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Toxicological information

Carcinogenicity

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Description of key information

In a 103-week carcinogenicity study, the read-across substance, bis(2 -ethylhexyl) adipate, was administered to F344 rats and B6C3F1 mice in the diet at 12000 or 25000 ppm.

Under the conditions of this bioassay, di(2-ethylhexyl)adipate was not carcinogenic for F344 rats.

Hepatocellular carcinomas or ademomas occurred in mice of both sexes in a dose-related fashion at incidences that were significantly higherfor high dose males and for low dose and high dose females than those in the controls. When compared with the incidence in historical laboratory control mice, however, the liver tumours in male mice could not be clearly related to the compound administration.

The test substance is not considered to be carcinogenic for the following reasons:

These tumours are very common in B6C3F1 mice.

There was no dose-response in female mice.

Time to first occurrence of the tumours was not altered by the test substance.

Observed incidences in male and female mice were well within NTP historical control data for this mouse strain.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
April 1977- May 1979
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 451 (Carcinogenicity Studies)
Deviations:
yes
Remarks:
Urinalysis, haematological and clinical biochemistry measurements were not reported
GLP compliance:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- 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

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-31
- Humidity (%): 10-88
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
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:
yes
Details on analytical verification of doses or concentrations:
The concentration 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 dietaryconcentration, the mean of the analytical concentration was usually within +/-10% of the theoretical.
Duration of treatment / exposure:
103 weeks
Frequency of treatment:
Ad libitum
Post exposure period:
Week 104-107
Dose / conc.:
12 000 ppm
Dose / conc.:
25 000 ppm
No. of animals per sex per dose:
50
Control animals:
yes, plain diet
Details on study design:
Dose selection rationale: based on results of a subchronic pre-study (14-week study)
Positive control:
None
Observations and examinations performed and frequency:
Body weight: yes, every 4 weeks.
Clinical observations: twice daily.
Sacrifice and pathology:
Necropsy: Carbon dioxide inhalation.

GROSS PATHOLOGY and HISTOPATHOLOGY: Yes

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 .
Statistics:
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).
The approximate 95% confidence interval for the relative risk of each dose group compared with its control was calculated from the exact interval on the odds ratio (Gart, 1971).
Clinical signs:
no effects observed
Description (incidence and severity):
No compound- related clinical signs were observed.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
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):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Several non-neoplastic lesions were seen in control and dosed rats. None appeared to be related to the test substance.
A variery of neoplasms were seen in both controil and dosed rats. Tumours noted were those routinely seen in this strain of rat and they occurred in comparable numbers in control and dosed rats.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Several non-neoplastic lesions were seen in control and dosed rats. None appeared to be related to the test substance.
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
A variery of neoplasms were seen in both controil and dosed rats. Tumours noted were those routinely seen in this strain of rat and they occurred in comparable numbers in control and dosed rats.
Relevance of carcinogenic effects / potential:
Under the conditions of this bioassay, di(2-ethylhexyl)adipate was not carcinogenic for F344 rats.
Key result
Dose descriptor:
NOAEL
Effect level:
12 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
Remarks on result:
other: 25000 ppm is considered to be equivalent to 600 mg/kg bw
Conclusions:
Under the conditions of this bioassay, di(2-ethylhexyl)adipate was not carcinogenic for F344 rats.
Endpoint:
carcinogenicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Justification for type of information:
Please see Section 13 below.
Reason / purpose for cross-reference:
read-across source
Relevance of carcinogenic effects / potential:
Under the conditions of this bioassay, di(2-ethylhexyl)adipate was not carcinogenic for F344 rats.
Key result
Dose descriptor:
NOAEL
Effect level:
12 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
Conclusions:
Under the conditions of this bioassay, di(2-ethylhexyl)adipate was not carcinogenic for F344 rats.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
600 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Klimisch 2 study

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on the above mentioned result, classification of diisodecyl adipate according to the CLP Regulation (EC) 1272/2008 is not necessary.

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