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Carcinogenicity

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Description of key information

Conclusion based on 2 -year carcinogenicty study in rats using chlorendic acid, which is present as an impurity in the chlorendic anhydride at up to 3 %w/w.

The carcinogenicity potential of the degradation of chlorendic anhydride - chlorendic acid - was determined using a method similar to OECD Test Guideline 453 (non GLP) with deviations.

There was clear evidence of carcinogenicity of chlorendic acid for male rats as shown by increased incidences of neoplastic nodules of the liver and acinar cell adenomas of the pancreas. Increased incidences of alveolar/bronchiolar adenomas and preputial gland carcinomas may also have been related to the administration of chlorendic acid. There was clear evidence of carcinogenicity of chlorendic acid for female rats as shown by increased incidences of neoplastic nodules and of carcinomas of the liver.

There was clear evidence of carcinogenicity of chlorendic acid for male mice as shown by increased incidences of hepatocellular adenomas and of hepatocellular carcinomas. There was no evidence of carcinogenicity of chlorendic acid for female mice given chlorendic acid in the diet at concentrations of 620 or 1,250 ppm for 103 weeks.

Additional studies were performed on chlorendic acid to identify its carcinogenicity using alternative methods. Chlorendic acid was identified as a promoting carcinogenic agent in rat liver according to the initiation-promotion assay, while the in vivo biochemical assay returned negative results.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1987
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Deviations:
yes
Remarks:
Ophthalmological examination, urinalysis, haematology, and biochemistry were not included.
GLP compliance:
no
Specific details on test material used for the study:
- Supplier: Hooker Chemical Co. (Niagara Falls, New York)
- Batch: 6745
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Females (if applicable) nulliparous and non-pregnant: Yes
- Age at study initiation: 57 days
- Housing: Five animals per cage in Polycarbonate (Hazleton Systems, Inc., Aberdeen, MD)
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

DETAILS OF FOOD AND WATER QUALITY: Laboratory grade feed and water

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 73.6°F +/- 1.4°C
- Humidity (%): 48.75% +/- 8.35%
- Air changes (per hr): 10-12
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): Every 2 weeks
- Storage temperature of food: 5°C for no more than 2 weeks
- Mixing appropriate amounts with (Type of food): Purina Rodent Laboratory Chow 5001

VEHICLE
- Concentration in vehicle: 0, 620, or 1 250 ppm
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
see attached document (appendix J)
Duration of treatment / exposure:
103 weeks
Frequency of treatment:
Formulated diets available ad libitum.
Dose / conc.:
0 ppm
Dose / conc.:
620 ppm
Dose / conc.:
1 250 ppm
No. of animals per sex per dose:
50 animals per sex per dose
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: A subchronic toxicity study was performed before the study with doses at up to 10,000 ppm.
Positive control:
none
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly for the first 13 weeks. Monthly thereafter.

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No. Calculation was made by cage.

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: Yes

Examination included gross lesions, skin, madibular lymph nodes, mammary gland, salivary glands, sternum including bone marrow, thymus, trachea, lungs and bronchi, heart, thyroid gland, parathyroids, esophagus, stomach, pancreas, small intestine, colon, mesenteric lymph nodes, liver, spleen, kidneys, adrenal glands, urinary bladder, prostate/tests or ovaries/uterus, brain, pituitary gland tissue masses or suspected tumours, and regional lymph nodes tissues.
Statistics:
Statistics were applied for survival analysis (Cox test), calculation of incidence, analysis of tumour incidence and historical control data.
Clinical signs:
no effects observed
Description (incidence and severity):
There was no evidence of a compound-related effect on physical appearance or behaviour.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
No significant differences in survival were observed between any groups of either sex. The relatively lower survival of control and male rats treated at 1250 ppm compared with that of the low dose group or with historical rates cannot be explained on the basis of available information.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Mean body weights of male rats treated at 1250 ppm were 5% to 10% lower than control throughout the study.
Mean body weights of female rats treated at 1250 ppm were 10% lower than control after week 11 and 20% lower after week 57.
Mean body weights of female rats treated at 620 ppm were approximately 5% lower than those of the controls by week 10 and 10% lower by week 45.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
The average daily feed consumption per animal was 96% for male rats treated at 620 ppm compared to the control.
The average daily feed consumption per animal was 94% for male rats treated at 1250 ppm compared to the control.
The average daily feed consumption per animal was 122% for female rats treated at 620 ppm compared to the control.
The average daily feed consumption per animal was 96% for female rats treated at 1250 ppm compared to the control.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
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, treatment-related
Description (incidence and severity):
Changes related to the effects observed in the hispathological examination.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Calculi were observed at increased incidence in the kidneys of female rats treated at 620 ppm.
Histopathological findings: neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Cystic degeneration, focal cellular change, granulomatous inflammation, pigmentation, and bile duct hyperplasia were observed at increased incidences in treated male or female rats. Neoplastic nodules in male and female rats and hepatocellular carcinomas in female rats occurred with significant positive trends. The incidences of neoplastic nodules in treated male rats and female rats treated at 1250 ppm, and of hepatocellular carcinomas in female rats treated at 1250 ppm, were significantly greater than those in the controls.

Focal hyperplasia of the pancreatic acinus was observed in treated male rats. Acinar cell adenomas in male rats occurred with a significant positive trend, and the incidence in the group treated at 1250 ppm was significantly greater than that in the controls.

Alveolar/bronchiolar adenomas in male rats occurred with a significant positive trend, and the incidence in the group treated at 1250 ppm was significantly greater than that in the controls.

The incidence of carcinomas in the preputial gland at 620 ppm in male rats was significantly greater than those in the controls.

Uterine cysts were observed at increased incidence in female rats treated at 1250 ppm. The incidence of endometrial stromal polyps in female rats treated at 620 ppm was significantly greater than that in the controls.

Sarcomas, fibrosarcomas, or neurofibrosarcomas (combined) of the salivary gland were observed. The incidences of nephropathy in treated female rats were notably lower than that in the controls.

Lymphoid hyperplasia was observed in the kidneys of male rats.

The incidence of fibroadenomas in the mammary gland in female rats treated at 1250 ppm was significantly lower than that in the controls.

Pheochromocytomas and pheochromocytomas or malignant pheochromocytomas (combined) occurred in adrenal glands of male rats with significant negative trends, and the incidences in the treated groups were significantly lower than those in the controls.

Interstitial cell tumors in testes of male rats occurred with a significant negative trend, and the incidences in the treated groups were significantly lower than that in the controls.

Adenomas and adenomas or carcinomas (combined) in the pituitary gland of female rats occurred with significant negative trends, and the incidences in the group treated at 1250 ppm were significantly lower than those in the controls.
Other effects:
no effects observed
Relevance of carcinogenic effects / potential:
There was clear evidence of carcinogenicity of chlorendic acid for male rats as shown by increased incidences of neoplastic nodules of the liver and acinar cell adenomas of the pancreas. Increased incidences of alveolar/bronchiolar adenomas and preputial gland carcinomas may also have been related to the administration of chlorendic acid. There was clear evidence of carcinogenicity of chlorendic acid for female rats as shown by increased incidences of neoplastic nodules and of carcinomas of the liver.
Key result
Dose descriptor:
LOAEL
Effect level:
620 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
histopathology: neoplastic
Key result
Critical effects observed:
no
Lowest effective dose / conc.:
620 ppm
System:
hepatobiliary
Organ:
bile duct
liver
pancreas
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified
Critical effects observed:
no
Lowest effective dose / conc.:
620 ppm
System:
respiratory system: lower respiratory tract
Organ:
lungs
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified
Critical effects observed:
no
Lowest effective dose / conc.:
620 ppm
System:
male reproductive system
Organ:
preputial gland
Treatment related:
yes
Dose response relationship:
no
Relevant for humans:
not specified
Critical effects observed:
no
Lowest effective dose / conc.:
620 ppm
System:
female reproductive system
Organ:
uterus
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified
Critical effects observed:
no
Lowest effective dose / conc.:
620 ppm
System:
urinary
Organ:
kidney
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified
Conclusions:
There was clear evidence of carcinogenicity of chlorendic acid for male rats as shown by increased incidences of neoplastic nodules of the liver and acinar cell adenomas of the pancreas. Increased incidences of alveolar/bronchiolar adenomas and preputial gland carcinomas may also have been related to the administration of chlorendic acid. There was clear evidence of carcinogenicity of chlorendic acid for female rats as shown by increased incidences of neoplastic nodules and of carcinomas of the liver.
Executive summary:

The carcinogenicity potential of chlorendic acid was determined using a method similar to OECD Test Guideline 453 (non GLP) with deviations. Rats were exposed at concentrations of 0, and 620, 1250 ppm of chlorendic acid in food for 103 weeks. Clinical signs, body weight, and food consumption were recorded. At the end of the study, surviving animals were subjected to gross necropsy and histopathology.

There was clear evidence of carcinogenicity of chlorendic acid for male rats as shown by increased incidences of neoplastic nodules of the liver and acinar cell adenomas of the pancreas. Increased incidences of alveolar/bronchiolar adenomas and preputial gland carcinomas may also have been related to the administration of chlorendic acid. There was clear evidence of carcinogenicity of chlorendic acid for female rats as shown by increased incidences of neoplastic nodules and of carcinomas of the liver.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
T25
16.7 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Good
System:
hepatobiliary
Organ:
liver

Additional information

Justification for classification or non-classification

The substance as a whole is classified as a possible carcinogen based on the classification of an impurity, chlorendic acid. If this impurity is present at < 0.1 %w/w the substance would not be classifed.