Registration Dossier

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

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,