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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
chronic toxicity: inhalation
Remarks:
combined repeated dose and carcinogenicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study and GLP
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2005

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: solid
Details on test material:
purity of test substance: greater than 99.9%

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 4 weeks
- Housing: individually
- Diet ad libitum
- Water ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23
- Humidity (%): 55
- Air changes (per hr): 6
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: clean air
Remarks on MMAD:
MMAD / GSD: not applicable (vapour)
Details on inhalation exposure:
whole-body exposure:
solid p-dichlorobenzene was liquified in a reservoir flask with a thermostatted water bath heated at 70°C. Clean air was bubbled through the liquid p.dichlorobenzene.-air flow containing the saturated p-dichlorobenzene vapor was conditioned at 60°C by passing through a thermostatted condenser and then diluted with a large volumeof clean air in order to prevent aerosoliuation of vaporized p-dichlorobenzene in the airflow. finally thee diluted vapor-air mixture was supplied to the inhalation exosure chamber with a dymanic air flow of 1900 l(min
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
by gas chromatography
Duration of treatment / exposure:
2 years
Frequency of treatment:
6 hr/day, 5 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 20, 75, 300 ppm
Basis:

No. of animals per sex per dose:
50 rats/sex/dose
Control animals:
yes
Details on study design:
Groups of rats were exposed to p-dichlorobenzene via inhalation 6 hours a day 5 days a week for 2 years; control rats were exposed to clean air. Animals were observed for clinical signs and mortality body weight development and food consumption; all animals underwent complete necropsy, organs were weighed and examined for macroscopic lesions. Tissues for histopathological evaluation were preserved.
Positive control:
no

Examinations

Observations and examinations performed and frequency:
-Animals were observed for clinical signs and mortality body weight development and food consumption
Sacrifice and pathology:
all animals underwent complete necropsy, organs were weighed and examined for macroscopic lesions. Tissues for histopathological evaluation were preserved.
Statistics:
chi-square test, Peto test, Fisher's exact test, Dunnett's test

Results and discussion

Results of examinations

Details on results:
Survival, body weight and food consumption:
There was no significant decrease in survival rate between any exposed group of either sex and respective control except for the decreased survival rate of 300 ppm-exposed males as indicated by the Logrank analysis.
A total of 32 deaths consisting of 10 leukemia, 9 other tumors of various organs, 11 chronic progressive nephropathy(CPN) and 2 unconfirmed deaths as the cause of death occured in the 300 ppm-exposed males, while 17 deaths of the male control consisted of 3 leukemia, 8 other tumors and 6 CPN. Therefore, the significant decrease in the survival rate of 300 ppm-exposed males was attributed to an increase in number of leukemia and CPN deaths.
There was no difference in growth rate of food consumption between any p-DCB-exposed group of either sex and the respective control throughout the 2 -year exposure period.
Pathology:
Significant increase in the incidences of neoplastic nor tumor-related lesions were recognized in any organ of the PCB-exposed rat groups of either sex. Notably, any renal tumor was not induced in the p-DCB-exposed rats of either sex. In addition, although leukemia deaths were increased in the 300 ppm-exposed male rats, the incidences of leukemia were not dose-related.
Incidence of centrilobular hypertrophy of hepatocytes was increased in the 300 ppm-exposed male rats.
Increased incidences of papilarry mineralization and hyperplasia of the pelvic urothelium in the kidney were noted in the 300 ppm-exposed male rats. High incidences of CPN which is known as a spontaneous disease of aged rats were observed in all the exposed and control groups of both sexes. The incidences and severities of CPN were not related to the p-DCB exposure, but the average grade of severity was more profound in males than in females.
Any histopathological change indicating excessive accumulation of alpha2u-globulin in the epithelial cells of renal proximal tubules was not found in this 2 -year inhalation study.
In the nasal cavity, incidences of the eosinophilic globules were increased in the olfactory epithelium having marked grade of severity in the females exposed to 75 and 300 ppm and in the respiratory epithelium having slight grade of severity in the 300 ppm-exposed females.
The increased incidences of the eosinophilic globules were closely associated with a marked decrease in the number of olfactory cells in the olfactory epithelium of 300 ppm -exposed females. Incidence of the respiratory metaplasia of the nasal gland epithelium was increased in the females exposed to 300 ppm. The eosinophilic globules were abundantly present in both the supporting cells of the olfactory epithelium and the ciliated and non-ciliated cells of the respiratory epithelium.

Effect levels

Dose descriptor:
NOAEC
Effect level:
ca. 75 ppm
Sex:
male/female
Basis for effect level:
other: The NOAEC for systemic effects in liver and kidney is 75 ppm .

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

re was n Survival, body weight and food consumption:

There was no significant decrease in survival rate between any exposed group of either sex and respective control except for the decreased survival rate of 300 ppm-exposed males as indicated by the Logrank analysis.

A total of 32 deaths consisting of 10 leukemia, 9 other tumors of various organs, 11 chronic progressive nephropathy(CPN) and 2 unconfirmed deaths as the cause of death occured in the 300 ppm-exposed males, while 17 deaths of the male control consisted of 3 leukemia, 8 other tumors and 6 CPN. Therefore, the significant decrease in the survival rate of 300 ppm-exposed males was attributed to an increase in number of leukemia and CPN deaths.

There was no difference in growth rate of food consumption between any p-DCB-exposed group of either sex and the respective control throughout the 2 -year exposure period.

Pathology:

Significant increase in the incidences of neoplastic nor tumor-related lesions were recognized in any organ of the PCB-exposed rat groups of either sex. Notably, any renal tumor was not induced in the p-DCB-exposed rats of either sex. In addition, although leukemia deaths were increased in the 300 ppm-exposed male rats, the incidences of leukemia were not dose-related.

Incidence of centrilobular hypertrophy of hepatocytes was increased in the 300 ppm-exposed male rats.

Increased incidences of papilarry mineralization and hyperplasia of the pelvic urothelium in the kidney were noted in the 300 ppm-exposed male rats. High incidences of CPN which is known as a spontaneous disease of aged rats were observed in all the exposed and control groups of both sexes. The incidences and severities of CPN were not related to the p-DCB exposure, but the average grade of severity was more profound in males than in females.

Any histopathological change indicating excessive accumulation of alpha2u-globulin in the epithelial cells of renal proximal tubules was not found in this 2 -year inhalation study.

In the nasal cavity, incidences of the eosinophilic globules were increased in the olfactory epithelium having marked grade of severity in the females exposed to 75 and 300 ppm and in the respiratory epithelium having slight grade of severity in the 300 ppm-exposed females.

The increased incidences of the eosinophilic globules were closely associated with a marked decrease in the number of olfactory cells in the olfactory epithelium of 300 ppm -exposed females. Incidence of the respiratory metaplasia of the nasal gland epithelium was increased in the females exposed to 300 ppm. The eosinophilic globules were abundantly present in both the supporting cells of the olfactory epithelium and the ciliated and non-ciliated cells of the respiratory epithelium.

Applicant's summary and conclusion

Executive summary:

Chronic toxicity of para-dichlorobenzene were examined by exposing 50 F344 rats of both sexes by inhalation to p-DCB vapor at a target concentration of 0 (control), 20, 75 or 300 ppm for 6 hr/day, 5 days/week and 2 years. The study was performed according to OECD TG 453 and GLP conditions.

No increase in tumor incidence was found in any p-DCB-exposed rat of either sex. Centrilobular hypertrophy of hepatocytes and papilarry mineralization and pelvic urothelial hyperplasia of the kidney were noted in the 300 ppm-exposed rats. Treatment- and age related increases in incidences of the eosinophilic globules of the respiratory and olfactory epithelia in female rats and incidences of the respiratory metaplasia of the nasal gland epithelium in rats were noted. The nasal lesion was the most sensitive endpoint of chronic inhalation toxicity.

The NOAEC for systemic effects in liver and kidney is 75 ppm .