±4.8	114.8±17.8
2% diethyl phthalate	44.6±3.1	69.2±2.6*
2% diethylhexyl adipate	39.4±3.3*	39.0±6.9*
2% adipate	52.8±3.3*	119.6±24.4
2% ethylhexyl alcohol	40.0±4.6*	59.2±23.9*
2% hexanol	47.5±3.1	110.5±24.3
4% hexanol	45.0±2.2	134.1±22.6
8% hexanol	41.8±1.1	156.5±25.9*
2% ethylhexanoic acid	38.1±4.9*	36.7±17.3*
2% hexanoic acid	46.4±3.0	91.6±12.6*
4% hexanoic acid	47.5±2.7	121.6±14.3
8% hexanoic acid	45.4±3.8	106.3±8.9
2% ethylhexyl aldehyde	36.2±3.9*	47.4±8.1*
2% hexyl aldehyde	41.0±2.6*	42.6±12.8*
Significantly different from control P<0.05 in Student’s two-tailed test

Applicant's summary and conclusion

Conclusions:

The results of this study demonstrate that other plasticizers with an ester linkage to 2-ethylhexanol, 2-ethylhexanol itself, and its analogues 2-ethylhexanoic acid and 2-ethylhexyl aldehyde produce a hypolipidemic effect in association with their action of the branched-chain alcohol and carboxylic acid to that of their straight-chain analogues, it was somewhat surprising that both the 2-ethylhexyl ald~hyde exanoic and hexyl aldehyde produced a decrease in serum lipids.
Primarily due to the relationship between the proliferation of peroxisomes and Hect of the ensuing hypolipidemia, peroxisomes have been implicated in lipid metabo'ism.

At least two enzymes involved in fatty acid metabolism, carnitine acyl transferase and a fatty acyl-CoA oxidation complex, have been identified in mammalian peroxisome fractions and their activities are induced by several peroxisome-proliferating hypolipidemic agents including the plasticizer DEHP. The serum lipid lowering effect of these plasticizers may in addition be attributed to their inhibitory action on lipid biosynthesis

While the acute toxicity of DEHP and other plasticizers is extremely low, there is a concern about the chronic action of these widely distributed compounds.
reports indicate that these compounds are carcinogenic in test animals. Reports have shown that other peroxisome-proliferating hypolipidemic compounds are also carcinogenic in animals but produce negative results in conventional mutagenicity tests peroxisome-proliferating action of compounds may prove a useful screen for their potential carcinogenic action.

Executive summary:

Male rats were administered diets containing the plasticizers di-(2-ethylhexyl) adipate and di-(ethyl)phthalate, 2-ethylhexanol. hexanol. 2·ethylhexanoic acid. hexanoic acid, 2-ethylhexyl aldehyde, and hexyl aldehyde for 3 weeks. and serum triglyceride and cholesterol values were determined. Only those compounds which had been found to produce a proliferation of hepatic peroxisomes produced a decrease in both serum lipids,