Registration Dossier

Administrative data

Description of key information

 Oral:
In a 13 week rat study species-specific kidney toxicity [alpha-2µ-microglubulin nephropathy]) was reported at 300 mg/kg bw/day. For effects other than kidney toxicity the NOAEL in males and females was 600 mg/kg bw /day (NTP 1987).
In a 52 week study with beagle dogs the relative and absolute organ weights (adrenal gland, thyroid gland) were increased in both sexes at >= 50 mg/kg/bw without histopathological changes. Together with the observed changes in liver and kidneys the overall NOAEL in that study is 10 mg/kg bw/day (Naylor 1996).
Thus, the lower NOAEL of 10 mg/kg bw/day was determined in a one year oral dog study. This NOAEL has to be considered in the risk characterisation of p-dichlorobenzene because there is no evidence that this specie with the higher sensitivity for p-dichlorobenzene exposure is a less appropriate model for humans than rodents (EU RAR, 2004). Therefore, the NOAEL of 10 mg/kg bw/day will be taken as starting point for the derivation of the systemic, oral, longterm DNEL for worker and consumer.
Inhalation
In a repeated dose inhalation toxicity study in rats (2 years) the NOAEC was 75 ppm for systemic effects in liver and kidney (Centrilobular hypertrophy of hepatocytes and papillary mineralization and pelvic urothelial hyperplasia of the kidney were noted in the 300 ppm-exposed rats) as well as local effects at the respiratory tract (AISO 2005).
Dermal:
There are no valid data available

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: No OECD guideline defined.
Principles of method if other than guideline:
Repeated dose toxicity study: p-dichlorobenzene was applied to dogs in gelatine capsules once per day, 5 days per week for 52 weeks
GLP compliance:
yes
Limit test:
no
Species:
dog
Strain:
Beagle
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source:
- Age at study initiation: 7 months
- Weight at study initiation: males: 6.8-11.4 kg; females 6.9-11.1 kg
- Fasting period before study:
- Housing: individual
- Diet ad libitum
- Water ad libitum
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
details not provided
animal housing ans husbandry in accordance witht he provisions of
" guide to the care and use of laboratory animals"
USPHS-NIH publication No. 86-23
Route of administration:
oral: capsule
Vehicle:
other: Gelatin Capsule
Details on oral exposure:
p-dichlorobenzene was applied in gelatine capsules once per day, 5 days per week
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
1 year
Frequency of treatment:
once per day, 5 days/week, 52 weeks
Remarks:
Doses / Concentrations:
0, 10, 50, 150/100/75 mg/kg bw/day
Basis:

No. of animals per sex per dose:
5/sex/dose
Control animals:
yes
Details on study design:
in a one-year oral toxicity studc p-dichlorobenzene was administered to Beagle dogs byy capsule once per day , at dose levels of 0, 10, 50, 150 mg/kg bw/day. The highest dose was reduced at first to 100 and then to 75 mg/kg bw/day due to exessive toxicity.. treatment was determined after one year and animals were subjected to detailed examination
Positive control:
no
Observations and examinations performed and frequency:
daily observations, body weight determination once per week, food consumption ophthalmoscopic examination, hematology ,. clinical chemistry , urinalysis
Sacrifice and pathology:
all animals that died and those sacrificed on shedul were subjected to gross pathological examination: organ weights andhistopathological examination
Other examinations:
no
Statistics:
e. g.: Dunnett's multiple comparison test, decision-tree anlysis, Fisher's exact test, Grubb's test
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
effects observed, treatment-related
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: relative and absolute organ weights (adrenal gland, thyroid gland) increased in both sexes at >= 50 mg/kg/bw without histopathological changes and mainly the observed changes in liver and kidneys from 50 mg/kg bw/day
Critical effects observed:
not specified

Due to the severe toxicity at the highest dose (letality observed at 150 mg/kg/day after 12 days), the initial dose of 150 mg/kg/day was adjusted to 100 mg/kg/day at the third week and 75 mg/kg/day at the sixth week.

Executive summary:

EU RAR 2004:

“ In a one-year oral toxicity study (GLP) in Beagle dogs, 1,4-dichlorobenzene was administered via capsule at doses of 10, 50 and 150 mg/kg/day (5 animals/sex/dose) and a control group of 5 animals/sex (of the same age of 7 months than treated animals); due to the severe toxicity at the highest dose (lethality observed at 150 mg/kg/day after 12 days), the initial dose of 150 mg/kg/day was adjusted to 100 mg/kg/day at the third week and 75 mg/kg/day at the sixth week. Two males and one female at 150 mg/kg/day died during the study (1 male at D12 and 1 at D25 and 1 female at D24); one control dog died at D83 to jejunal displacement; two treated animals (one male and one female) died from inflammatory lung lesions, associated in one female with pulmonary hemorrhages: the possibility that death was treatment related cannot be ruled out; the cause of death of the third animal was not clearly determined. All animals died (2 males, 1 female) during treatment, had congestion or hemorrhage in different tissue [congestion (2 males) and hemorrhage (1male) of intestine, hemorrhage of lung (1male, 1 female) and hemorrhage of lymph node (female)]. As pulmonary inflammation was observed in dogs and can be caused by nematodes parasites (filariasis, oxocaris), such parasites were researched in the lung mesenteric lymph node but not detected. At the highest dose (150 and then 75 mg/kg/day) were observed hypoactivity, emesis, deshydratation, emaciation in animals died during the study and decreased body weight gain during the first month. A mild anemia reversible at one year was observed in both sexes at 6 months at the highest dose and the platelet count was increased in high dose female (3 out of 4 female were affected (mean: 431.25 + 108 (p<0.05); control: 267.00 + 68). A marrow erythroid hyperplasia in one high dose female and a splenic excessive hematopoesie in high dose animals (2 females, 1 male) were observed. In the liver statistically significant dose dependent increased absolute and relative liver weight in high dose (x 1.5) and mid dose of both dog sexes was noted. A statistically significant dose dependent increased of liver enzymes was noted: alkaline phosphatases were increased in both sexed´s from 50 mg/kg/day [at high dose in 2/3 males (x 7.3) (p< 0.05) and in 4/4 females (x 7.8) (p<0.01); at 50 mg/kg/day in 5/5 males (x 7.2) and 5/5 females (x 4.3)); ALAT were increased (p< 0.05) in ¾ females at high dose (x 3.5); GGT were increased (p< 0.05) in ¾ females at high dose (x 2.6). Histological liver findings show hepatocellular hyoertrophia in all males and females in mid and high dose groups with hepatocellular pigment deposition in some animals (2/5); bile duct hyperplasia was reported in 1 male and 1 female at the high dose, with hepatic portal inflammation in males (2/5) of the high dose group. Increased kidney weight at high and mid doses females and kidney duct epithelial vacuolization (in high dose: 1 male and 2 females; low dose: 1 female) were observed. A statistically significant increased relative adrenal weight in high dose female and thyroid weight in mild dose female were noted. No significant neoplasic findings were reported. In this study, the NOAEL was 10 mg/kg/day (Naylor, 1996)”.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
10 mg/kg bw/day
Study duration:
chronic
Species:
dog
Quality of whole database:
Although only as secondary citation availble the results of this carefully performed study (Klimisch score 2) demonstrate that the dog is more susceptible than rodents after oral administration of p-dichlorobenzene

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
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
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
GLP compliance:
yes
Limit test:
no
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
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
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
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
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.
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 .
Critical effects observed:
not specified

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.

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 .

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
450 mg/m³
Study duration:
chronic
Species:
rat
Quality of whole database:
This long term study meets the criteria of the tonnage band . It is a rat inhalation study which is performed according to OECD TG 453 and under GLP condition and as such evaluated with Klimisch sore 1

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
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
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
GLP compliance:
yes
Limit test:
no
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
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
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
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
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.
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 .
Critical effects observed:
not specified

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.

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 .

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
450 mg/m³
Study duration:
chronic
Species:
rat
Quality of whole database:
This long term study meets the criteria of the tonnage band . It is a rat inhalation study which is performed according to OECD TG 453 and under GLP condition and as such evaluated with Klimisch sore 1

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

ORAL EXPOSURE:

According to Bomhard (1988) male and female rats were applied with 75, 150, 300 or 600 mg/kg bw/day by gavage for 13 weeks. Hyaline droplet accumulation in renal cells were observed, associated with an increase in the urinary excretion of proteins and lactate dehydrogenases and epithelial cell excretion in male rats from 75 mg/kg/day. The NOAEL was <75 mg/kg bw/day for that effect (that was later shown to be species-specific [alpha-2µ-microglubulin nephropathy]). The NOAEL for other toxicity than kidney toxiciy was 600 mg/kg/day (tested parameters were: bodyweight, food/water consumption, urine, blood, liver weight and histopathology) (Bomhard 1988).

Additionally in another 13 week study male and female rats were applied with 300, 600, 900, 1200 or 1500 mg/kg bw/day. The study revealed renal tubular cell abnormalities with inclusions of eosinophil droplets beginning from 300 mg/kg/day in the males, followed by tubular cell degeneration and necrosis. Hepatic anomalies (statistically significant increased liver weight) appeared at 900 mg/kg/day or more in both sexes. Local degeneration and necrosis of hepatocytes began to appear at 1,200 mg/kg/day. At 1,200 and 1,500 mg/kg/day, bone marrow hypoplasia, lymphoid depletions of the spleen and thymus, and signs of general toxicity were observed in both sexes. The NOAEL for male rats based on species-specific kidney toxicity in this study is 300 mg/kg bw/day and for females and males for effects other than kidney toxicity was 600 mg/kg bw /day (NTP 1987).

EU RAR 2004 described also following study:

“ In a one-year oral toxicity study (GLP) in Beagle dogs, 1,4-dichlorobenzene was administered via capsule at doses of 10, 50 and 150 mg/kg/day (5 animals/sex/dose) and a control group of 5 animals/sex (of the same age of 7 months than treated animals); due to the severe toxicity at the highest dose (lethality observed at 150 mg/kg/day after 12 days), the initial dose of 150 mg/kg/day was adjusted to 100 mg/kg/day at the third week and 75 mg/kg/day at the sixth week. Two males and one female at 150 mg/kg/day died during the study (1 male at D12 and 1 at D25 and 1 female at D24); one control dog died at D83 due to jejunal displacement; two treated animals (one male and one female) died from inflammatory lung lesions, associated in one female with pulmonary hemorrhages: the possibility that death was treatment related cannot be ruled out; the cause of death of the third animal was not clearly determined. All animals died (2 males, 1 female) during treatment, had congestion or hemorrhage in different tissues [congestion (2 males) and hemorrhage (1male) of intestine, hemorrhage of lung (1 male, 1 female) and hemorrhage of lymph node (1 female)]. As pulmonary inflammation was observed in dogs and can be caused by nematodes parasites (filariasis, oxocaris), such parasites were researched in the lung mesenteric lymph node but not detected.

At the highest dose (150 and then 75 mg/kg/day) were observed hypoactivity, emesis, deshydratation, emaciation in animals died during the study and decreased body weight gain during the first month. A mild anemia reversible at one year was observed in both sexes at 6 months at the highest dose and the platelet count was increased in high dose female (3 out of 4 female were affected (mean: 431.25 + 108 (p<0.05); control: 267.00 + 68). A marrow erythroid hyperplasia in one high dose female and a splenic excessive hematopoiese in high dose animals (2 females, 1 male) were observed.

In the liver statistically significant dose dependent increased absolute and relative liver weight in high dose (x 1.5) and mid dose of both dog sexes was noted. A statistically significant dose dependent increased of liver enzymes was noted: alkaline phosphatases were increased in both sexes from 50 mg/kg/day [at high dose in 2/3 males (x 7.3) (p<0.05) and in 4/4 females (x 7.8) (p<0.01); at 50 mg/kg/day in 5/5 males (x 7.2) and 5/5 females (x 4.3)]; ALAT were increased (p<0.05) in 3/4 females at high dose (x 3.5); GGT were increased (p<0.05) in 3/4 females at high dose (x 2.6). Histological liver findings show hepatocellular hypertrophia in all males and females in mid and high dose groups with hepatocellular pigment deposition in some animals (2/5); bile duct hyperplasia was reported in 1 male and 1 female at the high dose, with hepatic portal inflammation in males (2/5) of the high dose group.

Increased kidney weight at high and mid doses females and kidney duct epithelial vacuolization (in high dose: 1 male and 2 females; low dose: 1 female) were observed.

A statistically significant increased relative adrenal weight in high dose female and thyroid weight in mild dose female were noted.

No significant neoplasic findings were reported.

In this study, the NOAEL was 10 mg/kg/day (Naylor, 1996)”.

INHALATION EXPOSURE:

A 2-year chronic inhalation study was performed on rats and mice. Chronic toxicity of 1,4-dichlorobenzene were examined by exposing 50 F344 rats of both sexes by inhalation to 1,4-dichlorobenzene vapour at a target concentration of 0 (control), 20, 75 or 300 ppm for 6 hr/day, 5 days/week and 2 years. No increase in tumor incidence was found in any 1,4-dichlorobenzene -exposed rat of either sex. Centrilobular hypertrophy of hepatocytes and papillary 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 NOAEC for systemic effects in liver and kidney is 75 ppm (AISO 2005).

Chronic toxicity of 1,4-dichlorobenzene were also examined by exposing 50 BDF1 mice of both sexes by inhalation to test compound vapor at a target concentration of 0 (control), 20, 75 or 300 ppm for 6 hr/day, 5 days/week and 2 years. Incidences of hepatocellular carcinomas, hepatoblastomas and hepatic histiocytic sarcomas in the 300 ppm-exposed male mice, and hepatocellular adenomas and carcinomas and hepatoblastomas in the 300 ppm-exposed female mice were increased. An increase in the incidences of most of those liver tumors was dose-related. Treatment- and age related increases in incidences of the respiratory metaplasia of the nasal gland epithelium and the olfactory epithelium in mice were noted. The NOAEC for male and female mice was 75 ppm (AISO 2005).

In addition to the systemic toxicity 1,4-dichlorobenzene after chronic inhalation exposure leads to effects in the nasal cavity mainly in female rats at 300 ppm (respiratory as well as olfactory epithelium). With 75 ppm no effects occurred at the respiratory epithelium. Nearly all female rats in all groups, including controls, showed eosinophilic globules in the olfactory epithelium (49/46/46/50 after 0/20/75/300 ppm, respectively). Whereas there was no effect on the number of animals affected, the severity increased slightly from mostly grade 1 and 2 in controls and the 20 ppm group, compared to grade 2-3 at 75 and 300 ppm.

According to Stropp (2006) the slight increase of severity of eosinophilic granules should be interpreted as a marker of exposure, but not as an adverse effect due to the following reasons:

1. In general, eosinophilic globules are typically seen in the olfactory epithelium of rats and mice. They have been found to increase with age. The exact composition of the material remains to be determined, but may represent proteinaceous material that accumulates in the cell. Their functional consequences are unknown.

2. The slight increase of severity of eosinophilic granules with 1,4-dichlorobenzene at 75 ppm occurred at the end of a 2 year inhalation exposure and was not related to any other effect at the olfactory epithelium, especially there was no evidence of degeneration

3. Observation occurred in one species and one sex only

In summary, nasal lesions indicating irritancy, were shown at 300 ppm, with 75 ppm as NOAEC. This conclusion is confirmed by the European Risk Assessment from 2004 that defined the overall NOAEC based on the long term inhalation study in rats and mice with 75 ppm. The eosinophilic changes in female rats were recognized, but not regarded to be of relevance for the NOAEC (Stropp 2006). Therefore the overall NOAEC for local and systemic toxicity is 75 ppm.

DERMAL EXPOSURE:

There are no valid data available to characterize the repeated dosing using the dermal application route.

CONCLUSION

Oral:

In a 13 week rat study species-specific kidney toxicity [alpha-2µ-microglubulin nephropathy]) was reported at 300 mg/kg bw/day. For effects other than kidney toxicity the NOAEL in males and females was 600 mg/kg bw /day (NTP 1987).

In a 52 week study with beagle dogs the relative and absolute organ weights (adrenal gland, thyroid gland) were increased in both sexes at >= 50 mg/kg/bw without histopathological changes. Together with the observed changes in liver and kidneys the overall NOAEL in that study is 10 mg/kg bw/day (Naylor 1996).

Thus, the lower NOAEL of 10 mg/kg bw/day was determined in a one year oral dog study. This NOAEL has to be considered in the risk characterisation of p-dichlorobenzene because there is no evidence that this specie with the higher sensitivity for p-dichlorobenzene exposure is a less appropriate model for humans than rodents (EU RAR, 2004). Therefore, the NOAEL of 10 mg/kg bw/day will be taken as starting point for the derivation of the systemic, oral, longterm DNEL for worker and consumer.

Inhalation

In a repeated dose inhalation toxicity study in rats (2 years) the NOAEC was 75 ppm for systemic effects in liver and kidney (Centrilobular hypertrophy of hepatocytes and papillary mineralization and pelvic urothelial hyperplasia of the kidney were noted in the 300 ppm-exposed rats) as well as local effects at the respiratory tract (AISO 2005).

Dermal:

There are no valid data available


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Although only as secondary citation availble the results of this carefully performed study (Klimisch score 2) demonstrate that the dog is more susceptible than rodents after oral administration of p-dichlorobenzene

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
This study is performed according to OECD TG 453 and under GLP conditions and therefore evaluated with Klimisch score 1

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
This study is performed according to OECD TG 453 and under GLP conditions and therefore evaluated with Klimisch score 1

Justification for classification or non-classification

Based on the discussed data no classification or labelling is required