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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
Remarks:
combined repeated dose and carcinogenicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Reliable scientific study, precedes establishment of guidelines and GLP

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1954
Report Date:
1954

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Deviations:
yes
Remarks:
As this study precedes establishment of guideline, deviations would have occurred from the guideline later accepted.
GLP compliance:
no
Remarks:
precedes establishment of GLP
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid: viscous

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
4 per sex per dose group. Housed individually in wire mesh cages. Food and water was available ad libitum.

Administration / exposure

Route of administration:
oral: feed
Vehicle:
cotton seed oil
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
lifetime
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0.33% (equivalent to 30 mg/kg bw/d)
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
1.0 % (equivalent to 200 mg/kg bw/d)
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
3.0 % (equivalent to 600 mg/kg bw/d)
Basis:
nominal in diet
No. of animals per sex per dose:
15
Control animals:
yes, plain diet
Details on study design:
Sprague-Dawley rats (15 males and 15 females/group) were provided with diet containing TEC at concentrations of 0, 0.33, 1.0 or 3.0% (estimated as 0, 165, 500 or 1500 mg/kg/day) in Rockland Rat Meal, 93.5-95% cottonseed oil, for two years. Weanling rats were maintained at the laboratory for one week before being placed on their respective control or treated diets. Animals were maintained throughout the study in individual suspended wire mesh cages, housed in air conditioned quarters, with food and water available ad libitum. Clinical observations were made daily (except Sunday) and individual body weights were measured weekly. Blood and urine evaluations were conducted at specified intervals. Scheduled interim sacrifices of animals included macroscopic examinations of thoracic and abdominal organs and microscopic examinations of the kidney and liver tissues. All animals that died spontaneously during the study, as well as all animals remaining at the termination of study (one or two years), were examined by a pathologist. At terminal sacrifice, microscopic examinations were made of kidney, liver, heart, lungs, spleen, stomach, small intestine, adrenals, ovaries, uterus, testes and seminal vesicles.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
transiently decreased body weights
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
transient effects of decreased food intake associated with transiently decreased body weights.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
Body weight data showed that males in the high-dose group had transiently lower weights, but there were no significant differences between the growth of TEC treated animals and control animals for the high-dose females or either sex in the low- and mid-dose groups. The effect in high-dose males may be attributable to their lower food consumption as compared to males in the other dose groups. There were no significant differences observed between treated and control groups for clinical evaluations or mortality. There were no significant differences between the groups for the following blood examinations: hemoglobin, erythrocyte count, nonprotein nitrogen and sugar determination. Urine tests for reaction, albumin, reducing substances and microscopic evaluation were all considered to be normal.
Terminal and interim autopsies disclosed no findings that were significant or attributable to TEC treatment. Size and weight of organs of the principal tissues at the time of autopsy were unremarkable. There were no significant differences between treated and control animals in comparison to the pathological findings.

Effect levels

Dose descriptor:
NOAEL
Effect level:
600 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Initial doses were from 0.2 to 2.0 g/kg bw/d, as reviewed by JECFA. The 2.0 g/kg bw/d concentration was chosen by JECFA as the point of departure for risk assessment.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
In a chronic (2-year) dietary oral toxicity study in rats with triethyl citrate, the NOAEL is 3% (estimated as 600 mg/kg/day), under the conditions of this study.