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Repeated dose toxicity: oral

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Administrative data

chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
April 1977- May 1979
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions

Data source

Reference Type:
study report

Materials and methods

Test guideline
equivalent or similar to guideline
other: OECD 451 (Carcinogenicity study)
Urinalysis, haematological and clinical biochemistry measurements were not reported
Principles of method if other than guideline:
The aim of this study was to detect any carcinogenic potential of DEHA. Additionally clinical signs, body weights, survival, gross pathology also detecting in detail nonneoplastic effects in the tissue, and histopathology were performed.
GLP compliance:
Limit test:

Test material

Constituent 1
Chemical structure
Reference substance name:
Bis(2-ethylhexyl) adipate
EC Number:
EC Name:
Bis(2-ethylhexyl) adipate
Cas Number:
Molecular formula:
bis(2-ethylhexyl) adipate
Details on test material:
Supplier: W.R. Grace Co.(Fords, NJ)
- Name of test material (as cited in study report): di(2-ethylhexyl)adipate
- Substance type: a clear colourless liquid
- Analytical purity: 101.4 % for Lot No. GC-2-27-76 and 100.5 % for Lot No. 0-62-494 (ester titration, Thin-layer chromatography results: one component for both lots.)
- Lot/batch No.: GC-2-27-76.; Lot no. 0-62-494 was used for the final 46 weeks of the chronic studies.
- Storage condition of test material: at 4 degrees Celcius

Test animals

Fischer 344
Details on test animals or test system and environmental conditions:
- Source: NCI Frederick cancer Research Center, Maryland
- Age at study initiation: 3 weeks
- Housing: 5 per cage
- Diet :e.g. ad libitum
- Water :e.g. ad libitum
- Acclimatisation period: 2 weeks

- Temperature (°C): 18-31
- Humidity (%): 10-88
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: feed
unchanged (no vehicle)
Details on oral exposure:
Dietary preparation:
Test diets were prepared by mixing the chemical with an aliquot of powdered Wayne® Lab Blox animal feed (Allied Mills, Chicago, IL), placing the mixture in a Patterson-Kelly twin-shell intensifier bar V-blender with the remainder of the feed, and mixing for 10 minutes . Test diets were sealed in labelled plastic bags and stored at 4°C for no longer than 14 days.
Analytical verification of doses or concentrations:
Details on analytical verification of doses or concentrations:
The amounts of di(2-ethylhexyl)adipate in selected batches of feed were measured by vapor-phase chromatography of 50-ml methanol extracts of 2-g samples. At each dietary concentration, the mean of the analytical concentration was usually within +/-10 % of the theoretical.
Duration of treatment / exposure:
103 weeks
Frequency of treatment:
Diet was available ad libitum for 103 weeks
Doses / concentrations
Doses / Concentrations:
12000, 25000 ppm (600, 1250 mg/kg bw)
nominal in diet
No. of animals per sex per dose:
50 rats
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: based on performed subchronic pre-study (14-week study)
Positive control:
No positive control used.


Observations and examinations performed and frequency:
Body weight: yes, recorded every 4 weeks.
Clinical observations: twice daily.
In addition, survival was recorded.

Sacrifice and pathology:
Necropsy: CO2 inhalation.


Gross and microscopic examinations were performed on major tissues, major organs, and all gross lesions from killed animals and from animals found dead. Tissues were preserved in 10 % neutral buffered formalin, embedded in paraffin, sectioned, and stained with hematoxylin and eosin . The following tissues were examined microscopically: skin, lungs and bronchi, trachea , bone and bone marrow, spleen, lymph nodes, heart, salivary gland, liver, pancreas, stomach, small intestine, large intestine, kidneys, urinary bladder, pituitary, adrenal, thyroid, parathyroid, mammary gland, prostate and seminal vesicles or uterus, testis or ovary, brain, thymus, larynx, and esophagus. Necropsies were performed on all animals found dead unless precluded in whole or in part by autolysis or cannibalization. Thus, the number of animals from which particular organs or tissues were examined microscopically varies and does not necessarily represent the number of animals that were placed on study in each group.

Other examinations:
No other examinations were performed.
Probabilities of survival were estimated by the product-limit procedure of Kaplan and Meier (1958). Animals were statistically censored as of the time that they died of other than natural causes or were found to be missing; animals dying from natural causes were not statistically censored .
Statistical analyses for a possible dose-related effect on survival used the method of Cox (1972) for testing two groups for equality and Tarone's (1975) extension of Cox's methods for testing for a dose-related trend .
One-tailed P values have been reported for all tests except the departure from linearity test, which is reported only when its two-tailed P value is less than 0.05.
The incidence of neoplastic or non-neoplastic lesions has been given as the ratio of the number of animals bearing such lesions at a specific anatomic site (numerator) to the number of animals in which that site is examined (denominator).
The one-tailed Fisher exact test (Cox, 1970) was used to compare the tumor incidence of a control group with that of a group of dosed animals at each dose level.
The Cochran-Armitage test for linear trend in proportions, with continuity correction (Armitage, 1971), was also used. Life table methods were used to analyze the incidence of tumors. Curves of the proportions surviving without an observed tumor were computed as in Saffiotti et al . (1972).

Results and discussion

Results of examinations

Details on results:
CLINICAL SIGNS AND MORTALITY: No compound- related clinical signs were observed.

BODY WEIGHT AND WEIGHT GAIN: Mean body weights of high-dose rats of either sex were lower than those of the controls throughout the study.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): no data


HAEMATOLOGY: not examined


URINALYSIS: not examined

NEUROBEHAVIOUR: not examined

ORGAN WEIGHTS: not examined

GROSS PATHOLOGY: no compound-related effects occurred.

HISTOPATHOLOGY: NON-NEOPLASTIC: No compound-related lesions were observed.

HISTOPATHOLOGY: NEOPLASTIC (if applicable): Tumors that were noted were those seen routinely in this strain of rat, and they occurred in comparable numbers in control and dosed rats. There were no compound-related effects.

HISTORICAL CONTROL DATA (if applicable): no data

Effect levels

Dose descriptor:
Effect level:
12 000 ppm
Basis for effect level:
other: Mean body weights of high-dose rats of either sex were lower than those of the controls throughout the study.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion