Triethyl O-acetylcitrate

Carcinogenicity

Administrative data

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1950

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1950

Reference 2

Reference Type:

secondary source

Title:

Unnamed

Year:

2004

Report date:

2004

Materials and methods

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Three groups of 20 rats each (approximately 12 weeks of age) received diets containing the test substance (ATBC) at concentrations of 200, 2000 or 20,000 ppm. A group of 40 rats received the basal diet without test substance and served as the control group. Animals had access to their respective diets ad libitum for approximately two years. Animals were observed daily for behavior and general condition and body weights were measured weekly. All animals that died spontaneously during the experiment and those surviving to study termination were subjected to a necropsy and tissues were examined histologically. Because of unexplained transient depression of the rate of growth of all three experimental groups from week 5 to 15, two additional groups of 10 rats each received the test substance in the diet at concentrations of 200 and 2000 ppm and one group of 20 rats that served as the control, received the untreated diet for one year. All animals in these additional groups that died spontaneously and those sacrificed at the end of the one year treatment period were studied for pathological changes.

GLP compliance:

no

Remarks:

pre-dates GLP

Test material

Test material information

Constituent 1

Reference substance name:

Tributyl O-acetylcitrate

EC Number:

201-067-0

EC Name:

Tributyl O-acetylcitrate

Cas Number:

77-90-7

Molecular formula:

C20H34O8

IUPAC Name:

Acetyltributylcitrate

Specific details on test material used for the study:

purity = 99.4%

Test animals

Species:

rat

Strain:

Sherman

Sex:

not specified

Details on test animals or test system and environmental conditions:

12 weeks of age at start of study

Administration / exposure

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on exposure:

Three groups of 20 rats each (approximately 12 weeks of age) received diets containing the test substance (ATBC) at concentrations of 200, 2000 or 20,000 ppm. A group of 40 rats received the basal diet without test substance and served as the control group. Animals had access to their respective diets ad libitum for approximately two years.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

2 years

Frequency of treatment:

daily

Post exposure period:

none

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 ppm (nominal)

Doses / concentrations 2

Dose / conc.:

200 ppm (nominal)

Doses / concentrations 3

Dose / conc.:

2 000 ppm (nominal)

Doses / concentrations 4

Dose / conc.:

20 000 ppm (nominal)

No. of animals per sex per dose:

20 for each test dose; 40 with untreated diet as control

Control animals:

yes, plain diet

Details on study design:

Animals were observed daily for behavior and general condition and body weights were measured weekly. All animals that died spontaneously during the experiment and those surviving to study termination were subjected to a necropsy and tissues were examined histologically. Because of unexplained transient depression of the rate of growth of all three experimental groups from week 5 to 15, two additional groups of 10 rats each received the test substance in the diet at concentrations of 200 and 2000 ppm and one group of 20 rats that served as the control, received the untreated diet for one year. All animals in these additional groups that died spontaneously and those sacrificed at the end of the one year treatment period were studied for pathological changes.

Examinations

Observations and examinations performed and frequency:

Animals were observed daily for behavior and general condition and body weights were measured weekly.

Sacrifice and pathology:

All animals that died spontaneously during the experiment and those surviving to study termination were subjected to a necropsy and tissues were examined histologically.

Statistics:

not stated

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Description (incidence and severity):

There were no treatment-related clinical observations.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

Twelve of the 60 rats fed test diets and eight of the 40 control rats died prior to scheduled sacrifice. There was no significant difference in time of death or percentage mortality among the three treated groups and controls.

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

In the main study, a transient reduction in body weight gain was observed in animals in all three treated groups, 200, 2000 and 20000 ppm. This decrease in body weight gain was not seen in the additional study of animals treated for one year at dietary concentrations of 200 and 2000 ppm. Since this finding was not reproducible it is considered to be and artifact. Statistical analysis indicated that there were no significant differences between the body weights of the treated animals compared to the concurrent controls.

Description (incidence and severity):

Inflammatory disease of the lungs was the most frequent finding necropsy of these animals, it is likely that this was caused by infection rather than treatment with ATBC. Lymphoid tumors of the pleural and abdominal cavities, with some infiltration of the associated organs, were seen in both treated and control animals at comparable rates and, therefore, were not considered to be treatment-related. Careful examination of the endocrine system did not reveal evidence of abnormality in any of the animals. There were no significant differences between treated and control animals in comparisons of the pathological findings.

Effect levels

Key result

Dose descriptor:

NOAEL

Effect level:

>= 100 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

other: NOAEL indicated as > 1000 mg/kg/day

Remarks on result:

other:

Remarks:

Under the conditions of this study, the NOAEL appears to be 20,000 ppm (estimated as 1000 mg/kg/day) ATBC in the diet; however, considering the pre-GLP timing of the study and the lack of experimental detail available in the study report, a more conservative and appropriate NOAEL may be 2000 ppm (estimated as 100 mg/kg/day) ATBC in the diet.

Applicant's summary and conclusion

Conclusions:

ATBC was tested in a 2 year feeding study in rats. No systemic toxicity observed up to 20,000 ppm (1000 mg/kg/day). NOAEL determined to be greater than or equal to 100 mg/kg/day; LOAEL = 1000 mg/kg/day.

Executive summary:

ATBC was tested in a 2 year feeding study in rats. No systemic toxicity observed up to 20,000 ppm (1000 mg/kg/day). NOAEL determined to be greater than or equal to 100 mg/kg/day; LOAEL = 1000 mg/kg/day.