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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: no clinical chemistry data
Cross-reference
Reason / purpose:
reference to same study

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Toxic responses to acute, subchronic, and chronic oral administrations of monochlorobenzene to rodents
Author:
Kluwe WM, Dill G, Persing A, Pters A
Year:
1985
Bibliographic source:
Journal of toxicology and environmetal health, 15:745-767
Reference Type:
publication
Title:
Toxicology and carcinogenesis studies of chlorobenzene (CAS No.108-90-7) in F344/N rats and B6C3F1 (gavage studies)
Author:
National Toxicology Program (NTP)
Year:
1985
Bibliographic source:
Technical Report No. 261, NIH Publication, No. 86-2517.

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
other: OECD TG 451
Deviations:
yes
Remarks:
- Only 2 doses level instead of 3 were administered. Some organs were not microscopically analyzed. Food intake was not determined. No blood smear was obtained from the animals.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): chlorobenzene
- Physical state: Liquid
- Analytical purity: < 99%
- Impurities (identity and concentrations): 15 impurities with a combined area of less than 0.1 % of the major peak.
- Stability under test conditions: Chlorobenzene at a concentration of 2% (w/v) was found to be stable at 25°C for 7 days
- Lot/batch No.: 77022
- Storage condition of test material: Chlorobenzene was stored in the dark at room temperature at the performing laboratory

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories (Portage, MI, USA)
- Age at study initiation: 7 weeks
- Weight at study initiation: 206 g (males); 110 g (females)

- Housing: five animals/polycarbonate cage
- Diet (e.g. ad libitum): Purina Laboratory Chow (pellets), Ralston Purina Co. (St.Louis, MO, USA) ad libitum
- Water (e.g. ad libitum): Edstrom automatic watering system (Waterford, WI, USA)
- Acclimation period: 17 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-26 °C
- Humidity (%): 40%-70%
- Air changes (per hr): 15 changes of room air per hour were provided.
- Photoperiod (hrs dark / hrs light): 12 hours dark/12 hrs light


Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
Appropriate amount of chlorobenzene and corn oil were mixed with a stirring bar of 15 minutes in a graduate cilinder to preparare highest dose. Lower dose levels prepared by sequential dilution of measured volume of high dose formulation with corn oil.

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples of chlorobenzene/corn oil mixtures were periodically analyzed at Betelle Columbus Laboratories. Results of these analyses ad of the refereeanalyses at Midewest Research Institute indicated that the analyzed mixtures were properly formulated.
Duration of treatment / exposure:
103 weeks
Frequency of treatment:
5 days per weel
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 60, 120 mg/kg bw/day
Basis:

No. of animals per sex per dose:
50
Control animals:
yes
Positive control:
not applicable

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily for mortality and morbidity

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

DERMAL IRRITATION (if dermal study): No

BODY WEIGHT: Yes
- Time schedule for examinations: by cage every week for the first 13 weeks and monthly thereafter

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

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:
GROSS PATHOLOGY: Yes; grossly visible lesions were performed on major tissues and organs.
HISTOPATHOLOGY: Yes; tissue masses, skin, mandibular or mesentric lymph nodes, mammary gland, salivary gland, bone marrow, sternebrae, thymus, trachea, lung and bronchi, heart, thyroid, parathyroid, esophagus, stomach, small intestine, colon, liver, pancreas, spleen, kidneys, adrenals, urinary bladder, prostate/testes or ovaries/uterus, brain, and pituitary were microscopally examined.
Statistics:
see "Any other information on materials and methods"

Results and discussion

Results of examinations

Details on results:
CLINICAL SIGNS AND MORTALITY
The survival of high dose male rats was significantly less than that observed for the vehicle controls (p=0.033). No other significant differences in survival were observed.
No compound-related clinical sings of toxicity were observed at any time during the study.
BODY WEIGHT AND WEIGHT GAIN
Throughout the studies, mean body weights of dosed and vehicle control male rats were comparable. During the second year of the studies, mean body weights of dosed female rats were greater than those of the vehicle controls. No compound-related clinical signs of toxicicty were observed at any time during the studies.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
Liver: Chlorobenzene was associated with an increased occurence of neoplastic nodules in the livers of male rats. Generally considered to be late-occurig lesions, the first neoplastic nodule of the liver was detected in a vehicle control male rat that died at week 89, and the majority in all groups were detected at study termination. The incidence of neoplastic nodules of the liver in male rats surviving for at least 89 weeks were 4/44 (9%), 2/48 (4%), 4/40 (10%) , and 8/32 (25%) in the untreated control, vehicle control, low dose, and high dose groups, respectively. Pairwise comparisons by the Fisher exact test indicated that the incidence in high dose male rats was significantly (p<0.05) increased in comparison to the vehicle controls or the combined (vehicle and untreated) controls.
Chlorobenzene was associated with an increased occurence of neoplastic nodules in the high dose (120 mg/kg/day) male rats in composite control group. The increase in the neoplastic nodules of the liver in male rats, therefore, was considered to be chlorobenzene.
Testis: Interstitial cell tumors were observed with a significant positve trend by the life table tes, and the incidence in the high dose group was significantly higher that in that vehicle controls by the life table test. Statistical significance was not indicated by either the incidental tumor of Fisher exact tests. One of the interstitial cell tumors in a vehicle control rat was malignant; none of the tumors in the dosed group were malingnant.
Urinary bladder: A transitional cell papilloma was found 1/46 (2%) low dose and 1/45 (2%) high dose male rats. This tumor type was not observed in untreated or vehicle controls.
Kidney: A tubular cell adenocarcinoma was observed in one high dose female rat. This tumor type was not observed in untreated controls, vehicle controls, or low dose female rats.
Pituitary: Adenomas in female rats, and adenomas, adenocarcinomas, or carcinomas in male rats occurred with significantl negative trends. The incidences in the high dose groups were significantly lower than those in the controls.
Uterus: Endometrial stromal polyps were observed with a significantly lower incidence in the low dose group than in controls.
HISTOPATHOLOGY: NON-NEOPLASTIC
An apparent increase in the occurrence of hepatocellular necrosis, and decreases in the occurences of of hepatocellular basophilic cytoplasmic change and granulomatous inflammation, were observed in chlorobenzene-treated male and female rats. Upon a blind review of all liver sections by an indipendent pathologist, however, the occurrence of hepatocellular necrosis in chlorobenzene-treated rats was found to be similar to that in controls. Both diagnosticians generally graded the necrotic lesions as minimal to mild severity in all groups. Therefore, the evidence for mild chlorobenzene-induced hepatocellular necrosis in these studies is considered equivocal.

Effect levels

Dose descriptor:
other: NOAEL (systemic)
Effect level:
ca. 120 mg/kg bw/day (actual dose received)
Sex:
male/female

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Executive summary:

103 weeks chronic toxicity studies of orally administered (gavage, 5d/w, 0, 60, 120 mg/kg bw/day, corn oil) monochlorobenzene were conducted in male and female F344 rats. Monochlorobenzene did not produce any evidence of systemic toxicity. Thus, the NOAEL (systemic) for male and female rats is considered to be 120 mg/kg bw/day