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Carcinogenicity

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Description of key information

Renal tumor formation in male rats following oral application of p-dichlorobenzene occurs via sex and species-specific mechanism and should be considered as not relevant for humans. Following inhalation exposure of p-dichlorobenzene to rats no renal tumors were detected.
1,4-dichlorobenzene induced liver tumor formation in the mouse. A clear quantitative correlation between hepatotoxicity and hepatocarcinogenicity could not be determined and the mechanism of tumor formation is not yet known. Additionally, some other tumor incidences were enhanced, however not in a dose dependent manner.

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: OECD guideline not defined. Administration 5 days/week ( not justified in study report). No GLP study.
Reason / purpose:
reference to same study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 451 (Carcinogenicity Studies)
Principles of method if other than guideline:
Method: other: Carcinogenicity test
GLP compliance:
not specified
Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source:
- Age at study initiation: 8 weeks
- Weight at study initiation:
- Fasting period before study:
- Housing: in groups of 5
- Diet ad libitum
- Water ad libitum
- Acclimation period: 14 d

ENVIRONMENTAL CONDITIONS
-Temperature (°C): 21-23
- Humidity (%): 40-60
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 / 12

Route of administration:
oral: gavage
Type of inhalation exposure (if applicable):
not specified
Vehicle:
not specified
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
2 yr
Frequency of treatment:
once daily, 5 d/wk
Post exposure period:
no data
Remarks:
Doses / Concentrations:
300 or 600 mg/kg bw d
Basis:

No. of animals per sex per dose:
Groups of 50 male and female mice were administered 0, 300, or 600 mg/kg 1,4-dichlorobenzene, 5 days per week for 103 weeks.
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: none
Positive control:
no
Observations and examinations performed and frequency:
survival, clinical signs , body weight development
Sacrifice and pathology:
Necropsy was performed on all animals including those found dead: organs and tissues were preserved and examined macroscopically and microscopically
Details on results:
SURVIVAL and BODY WEIGHT DEVELOPMENT
survival and mean body weights of males and females comparable to that of vehicle control; 
NON-NEOPLASTIC LESIONS
increased incidences of nonneoplastic liver lesions in males and females including alteration in cell size; 
hepatocellular degeneration, and individual cell necrosis; 
increased incidences of nephropathy in males; 
renal tubular regeneration in females;
NEOPLASTIC LESIONS
--increased incidences of hepatocellular carcinomas at 600 mg/kg 
in males (vehicle control: 14/50, low dose: 11/49, high dose: 32/50) and 
in females (5/50, 5/48, 19/50); 
--increased incidences of hepatocellular adenomas 
in males at 300 and 600 mg/kg (5/50, 13/49, 16/50) and 
in females at 600 mg/kg (10/50, 6/48, 21/50); 
--hepatoblastomas in 4/50 males at 600 mg/kg but not in vehicle control; 
--increase in thyroid gland follicular cell hyperplasia in males at 300 and 600 mg/kg (1/47, 4/48, 10/47); 
--marginal positive trend in the incidence of follicular cell adenomas of the thyroid gland in females (0/48, 0/45, 3/46); 
--positive trend of pheochromocytomas (benign or malignant, combined) of the adrenal gland in dosed males, 
the incidence at 600 mg/kg was significantly greater than in the vehicle control (0/47, 2/48, 4/49); 
--incidence of adrenal gland medullary hyperplasia in males was 2/47 (vehicle control), 4/48 (low dose) and 4/49 (high dose); 
--incidence of focal hyperplasia of the adrenal gland capsule in males was 11/47 (vehicle control), 21/48 (low dose) and 28/49 (high dose); 
clear evidence of carcinogenicity for male and female B6C3F1 mice (increased incidences of hepatocellular carcinomas and adenomas).
Dose descriptor:
LOAEL
Effect level:
ca. 300 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: slight hepatocellular degeneration and slight individual cellular necrosis from 300 mg/kg/day. Nephropathy was seen in both sexes from 300 mg/kg/day.
Remarks on result:
other: Effect type: toxicity (migrated information)

NTP, 1987: Gavage study in B6C3F1 mice, 103 weeks, 5 days/week

           dose (mg/kg bw and day)
   sex  0 300 600 
 surviving animals after 103 weeks  M  28/50  32/50  30/50
   F  35/50  36/50  25/50
 neoplastic lesions        
 liver: hepatocellular adenoma3,4)  M  5/50 (10%)  13/49 (27%)*2)  16/50 (32%)*2)
     10/50 (29%)  6/48 (13%)  21/50 (42%)*2)
 liver: hepatocellular carcinoma 3,5)  M  14/50 (28%)  11/49 (22%)  32/50 (64%)**1)
   F  5/50 (10%)  5/48 (10%)  19/50 (38%)**1)
 liver: hepatocellular adenoma and carcinoma3,6)  M  17/50 (34%)  22/49 (45%)  40/50 (80%)**1)
   F  15/50 (30%)  10/48 (21%)  36/50 (72%)**1)
 liver: hepatoblastoma7)  M  0/50 (0%)  0/50 (0%)  4/50 (8%)
 adrenal medulla: pheochromocytoma, benigne  M  0/47 (0%)  2/48 (4%)  3/49 (6%)
   F  0/49 (0%)  3/46 (7%)  1/49 (2%)
 adrenal medulla: pheochromocytoma, maligne  M  0/47 (0%)  0/48 (0%)  1/49 (2%)
 adrenal medulla: pheochromocytoma, benigne and maligne9)  M  0/47 (0%)  2/48 (4%)  4/49 (8%)8)
         
non neoplasic lesions        
 liver: hepatocellular degeneration  M  0/50 (0%)  36/49 (73%)**1)  39/50 (78%)**1)
   F  0/50 (0%)  8/48 (17%)1)  36/50 (72%)**1)
 liver: focal necrosis  M  1/50 (2%)  35/49 (71%)**1)  37/50 (74%)**1)
   F  1/50 (2%)  4/48 (8%)  30/50 (60%)**1)
 liver: cell size alterations  M  0/50 (0%)  38/49 (78%)**1)  40/50 (80%)**1)
   F   0/50 (0%)  4/48 (8%)*2)  27/50 (54%)**1)
 adrenal gland capsule: hyperplasia  M  11/41 (23%)  21/48 (44%)  28/49 (57%)**1)
 Tyroid gland: hyperplasia  M  1/47 (2%)  4/48 (8%)  10/47 (21%)**1)
 splenic nodules: focal hyperplasia  F  2/50 (4%)  2/48 (4%)  10/46 (22%)**1)
 mandibular lymph nodes: hyperplasia  M  1/46 (2%)  12/41 (33%)**1)  10/47 (21%)**1)
 kidney: regeneration of tubules  F  4/50 (8%)  7/47 (15%)  13/46 (28%)**1)

1)**p<0,01 (Fisher´s exact test)

2)* p<0,05 (Fisher´s exact test)

3) p<0,01 (Cochran-Armitage trend test)

4) historical control data of test laboratory for hepatocellular adenoma

M: 20/150 (13%+/-3%), F: 5/148 (3,4%+/-1,2%);

Historical incidences in NTP studies, M: 0 -14/50=0 -28%; F: 0 -5/50=0 -10%

5) historical control data of test laboratory for hepatocellular carcinoma

M: 35/150 (23,3%+/-5%), F: 6/148 (4,1 +/-2%);

incidences in NTP studies, M: 5 -19/50=10 -38%; F: 0 -4/50=0 -8%

6) historical control data of test laboratory for hepatocellular adenoma and

Carcinoma M: 50/150 (33%+/-4%); F: 10/148 (7%+/-2%);historical incidences

in NTP studies, M: 7 -25/50%; F: 0 -5/50=0 -10%

7) p<0,02 (Cochran-Armitage trend test), historical control data of test

laboratory for hepatoblastoma M: 0/1091; F:0/1092 (vehicle control).

All hepatoblastomas were observed in animals also bearing hepatocellular

carcinomas.

8) p<0,04 (incidental tumor test)

9) p<0,04 (Cochran-Armitage trend test), historical control data of test laboratory for pheochromocytoma M: 7/148 (1 -4/50; 4,7%+/-3%)

RS-Freetext:
NOEL: males: < 300 mg/kg bw d; females: = 300 mg/kg bw d;
survival and mean body weights of males and females
comparable to that of vehicle control; increased incidences
of nonneoplastic liver lesions in males and females
including alteration in cell size; hepatocellular degenera-
tion, and individual cell necrosis; increased incidences of
nephropathy in males; renal tubular regeneration in females;
increased incidences of hepatocellular carcinomas at 600
mg/kg in males (vehicle control: 14/50, low dose: 11/49,
high dose: 32/50) and females (5/50, 5/48, 19/50); increased
incidences of hepatocellular adenomas in males at 300 and
600 mg/kg (5/50, 13/49, 16/50) and in females at 600 mg/kg
(10/50, 6/48, 21/50); hepatoblastomas in 4/50 males at 600
mg/kg but not in vehicle control; increase in thyroid gland
follicular cell hyperplasia in males at 300 and 600 mg/kg
(1/47, 4/48, 10/47); marginal positive trend in the
incidence of follicular cell adenomas of the thyroid gland
in females (0/48, 0/45, 3/46); positive trend of
pheochromocytomas (benign or malignant, combined) of the
adrenal gland in dosed males, the incidence at 600 mg/kg was
significantly greater than in the vehicle control (0/47,
2/48, 4/49); incidence of adrenal gland medullary hyper-
plasia in males was 2/47 (vehicle control), 4/48 (low dose)
and 4/49 (high dose); incidence of focal hyperplasia of the
adrenal gland capsule in males was 11/47 (vehicle control),
21/48 (low dose) and 28/49 (high dose); clear evidence of
carcinogenicity for male and female B6C3F1 mice (increased
incidences of hepatocellular carcinomas and adenomas).

Executive summary:

A two-year study on B6C3F1 mice at doses of 0, 300 and 600 mg/kg/day by gavage reported slight hepatocellular degeneration and slight individual cellular necrosis from 300 mg/kg/day. Nephropathy was seen in both sexes from 300 mg/kg/day.

The LOAEL for non carcinogenic effects was 300 mg/kg/day for both sexes. With respect to carcinogenicity there is

clear evidence of carcinogenicity for male and female B6C3F1 mice (NOAEL 300 mg/kg bw/day; increased incidences of hepatocellular carcinomas and adenomas).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
chronic
Species:
mouse
Quality of whole database:
This long term study meets the criteria of the tonnabe band. The study is very well performed and the applied procedure is equal to the respective guideline, but this is not explicit mentioned in the report. Therfore the study is evaluated with Klimisch score 2

Carcinogenicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: OECD guideline and GLP
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Principles of method if other than guideline:
Two-year inhalation studie at target concentration of 0, 20, 75, 300 ppm in mice.
GLP compliance:
yes
Species:
mouse
Strain:
other: BDF1 mice
Sex:
male/female
Details on test animals and environmental conditions:
no further data
Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
other: clean air
Details on 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 740 l/min
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
by gas chromatograpgy
Duration of treatment / exposure:
104 weeks
Frequency of treatment:
6h/day, 5 days/week
Post exposure period:
no
Remarks:
Doses / Concentrations:
0, 20, 75, 300 ppm
Basis:

No. of animals per sex per dose:
50 male and 50 female animals/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:
for general toxicity see the respective section on repeated dose toxicity
Dose descriptor:
NOAEC
Effect level:
75 ppm (nominal)
Sex:
male/female
Basis for effect level:
other: Under the conditions of this 2 years study, there was clear evidence of carcinogenic activity of p-dichlorobenzene forCrj:BDF1 male and female mice as shown by increased incidence of hepatocellular carcinoma (NOAEC ca. 450 mg/m³)
Remarks on result:
other: Effect type: carcinogenicity (migrated information)

JISHA, 1995: Inhalation study with BDF1 mice, 104 weeks, 6h/day, 5 days/week

              concentration (ml/m³)
   sex 0 20  75  300
 animals surviving 104 weeks  M  39/49  31/49  32/50  30/49
   F  28/50  25/50  23/49  26/50
 neoplastic lesions          
 lung: bronchiolar/alveolar carcinoma4)  F  1/50 (2%)5)  1/50 (2%)  1/49 (2%)  4/50 (8%)
 lymph node: malignant lymphoma  M  4/49 (8%)  7/49 (14%)  13/50 (26%)  8/49 (16%)
   F  21/50 (42%)  21/50 (42%)  18/50 (36%)  23/50 (46%)
 liver: hepatocellular adenoma 6)  M  13/49 (27%)  9/49 (18%)  7/50 (14%)  13/49 (27%)
   F3)  2/50 (4%)  10/50 (20%)  6/49 (12%)  20/50 (40%)**2)
 liver: hepatocellular carcinoma3,7)  M  12/49 (24%)  17/49 (34%)  16/50 (32%)  38/49 (76%9**2)
   F  2/50 (4%)  4/50 (8%)  2/49 (4%)  41/50 (82%)**2)
 liver: hepatocellular carcinoma and adenoma3)  M  20/49 (41%)  21/49 (43%)  18/50 (36%)  41/49 (84%)**2)
   F  4/50 (8%)  13/50 (26%)*1)  7/49 (14%)  45/50 (90%)**2)
 hepatoblastoma like features in carcinomas8)  M  0/12  2/17  1/16  8/38
   F  0/2  0/4  0/2  6/41
 liver: histiocytic sarcoma3,9,10)  0/49 (0%)  3/49 (6%)  1/50 (2%)  6/49 (12%)*1)
 non-neoplastic lesions          
 liver: centrilobular hypertrophy  M  0/49 (0%)   0/49 (0%)   0/50 (0%)  34/49 (68%)**2)
   F  0/50 (0%)   0/50 (0%)   0/49 (0%)  2/50 (4%)

1)* p<0.05 (Fisher´s exact test)

2)**p<0.01 (Fisher´s exact test)

3) p<0.01 (Cochran-Armitage trand test)

4) significant positive trend. p<0.05 (Peto-Test, prevalence method),

5) histological control data of test laboratory for bronchiolar/alveolar carcinoma M: 72/700 (10.3%; 1/50 -11/50=2 -22%),

F: 23/699 (3.3%; 0/50 -4/50=0 -8%)

6) histological control data of test laboratory for hepatocellular adenoma M: 119/700 (17%; 2/50 -15/50=4 -30%),

F: 33/699 (4.7%; 1/50 -5/50=2 -10%)

7) histological control data of test laboratory for hepatocellular carcinoma M: 171/700 (24.4%; 1/50 -19/50=2 -38%),

F: 15/699 (2.1%; 0/50 -2/50=0 -4%)

8) As a subtype of hepatocarcinomas hepatoblastoma like features were observed within a portion of hepatocarcinomas

(no. of animals with hepatoblastoma like features/no. of animals with hepatocarcinomas)

9) significant positive trend, P<0.01 (Peto-Test);

10) histological control data of test laboratory for histiocytic sarcoma M: 22/700 (3.1%; 0/50 -4/50=0 -8%),

F: 8/699 (1.1%; 0/50 -2/50=0 -4%); published historical intralaboratory control data for BDF1 mice, M: 2.8% (0 -12%)

(Katagiri et al., 1998)

Executive summary:

In male mice, a increased incidence of hepatocellular carcinoma was observed (control: 12/49, 20 ppm: 17/49, 75 ppm: 16/50, 300 ppm:38/49). Moreover, a increased incidence of histiocytic sarcoma of the liver in male mice (control: 0/49, 20 ppm: 3/49, 75 ppm:

1/50, 300 ppm: 6/49) was also observed.

In female mice , the increased incidence of hepatocellular carcinoma (control: 2/50, 20 ppm: 4/50, 75 ppm: 2/49, 300 ppm: 41/50) and hepatocellular adenoma (control: 2/50, 20 ppm: 10/50, 75 ppm: 6/49, 300 ppm: 20/50) were observed. Bronchiolar-alveolar carcinoma appeared in female mice (control: 1/50, 20 ppm: 1/50, 75 ppm: 1/49, 300 ppm: 4/50) showed at positive trend. This tumor incidence at the 300 ppm was suited to the upper limit of the histological control data in this institute.

Centrilobular hepatocellular hypertrophy (males at 300 ppm) and increase in mineralization of the testis (males at 75 ppm and 300 ppm) were also observed.

Under the conditions of this 2 years study, there was clear evidence of carcinogenic activity of p-dichlorobenzene forCrj:BDF1 male mice as shown by increased incidence of hepatocellular carcinoma.

There was clear evidence of carcinogenic activity for female Crj:BDF1 mice as shown by increased incidences of hepatocellular adenoma and carcinoma. And, slight increased incidence of bronchiolar-alveolar carcinoma in female mice were also indicated.

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

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Well conducted inhalation and oral 2 year carcinogenicity studies have been performed with 1,4-dichlorobenzene in rats and mice. Additional information can be drawn from an inhalation study with shorter exposure period (76 weeks in rats and 57 weeks in mice). After inhalation exposure no tumor induction became obvious in rats. However, the oral study revealed treatment related tumor formation in the kidney of male rats at the highest tested dose causing nephrotoxicity. In male and female mice hepatocellular tumors were seen in the 2-year oral and inhalation study.

KIDNEY: Renal tumors were found in male rats only after oral exposure to the nephrotoxic dose of 300 mg/kg bw 1,4-dichlorobenzene but not after inhalation of 1,4-dichlorobenzene vapour. The induction of tubular cell adenocarcinomas in the male rat by 1,4-dichlorobenzene can be attributed to the internationally accepted species- and sex-specific mechanisms of alpha2-µ-globulin mediated nephropathy. In the male rat, hyaline droplet accumulation and tubular nephropathy, as is strengthened by 1,4-dichlorobenzene, favours the formation of renal tumors. This mechanism is regarded to be of no relevance for humans.

Additionally, chronic progressive nephropathy (CPN), a spontaneously developing degenerative disease especially in male rats, can contribute to the formation of tumors in male rat kidney (Seely et al. 2002). The increased cell turnover that accompanies CPN could increase the probability for error during DNA replication, decrease the opportunity for DNA repair of such errors, and provide a stimulus for clonal proliferation. Furthermore, mitogenic stimulation of kidney cells by 1,4-dichlorobenzene can promote this process.

1,4-dichlorobenzene was shown to be no tumor initiating agent in rat kidney.

In conclusion, renal tumor formation occurs via sex- and species- specific mechanisms and should be considered as not relevant for humans.

LIVER: Enhanced frequencies of hepatocellular adenomas and carcinomas were observed in BDF1 mice after 1,4-dichlorobenzene inhalation exposure and in B6C3F1 mice after oral exposure. However, the incidences of hepatocellular tumors showed no dose dependency. Survival of 1,4-dichlorobenzene treated mice was comparable to that of controls, and was therefore not influenced by increased tumor formation. Liver tumors were mainly recorded in mice where hepatotoxicity occurred, but not in rats, where the compound was not hepatotoxic. However, although tumor formation in mouse liver mainly occurred in the presence of hepatotoxicity, no clear quantitative correlation could be determined. It has to be considered that 1,4-dichlorobenzene induces cellular proliferation in the livers of mice. Enhanced cell turnover favours tumor formation. Furthermore, hepatocellular tumors are the most frequently occurring neoplasm in untreated B6C3F1 and BDF1 mice.

1,4-dichlorobenzene showed no mutagenic potential in a wide range of internationally accepted and validated test systems, which are primarily relevant for classification. 2,5-DCP, the main metabolite of 1,4-dichlorobenzene, was also shown to exert no mutagenic properties. However, the reasons for reported low DNA binding of 1,4-dichlorobenzene in the mouse and effects in organ specific investigations are not yet elucidated.

These data show that 1,4-dichlorobenzene induced liver tumor formation in the mouse. A clear quantitative correlation between hepatotoxicity and hepatocarcinogenicity could not be determined and the mechanism of tumor formation is not yet known. Additionally, some other tumor incidences were enhanced, however not in a dose dependent manner.

Summary of p-DCB related tumor formation in 2 -year inhalation and gavage carcinogenicity studies in rats and mice:

              concentration (ml/m³) or dose (mg/kg bw and day)
 F344 rats-gavage (NTP 1987)  sex  0 (mg/kg)  150 (mg/kg)  300 (mg/kg) 600 (mg/kg) 
 kidney: tubular cell adenocarcinoma3)  M  1/50 (2%)  3/50 (6%)  7/50 (14%)*1)  
 BDF1 mice - inhalation (Jisha 1995)    0 (ml/m³)  20  (ml/m³)  75  (ml/m³)  300  (ml/m³)
 liver: hepatocellular adenoma5)  M  13/49 (27%)  9/49 (18%)  7/50 (14%)  13/49 (27%)
   F4)  2/50 (4%)  10/50 (20%)*1)  6/49) (12%)  20/50 (40%)**2)
 liver: hepatocellular carcinoma4,6)  M  12/49 (24%)  17/49 (34%)  16/50 (32%)  38/49 (76%)**2)
   F  2/50 (4%)  4/50 (8%)  2/49 (4%)  41/50 (82%)**2)
 liver: hepatocellular carcinoma and adenoma4 )  M  20/49 (41%)  21/49 (43%)  18/50 (36%)  41/49 (84%)**2)
   F  4/59 (8%)  13/50 (26%)*1)  7/49 (14%)  45/50 (90%)**2)
 B6C3F1 mice - gavage    0 (mg/kg)  150  (mg/kg)  300  (mg/kg)  600  (mg/kg)
 liver: hepatocellular adenoma4,7)  M  5/50 (10%)  --  13/49 (27%)*2)  16/50 (32%)*2)
   F  10/50 (20%)    6/48 (13%)  21/50 (42%)*2)
 liver: hepatocellular carcinoma4,8)  M  14/50 (28%)  --  11/49 (22%)  32/50 (64%)**1)
   F  5/50 (19%)    5/48 (10%)  19/50 (38%)**1)
 liver: hepatocellular adenoma and carcinoma4,9)  M  17/50 (34%)  --  22/49 (45%)  40/50 (80%)**1)
   F  15/50 (39%)    10/48 (21%)  36/50 (72%)**1)

1)* p<0.05 (Fisher´s exact test)

2)**p<0.01 (Fisher´s exact test)

3) p<0.05 (Cochran-Armitage trend test), historical control incidences in NTP studies for renal tubular cell adenocarcinoma in

F344 rats, M: 0,4%

4) p<0.01 (cochran-Armitage trend test)

5) historical control data of test laboratory for hepatocellular adenoma in BDF1 mice, M: 119/700 (17%, 2/50-15/50=4 -30%),F:

33/699 (4.7%; 1/50 -5/50=2 -10%)

6) historical control data of test laboratory for hepatocellular carcinoma in BDF1 mice, M: 171/700 (24.4%; 1/50 -19/50=2 -38%),

F: 15/699 (2.1%; 0/50 -2/50=0 - 4%)

7) historical control data of test laboratory for hepatocellular adenoma in B6C3F1 mice, M: 20/150 (13%+/-3%)

F: 5/148 (3,4%+/-1,2%); histological incidences in NTP studies, M: 0 -14/50= 0-28%; F: 0 -5/50=0 -10%

8) historical control data of test laboratory for hepatocellular carcinoma in B6C3F1 mice, M: 35/150 (23,3%+/-5%),

F: 6/148 (4,1 +/-2%); historical incidences in NTP studies, M: 5 -19/50= 10 -38%; F: 0 -4/50= 0 -8%

9) historical control data of test laboratory for hepatocellular adenoma and carcinoma in B6C3F1 mice, M: 50/150(33%+/-4%);

F: 10/148 (7%+/-2%); historical incidences in NTP studies, M: 7 -25/50= 14 -50%; F: 0 -5/50= 0 -10%

Conclusion:

The carcinogenic potential of 1,4-dichlorobenzene for the liver has been clearly demonstrated in

B6C3F1 and BDF1 mice from 600 mg/kg/day and from 300 ppm, with 3 types of tumors:

hepatocarcinomas, hepatoblastomas and histiocytosarcomas; the two previous one being very

rare tumours in mice. The kidney tumors in male rats have no relevance to humans because the underlying mechanism is male rat specific hyaline droplet nephropathy, which cannot be extrapolated to human.

A NOAEL for carcinogenic liver effects of 300 mg/kg/day via oral route in B6C3F1 mice and a

NOAEC of 75 ppm via inhalation route in BDF1 mice can be determinated and for kidney

adenocarcinoma a LOAEL of 150 mg/kg/day via oral route in F344 rats.

Based on the information on genotoxicity as well as mechanistic considerations (mitogenic mode of action) it is assumed that the tumor response in the mouse is due to a non-genotoxic mechanism. This is confirmed by the EU Risk Assessment that stated “Although a clear mechanism for the mouse carcinogenicity has not been demonstrated, the threshold mechanism for 1,4-dichlorobenzene is proposed…” (EU Risk Assessment 2004).


Justification for selection of carcinogenicity via oral route endpoint:
The study is very well performed and the applied procedure is equal to the respective guideline., but this is not explicit mentioned in the report. Therfore the study is evaluated with Klimisch score 2

Justification for selection of carcinogenicity via inhalation route endpoint:
This study is performed according to OECD TG 453 and under GLP conditions and therefore evaluated with Klimisch score 1

Carcinogenicity: via inhalation route (target organ): digestive: liver

Justification for classification or non-classification

According to EU Annex1 the substance is classified in Carcinogenicity Category 3; R40; Limited evidence of a carcinogenic effect. According to GHS (EU Regulation 1272/2008 of 16 December 2008) the substance is classified as Carcinogenic 2, H351.