Registration Dossier

Administrative data

Description of key information

No valid studies are available for inhalation and dermal repeated dose toxicity.

For oral toxicity, we used a NOAEL of 60 mg/kg/day derived in an oral sub-chronic toxicity study as a starting point for DNEL calculation; since the NOAEL in the chronic studies are equal or higher than the NOAEL for sub-chronic toxicity studies the starting point for DNEL calculation should be considered conservative. The same overall oral NOAEL of 60 mg/kg bw/day was also reported in the OECD SIDS Report on 1,2-dichlorobenzene (2001).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Comparable to guideline study with acceptable restrictions (food consumption not recorded; some serum parameters (sodium, urea, creatinine) not analysed; some organs (testes, epididymes) not weighted; some organs/tissues (spinal cord, aorta, peripheral nerves) not histopatholically examined)
Reason / purpose for cross-reference:
reference to other study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:
yes
Remarks:
; food consumption not recorded; some serum parameters (sodium, urea, creatinine) not analysed; some organs (testes, epididymes) not weighted; some organs/tissues (spinal cord, aorta, peripheral nerves) not histopatholically examined
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Portage, MI
- Age at study initiation: 4 week old plus 17 days of acclimation period
- Housing: five animals/polycarbonate cage
- Diet (e.g. ad libitum): Purina Lab Chow 3/79 to 10/79; Zeigler Bros. N1N07 10/79 to 3/81 (ad libitum)
- Water (e.g. ad libitum): Edstrom automatic watering system, Waterford, WI (ad libitum)
- Acclimation period: 17 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23°C
- Humidity (%): 40-60%
- Air changes (per hr): 15 room air changes/hour
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
Amount of dosage (if gavage): 5 mL/kg bw
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
13 w
Frequency of treatment:
5 d/w
Remarks:
Doses / Concentrations:
30, 60, 125, 250 or 500 mg/kg bw/d
Basis:
actual ingested
No. of animals per sex per dose:
10 animals/sex/dose
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: no
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: observed twice daily for clinical signs of toxicity

BODY WEIGHT: Yes
- Time schedule for examinations: individual weights measured weekly

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
- food consumption measured weekly

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes, blood withdrawn from orbital venous plexus
- Time schedule for collection of blood: one day before death
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: all animals
- Following parameters were examined: hematological profile (hemoglobin, RBC, WBC, hematocrit, MCV, platelet count, and reticulocyte count)


CLINICAL CHEMISTRY: Yes, blood samples were withdrawn by cardiac puncture after animals were anesthetized with sodium pentobarbital
- Time schedule for collection of blood: on the day of sacrifice
- Animals fasted: No data
- How many animals: all animals
- Following parameters were examined: alkaline phosphatase, serum glutamic pyruvic transaminase, gamma-glutamyltranspeptidase, bilirubin, cholesterol, triglycerides, blood urea nitrogen, glucose, total protein, and total globulin fractions


URINALYSIS: Yes
- Time schedule for collection of urine: one week before sacrifice; only animals of the control and the 500 mg/kg dose group
- Metabolism cages used for collection of urine: Yes (collection time 24h)
- Animals fasted: No data
- Following parameters were examined: uroporphyrins and coproporphyrins


NEUROBEHAVIOURAL EXAMINATION: No


OTHER:
- Total liver porphyrins from all animals
- Organ to body weight ratios:
Following organs weighed from all animals at necropsy: Lung, heart, liver, spleen, thymus, right kidney, brain, right testicle or right ovary, and uterus
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, on all animals not completely autolyzed or cannibalized.

HISTOPATHOLOGY: Yes.
- The following specimens were examined histologically for control and high dose groups: gross lesions, tissue masses, abnormal lymph nodes, skin, thigh muscle, mandibular or mesenteric lymph nodes, mammary gland, salivary gland, bone marrow, sternebrae, femur, or vertebrae, thymus, trachea, lungs 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.
- Additional histopathologic examinations were limited to the kidneys, thymus, and liver for rats administered 125 or 250 mg/kg.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food efficiency:
not specified
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
effects observed, treatment-related
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY
Two female rats receiving 500 mg/kg of 1,2-dichlorobenzene died, one at week 6 and one at week 9. One male each from the control, 30 mg/kg, and 125 mg/kg groups also died, presumably because of a gavage error (Table 1).

BODY WEIGHT AND WEIGHT GAIN
A dose-related decrease in weight gain was observed in male rats; however, except for the 500 mg/kg male rats, final body weights were within 7% of controls (refer to Table 1).

HAEMATOLOGY
Only minimal changes were observed in hematology. Minimal decreases in the hematocrit, the amount of hemoglobin, the number of red blood cells (significant only in males), and mean corpuscular volume were observed in male and female rats at the 500 mg/kg dose (Tables 3 and 4). The number of reticulocytes was increased slightly in high dose females. A minimal decrease in the number of lymphocytes and a small increase in the percentage of segmented neutrophils were observed in high dose males. These hematologic changes presumably reflect toxicity at the high dose. The number of platelets was increased at 60, 125, and 500 mg/kg in female but not in male rats. The reason for the increase in platelets is not apparent. This change is not considered to be biologically significant. 1,2-Dichlorobenzene did not affect the number of white cells, eosinophils, basophils, or monocytes.

CLINICAL CHEMISTRY
Only minimal changes were observed in clinical chemistry parameters. 1,2-Dichlorobenzene did not produce statistically significant increases in serum concentrations of SGPT (serum glutamic pyruvic transaminase), GGTP (gamma-glutamyl transpeptidase) or alkaline phosphatase (Tables 5 and 6). However, 1,2-dichlorobenzene produced slight dose-related increases in serum cholesterol at doses of 30, 125, 250, and 500 mg/kg (males) and 125-500 mg/kg (females), decreases in serum triglycerides at 500 mg/kg (males) and 250 mg/kg (females), and dose-related increases in total serum protein at 250-500 mg/kg (males) and at 30-500 mg/kg (females). All of these changes were relatively small; however, they may reflect hepatic effects of the test substance at these doses. Minimal increases in serum glucose levels in female rats were observed at 30 mg/kg and 125 to 500 mg/kg. Blood urea nitrogen was not affected in male or female rats receiving 500 mg/kg of 1,2-dichlorobenzene (Tables 5 and 6). However, 24-hour urine volume was increased 57% over controls in male rats receiving 500 mg/kg of 1,2-dichlorobenzene (Table 7).

ORGAN WEIGHTS
1,2-Dichlorobenzene increased liver weights in male and female rats in a dose-related manner (Table 2). Significant increases in liver weight/ body weight ratios were observed at the 125, 250, and 500 mg/kg doses in males and females. Decreases in the absolute organ weight and the organ weight/ body weight ratio for thymus in male rats at the 500 mg/kg dose may reflect general toxicity or organ-specific toxicity. However, slight increases in organ weight/ body weight ratios for lungs, kidney, and brain in male rats receiving 500 mg/kg without a corresponding effect on organ weight probably reflect the effect of the test substance on body weight.

GROSS PATHOLOGY
At necropsy, no consistent lesions were noted. The liver and kidneys from all rats (except for a few that died early in the study) were examined under long-range ultraviolet light. None had the positive reddish-brown pigmentation indicative of porphyria.

HISTOPATHOLOGY: NON-NEOPLASTIC
Microscopically, a number of lesions that appeared to be compound or dose related were observed. The two 500 mg/kg dose rats that died early had a moderate degree of centrolobular hepatocellular necrosis. Most of the surviving high dose rats (7/8 surviving females and 8/10 males) had liver lesions, either centrolobular degeneration or necrosis of individual hepatocytes. The necrosis of individual hepatocytes was characterized by randomly scattered hepatocytes that were pyknotic or karyolytic and had shrunken dark red cytoplasms. In addition, renal tubular degeneration was found in 6/10 high dose male rats and thymic lymphoid depletion was found in 4/10 high dose male rats.
The renal and thymic lesions were not present at the 250 mg/kg or 125 mg/kg doses. The individual hepatocellular necrosis persisted at the 250 mg/kg dose (4/9 males and 5/10 females). Individual hepatocellular necrosis was seen in one female rat at the 125 mg/kg dose. In addition, some focal hepatic necrosis was observed in one male rat at the 125 mg/kg dose that died early due to a ruptured esophagus and in two female rats at the 125 mg/kg dose; this was less pronounced than that observed at higher doses.
Yellow-green to gold pigment was observed in some of the livers at the 250 and 500 mg/kg doses. This pigment was periodic acid-Schiff (PAS) and Pens positive and was believed to be hemosiderin. Because the liver lesions found in rats receiving 250 mg/kg were considered to be potentially life-shortening by the original pathologist, doses of 60 and 120 mg/kg of 1,2-dichlorobenzene in corn oil were selected for rats in the 2-year study.

URINALYSIS
The urinary concentration of uroporphyrin and coproporphyrin was three to five times higher in male and female rats receiving 500 mg/kg of 1,2-dichlorobenzene than in controls (Table 7). However, this increase is not considered to be indicative of porphyria. The concentration of total porphyrins in the liver was not altered by 1,2-dichlorobenzene at any dose level (Table 7).
Key result
Dose descriptor:
NOAEL
Effect level:
60 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: no adverse effects observed
Key result
Dose descriptor:
LOAEL
Effect level:
125 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: minimal hepatocellular necrosis
Critical effects observed:
yes
Lowest effective dose / conc.:
125 mg/kg bw/day (nominal)
System:
hepatobiliary
Organ:
liver
Treatment related:
yes
Dose response relationship:
yes

Table 1: Survival and mean body weights of male rats administered 1,2-dichlorobenzene by gavage for 13 weeks

           Mean Body Weights [g]  
  Dose [mg/kg]  Survival *  Initial  Final  Change **   Final Body Weights Relative to Controls [%] ***
 0  9/10 93.3 ± 4.4  293.1 ± 7.8 +199.8 ± 4.9 -- 
 30  9/10 104.1 ± 2.9 305.4 ± 3.6 +201.3 ± 3.9  + 4
60  10/10  97.7 ± 5.9  292.9 ± 6.3  +195.2 ± 6.1  0
125  9/10  99.7 ± 3.4 281.4 ± 5.9  +181.7 ± 5.0  - 4
 250  9/9 ****  98.9 ± 4.9 275.8 ± 8.3  +176.9 ± 7.2  - 6
 500  10/10  101.8 ± 5.4 236.1 ± 12.1 +134.3 ± 11.4  - 19

* : Number surviving / number initially in the group

** : Mean weight change of the survivors of the group

*** : Weight of the dosed group relative to that of the controls

**** : One animal in this group was missexed.

Table 2: Organ weights of rats administered 1,2-dichlorobenzene by gavage for 13 weeks (a)

     Male                    Female      
Dose [mg/kg]    Body weight [g]  Lung  Liver  Thymus  Right kidney   Brain Body weight [g]   Liver

0   

               
   Mean [g]   274 ± 22 1.34 ± 0.18   8.75 ± 1.15  0.29 ± 0.09 0.97 ± 0.09  1.78 ± 0.08  169 ± 13   4.87 ± 0.24
 OW/BW (b)  -- 0.49 ± 0.07  3.18 ± 0.20   0.11 ± 0.03 0.35 ± 0.01   0.65 ± 0.05 --   2.90 ± 0.20

30   

               
   Mean [g]  275 ± 2  1.44 ± 0.17 9.00 ± 0.63  0.27 ± 0.07 0.94 ± 0.07  1.77 ± 0.07  166 ± 13   4.95 ± 0.53
   OW/BW  --  0.52 ± 0.06 3.28 ± 0.22  0.10 ± 0.02  0.34 ± 0.02   0.64 ± 0.02 --  2.98 ± 0.15 

 60   

               
     Mean [g] 269 ± 17  1.46 ± 0.20   8.34 ± 0.73  0.28 ± 0.06  0.95 ± 0.10  1.80 ± 0.06  166 ± 16  4.84 ± 0.44
     OW/BW  -- 0.54 ± 0.08   3.10 ± 0.15  0.10 ± 0.02  0.35 ± 0.03  0.67 ± 0.04  --  2.92 ± 0.16

 125   

               
     Mean [g] 261 ± 15  1.32 ± 0.14  8.98 ± 0.95  0.25 ± 0.02  1.02 ± 0.15  1.82 ± 0.07  164 ± 10  5.13 ± 0.53
     OW/BW --  0.51 ± 0.07   3.43 ± 0.22 (c)  0.10 ± 0.01  0.39 ± 0.06  0.70 ± 0.05  --  3.13 ± 0.20 (c)

 250   

               
     Mean [g] 258 ± 25  1.36 ± 0.15   9.62 ± 1.28  0.23 ± 0.08  0.95 ± 0.06  1.77 ± 0.09  160 ± 13  5.33 ± 0.51
     OW/BW --  0.53 ± 0.05   3.72 ± 0.29 (c) 0.09 ± 0.04   0.37 ± 0.03  0.69 ± 0.05  --  3.33 ± 0.18 (c)

 500   

               
     Mean [g] 224 ± 27 (c,e)  1.46 ± 0.69   10.27 ± 1.04 (c,d) 0.17 ± 0.11 (c,e)   0.91 ± 0.10  1.73 ± 0.08 165 ± 14   6.03 ± 0.54 (c,d)
     OW/BW  -- 0.66 ± 0.34 (c,d)   4.61 ± 0.47 (c,d)  0.07 ± 0.05 (c,e)  0.40 ± 0.02 (c,d)  0.78 ± 0.07 (c,d)  --  3.78 ± 0.30 (c,d)

(a) : Groups contained 9 or 10 animals

(b) : Organ weight / body weight * 100; [%]

(c) : Dosed group significantly different from controls; P<0.05

(d) : Positive dose-response trend; P<0.05

(e) : Negative dose-response trend; P<0.05

Table 3: Results of blood analysis in male rats administered 1,2-dichlorobenzene by gavage for 13 weeks (a)

       Dose [mg(kg]           
   0  30  60  125  250  500
 Hemoglobin [g/L]  16.5 ± 0.9 16.9 ± 0.6   16.8 ± 0.9 16.6 ± 0.5  16.5 ± 1.1  15.0 ± 0.5 (b,c)
 Hematocrit [%]  51 ± 3  53 ± 1  52 ± 1  49 ± 2  50 ± 3 46 ± 1 (b,c) 
 Red  blood cells [106 cu mm] 9.42 ± 0.53   9.70 ± 0.32  9.49 ± 0.48  9.46 ± 0.30  9.54 ± 0.63  8.57 ± 0.25 (b,c)
Mean corpuscular volume [µ3]  52 ± 1  53 ± 1  52 ± 1  50 ± 1 (b)  50 ± 1 (b)  51 ± 1 (c)
 Segs [%] 15 ± 4   19 ± 7  15 ± 3  16 ± 6  11 ± 4  22 ± 7 (b)
 Lymphocytes [%] 84 ± 4    80 ± 8  83 ± 4  83 ± 7  88 ± 5  78 ± 7 (b)

(a) : Groups contained 9 or 10 animals. Values presented represent the mean ± standard deviation.

(b) : Dosed group significantly different from controls; P<0.05

(c) : Negative dose-response trend; P<0.05

Table 4: Results of blood analysis in female rats administered 1,2-dichlorobenzene by gavage for 13 weeks (a)

       Dose [mg/kg]           
   0  30  60  125  250  500
 Mean corpuscular volume  [µ3] 54 ± 2   54 ± 1  53 ± 1  54 ± 1  53 ± 0.4 (b)  53 ± 1 (b,d)
 Platelets x 105 2.96 ± 0.39   4.09 ± 1.32  4.81 ± 0.63 (b)  5.85 ± 2.32 (b)  3.66 ± 0.63  5.24 ± 0.76 (b,c)
 Reticulocytes [%] 5.7 ± 2.2   4.7 ± 1.2  5.4 ± 0.7  5.8 ± 1.0  6.2 ± 1.2  8.2 ± 0.9 (b,c)

(a) : Groups contained 7 to 10 animals. Values presented represent the mean ± standard deviation.

(b) : Dosed group significantly different from controls; P<0.05

(c) : Positive dose-response trend; P<0.05

(d) : Negative dose-response trend; P<0.05

Table 5: Results of clinical chemistry in male rats administered 1,2-dichlorobenzene by gavage for 13 weeks (a)

       Dose [mg/kg]           
   0  30  60  125  250  500
 Cholesterol [mg/dL] 34 ± 4   51 ± 9 (b)  40 ± 7  43 ± 5 (b)  58 ± 6 (b)  71 ± 8 (b,c)
 Triglycerides [mg/dL]  242 ± 28  285 ± 50  264 ± 60  228 ± 56  236 ± 70  142 ± 75 (b,d)
 Total protein [g/dL]  7.0 ± 0.2  6.9 ± 0.4  7.1 ± 0.4  7.0 ± 0.2  7.5 ± 0.5 (b)  7.5 ± 0.3 (b,c)

(a) : Groups contained 9 or 10 animals. Values presented represent the mean ± standard deviation.

(b) : Dosed group significantly different from controls; P<0.05

(c) : Positive dose-response trend; P<0.05

(d) : Negative dose-response trend; P<0.05

Table 6: Results of clinical chemistry in female rats administered 1,2-dichlorobenzene by gavage for 13 weeks (a)

       Dose [mg/kg]          
   0  30  60  125  250  500
 Cholesterol [mg/dL]  49 ± 4  55 ± 7  55 ± 6  65 ± 4 (b)  62 ± 7 (b)  74 ± 7 (b,c)
Triglycerides [mg/dL]   180 ± 30  145 ± 33  172 ± 43  167 ± 32  141 ± 36 (b)  167 ± 17
 Glucose [mg/dL] 176 ± 16   204 ± 12 (b)  195 ± 15  212 ± 16 (b)  206 ± 21 (b)   209 ± 17 (b,c)
 Total protein [g/dL]  6.4 ± 0.3  6.9 ± 0.1 (b)  6.7 ± 0.2 (b)  6.8 ± 0.2 (b)  6.8 ± 0.3 (b)  7.5 ± 0.3 (b,c)

(a) : Groups contained 9 or 10 animals. Values presented represent the mean ± standard deviation.

(b) : Dosed group significantly different from controls; P<0.05

(c) : Positive dose-response trend; P<0.05

Table 7: Results of porphyrin analyses of urine in rats administered 1,2-dichlorobenzene by gavage for 13 weeks (a)

 Dose [mg/kg]   Coproporphyrin [µg/24 hours]   Uroporphyrin [mg/24 hours]   Volume [mL]
  Males      
 0 0.51 ± 0.23   1.38 ± 0.42  5.6 ± 1.8
 500  4.99 ± 2.54 (b)  5.85 ± 2.78 (b)  8.8 ± 2.8 (b)
 Females            
 0  0.46 ± 0.34  0.59 ± 0.14  3.1 ± 1.7
 500  2.53 ± 1.16 (b)  2.02 ± 0.88 (b)  5.3 ± 3.8

(a) : Groups contained 6 or 10 animals. Values presented represent the mean ± standard deviation.

(b) : Dosed group significantly different from controls; P<0.05

Conclusions:
Only minimal hepatocellular necrosis was observed at 125 mg/kg/day in a few rats. Therefore the NOAEL is 60 mg/kg/day.
Executive summary:

NTP report, 1985

A repeated dose toxicity study was conducted according to OECD Guideline 408. For 90 days, 1,2-dichlorobenzene was adminsitered to rats by gavage. The study was considered as reliable with restrictions (food consumption not recorded; some serum parameters not analysed; some organs not weighted; some organs/tissues not histopatholically examined).

For 13 weeks, male and female F344/N rats were dosed 5 days per week with 30, 60, 125, 250 or 500 mg/kg bw/day. According to guideline, 10 animals/sex/dose were used.

Two female rats receiving 500 mg/kg of 1,2-dichlorobenzene died, one at week 6 and one at week 9. One male each from the control, 30 mg/kg, and 125 mg/kg groups also died, presumably because of a gavage error. A dose-related decrease in weight gain was observed in male rats; however, except for the 500 mg/kg male rats, final body weights were within 7% of controls.

Only minimal changes were observed in hematology. Minimal decreases in the hematocrit, the amount of hemoglobin, the number of red blood cells (significant only in males), and mean corpuscular volume were observed in male and female rats at the 500 mg/kg dose. The number of reticulocytes was increased slightly in high dose females. A minimal decrease in the number of lymphocytes and a small increase in the percentage of segmented neutrophils were observed in high dose males. These hematologic changes presumably reflect toxicity at the high dose.

Only minimal changes were observed in clinical chemistry parameters. 1,2-Dichlorobenzene produced slight dose-related increases in serum cholesterol at doses of 30, 125, 250, and 500 mg/kg (males) and 125-500 mg/kg (females), decreases in serum triglycerides at 500 mg/kg (males) and 250 mg/kg (females), and dose-related increases in total serum protein at 250-500 mg/kg (males) and at 30-500 mg/kg (females). All of these changes were relatively small; however, they may reflect hepatic effects of the test substance at these doses. Minimal increases in serum glucose levels in female rats were observed at 30 mg/kg and 125 to 500 mg/kg.

Blood urea nitrogen was not affected, however, 24-hour urine volume was increased 57% over controls in male rats receiving the highest dose. The urinary concentration of uroporphyrin and coproporphyrin was three to five times higher in male and female rats receiving 500 mg/kg of 1,2-dichlorobenzene than in controls. However, this increase is not considered to be indicative of porphyria.

1,2-Dichlorobenzene increased liver weights in male and female rats in a dose-related manner. Significant increases in liver weight/ body weight ratios were observed at the 125, 250, and 500 mg/kg doses in males and females. Decreases in the absolute organ weight and the organ weight/ body weight ratio for thymus in male rats at the 500 mg/kg dose may reflect general toxicity or organ-specific toxicity.

At necropsy, no consistent lesions were noted. Microscopically, a number of lesions that appeared to be compound or dose related were observed. The two 500 mg/kg dose rats that died early had a moderate degree of centrolobular hepatocellular necrosis. Most of the surviving high dose rats had liver lesions, either centrolobular degeneration or necrosis of individual hepatocytes. In addition, renal tubular degeneration and thymic lymphoid depletion was found in high dose male rats. Individual hepatocellular necrosis was seen in one female rat at the 125 mg/kg dose. In addition, some focal hepatic necrosis was observed in one male rat at the 125 mg/kg dose that died early due to a ruptured esophagus and in two female rats at the 125 mg/kg dose; this was less pronounced than that observed at higher doses. Yellow-green to gold pigment was observed in some of the livers at the 250 and 500 mg/kg doses. This pigment was periodic acid-Schiff (PAS) and Pens positive and was believed to be hemosiderin. Liver lesions found in rats receiving 250 mg/kg were considered to be potentially life-shortening.

Because only minimal hepatocellular necrosis was observed at 125 mg/kg/day in a few rats. Therefore a NOAEL of 60 mg/kg/day is justified.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
60 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
We used an NOAEL of 60 mg/kg/day derived in a sub-chronic toxicity study as a starting point for DNEL calculation; since the NOAEL in the chronic studies are equal or higher than the NOAEL for sub-chronic toxicity studies the starting point for DNEL calculation should be considered conservative. The same overall oral NOAEL of 60 mg/kg bw/day was also reported in the OECD SIDS Report on 1,2-dichlorobenzene (2001).

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

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

In a 14-day study of rats (strain F344), 1,2-dichlorobenzene was administered orally at 0, 60, 125, 250, 500 or 1000 mg/kg bw. The highest dose resulted in 100% mortality by day 5 while 500 mg/kg bw resulted in reduced body weight gain (-12%). The toxicity of 1,2-dichlorobenzene was also examined during a 13-week study of male and female rats (F344) administered 1,2-dichlorobenzene (0, 30, 60, 125, 250 or 500 mg/kg bw) 5 days/week by gavage. Only minimal hepatocellular necrosis was observed at 125 mg/kg/day in a few rats. However, no evidence of treatment-related liver pathology in rats given 60 or 120 mg/kg/day in the 2-year NTP carcinogenicity bioassay and no increase in serum enzymes (SGPT, GGPT, alkaline phosphatase) for rats in the 13-week study justify 60 mg/kg/day as a NOAEL in the subchronic segment of this NTP study. Another 90-day toxicity study was conducted in Sprague-Dawley rats at doses of 25, 100 and 400 mg/kg/day in corn oil by gavage. This study identified a LOAEL of 100 mg/kg/day for changes in body and organ weight as well as pathological changes to the liver. An NOAEL of 25 mg/kg/day was therefore identified from this study, considering that only kidney weights in females were statistically significantly increased but with no consistent effects in histopathology, urinalysis or BUN. Despite the relative closeness of the doses in the subchronic and chronic studies (see section 5.8), the only adverse effect found in the chronic exposure study in rats was a slightly reduced body weight gain in high-dose males. The failure of 1,2-dichlorobenzene to elicit toxic responses in the chronic study indicates at the most a slight potential for progressive toxicity with continued 1,2-dichlorobenzene administration beyond 13 weeks. Therefore, the overall NOAEL of 60 mg/kg bw can be regarded as a chronic NOAEL with no further need for an assessment factor for duration extrapolation. In a two-year study, mice (strain B6C3F1) were administered 1,2-dichlorobenzene (0, 60 or 120 mg/kg bw) for 5 days/week. The NOAEL for female mice was 120 mg/kg bw (no treatment-related pathologies observed), and the NOAEL for male mice was 60 mg/kg bw (at 120 mg/kg bw; increased renal tubular regeneration). Based on the ECHA guidance route-to-route extrapolation from the oral animal data to the dermal and inhalation human risk assessment is appropriate for systemic toxicity. First-pass effects have to be not taken into account for 1,2-dichlorbenzene because the liver is the primary target organ and the liver is exposed to a compound independent of the route and independent of a potential first-pass metabolism. After oral intake the liver is directly exposed as first organ after absorption without dilution, whereas after dermal exposure or inhalation the liver is reached via systemic circulation after dilution. Therefore for liver toxicity oral intake is a worst case scenario (independent of a first pass metabolism) and for the target organ, liver (weight and histopathology), first-pass has not to be taken into account (see also waiving repeated-dose toxicity inhalation).

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
We used an NOAEL of 60 mg/kg/day derived in a sub-chronic toxicity study as a starting point for DNEL calculation; since the NOAEL in the chronic studies are equal or higher than the NOAEL for sub-chronic toxicity studies the starting point for DNEL calculation should be considered conservative. The same overall oral NOAEL of 60 mg/kg bw/day was also reported in the OECD SIDS Report on 1,2-dichlorobenzene (2001).

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver; urogenital: kidneys

Justification for classification or non-classification

Several repeated dose studies with a duration from 14 days to 2 years were conducted. Only slight effects on weights of livers and kidneys were found with no consistent effects in histopathology. The only adverse effect found in the chronic exposure study in rats was a slightly reduced body weight gain in high-dose males.

According to CLP classification criteria (Regulation (EC) No 1272/2008) a classification is not justified.