1,2-dichlorobenzene

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.2 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

12.5

Modified dose descriptor starting point:

NOAEC

Value:

52 mg/m³

Explanation for the modification of the dose descriptor starting point:

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 for more details.

AF for dose response relationship:

1

Justification:

Default factor;

AF for differences in duration of exposure:

1

Justification:

Several oral studies of rats and mice ranging from 10 days to 2 years duration indicate that the adverse effects include increases in liver and kidney weights and hepatotoxicity. From these repeat dose studies, the NOAEL for non-neoplastic effects was 60 mg/kg bw (cited from OECD SIDS for 1,2-dichlorobenzene). The NOAEL is independent from the duration of the studies – therefore an AF = 1 is justified.

AF for interspecies differences (allometric scaling):

1

Justification:

Default factor

AF for other interspecies differences:

2.5

Justification:

Default factor

AF for intraspecies differences:

5

Justification:

Default factor

AF for the quality of the whole database:

1

Justification:

Default factor

AF for remaining uncertainties:

1

Justification:

Default factor

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

21 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

Explanation for the modification of the dose descriptor starting point:

See long-term systemic DNEL derivation; 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 for more details.

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.2 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Modified dose descriptor starting point:

NOAEL

Value:

60 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

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 for more details.

AF for dose response relationship:

1

Justification:

Default factor

AF for differences in duration of exposure:

1

Justification:

Several oral studies of rats and mice ranging from 10 days to 2 years duration indicate that the adverse effects include increases in liver and kidney weights and hepatotoxicity. From these repeat dose studies, the NOAEL for non-neoplastic effects was 60 mg/kg bw (cited from OECD SIDS for 1,2-dichlorobenzene). The NOAEL is independent from the duration of the studies – therefore an AF = 1 is justified.

AF for interspecies differences (allometric scaling):

4

Justification:

Default factor

AF for other interspecies differences:

2.5

Justification:

Default factor

AF for intraspecies differences:

5

Justification:

Default factor

AF for the quality of the whole database:

1

Justification:

Default factor

AF for remaining uncertainties:

1

Justification:

Default factor

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

6 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

Explanation for the modification of the dose descriptor starting point:

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 for more details.

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

Systemic toxicity:

A subchronic gavage study in rats is available for 1,2-dichloro-benzene. Decreased survival time for female rats at 500 mg/kg bw was observed with pathological findings of hepatic centrilobular necrosis and hepatocellular degeneration, depletion of lymphocytes in the thymus and spleen. High-dose male rats showed renal tubular degeneration. A dose of 250 mg/kg bw induced necrosis of individual hepatocytes in both sexes of rats. A dose of 125 mg/kg bw displayed in rats minimal hepatocellular necrosis. Haematological changes were observed at 500 mg/kg bw in rats, which included a slight decrease in haematocrit and haemoglobin, and in the erythrocyte count for male rats. The NOAEL = 60 mg/kg bw (male + female rats) is derived in this study.

Taking into account ECHA default for respiratory volume of rats (0.38 m3/kg), Respiratory volume light activity for worker (10/6.7) and 2 times higher absorption after inhalation exposure compared to oral exposure the corrected inhalatory NOAEC is 52 mg/m3.

Default assessment factors are applied for intra- and inter-species variability and an assessment factor of 1 was applied for time extrapolation. Several oral studies of rats and mice ranging from 10 days to 2 years duration indicate that the adverse effects include increases in liver and kidney weights and hepatotoxicity. From these repeat dose studies, the NOAEL for non-neoplastic effects was 60 mg/kg bw (cited from OECD SIDS for 1,2-dichlorobenzene). The NOAEL is independent from the duration of the studies – therefore an AF = 1 is justified.

Reproductive Toxicity. In an unreliable inhalation 2-generation reproduction study in rats, no fertility effects were observed and reduced pup weight during lactation occurred at doses toxic to adults. The NOAEC and LOAEC (kidney and liver effects) for adult rats were 50 (0.3 mg/L) and 150 ppm (0.6 mg/L) respectively, and for reproductive toxicity and offspring growth and development were 150 ppm (0.6 mg/L) and 400 ppm (2.4 mg/L) respectively.

In developmental studies in rats and rabbits, developmental effects were only seen in rats at maternally toxic doses (400 ppm, 2.4 mg/L). As the NOAEC for reproductive toxicity (50 ppm = 0.3 mg/L = 300 mg/m³ for fertility) and the NOAEC of 400 ppm (2.4 mg/L = 2400 mg/³) for developmental toxicity are higher than the NOAEC for repeated dose toxicity (105.7 mg/m³) that is used as a starting point for the DNEL derivation for the DNEL longterm systemic, the derivation of a separate DNEL for reproductive toxicity (fertility and or developmental toxicity) is not necessary, because the DNEL for repeated dose toxicity covers both endpoints.

Local toxicity:

According to the harmonised classification - Annex VI of Regulation (EC) No 1272/2008 (CLP Regulation), 1,2-dichlorobenzene is classified as H315, H319, and H335. 1,2-dichlorobenzene is allocated to the moderate hazard band based on the irritation properties.

In a LLNA , 1,2-dichlorobenzene was a weak dermal sensitizer. Therefore a classification as GHS: Skin Sens. 1B (H317: May cause an allergic skin reaction) is justified.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Modified dose descriptor starting point:

NOAEC

Value:

26 mg/m³

Explanation for the modification of the dose descriptor starting point:

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 for more details.

AF for dose response relationship:

1

Justification:

Default factor

AF for differences in duration of exposure:

1

Justification:

Several oral studies of rats and mice ranging from 10 days to 2 years duration indicate that the adverse effects include increases in liver and kidney weights and hepatotoxicity. From these repeat dose studies, the NOAEL for non-neoplastic effects was 60 mg/kg bw (cited from OECD SIDS for 1,2-dichlorobenzene). The NOAEL is independent from the duration of the studies – therefore an AF = 1 is justified.

AF for interspecies differences (allometric scaling):

1

Justification:

Default factor

AF for other interspecies differences:

2.5

Justification:

Default factor

AF for intraspecies differences:

10

Justification:

Default factor

AF for the quality of the whole database:

1

Justification:

Default factor

AF for remaining uncertainties:

1

Justification:

Default factor

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5 mg/m³

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.6 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEL

Value:

60 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

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 for more details.

AF for dose response relationship:

1

Justification:

Default factor

AF for differences in duration of exposure:

1

Justification:

Several oral studies of rats and mice ranging from 10 days to 2 years duration indicate that the adverse effects include increases in liver and kidney weights and hepatotoxicity. From these repeat dose studies, the NOAEL for non-neoplastic effects was 60 mg/kg bw (cited from OECD SIDS for 1,2-dichlorobenzene). The NOAEL is independent from the duration of the studies – therefore an AF = 1 is justified.

AF for interspecies differences (allometric scaling):

4

Justification:

Default factor

AF for other interspecies differences:

2.5

Justification:

Default factor

AF for intraspecies differences:

10

Justification:

Default factor

AF for the quality of the whole database:

1

Justification:

Default factor

AF for remaining uncertainties:

1

Justification:

Default factor

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.6 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Modified dose descriptor starting point:

NOAEL

Value:

60 mg/kg bw/day

Justification:

Default factor

Justification:

Several oral studies of rats and mice ranging from 10 days to 2 years duration indicate that the adverse effects include increases in liver and kidney weights and hepatotoxicity. From these repeat dose studies, the NOAEL for non-neoplastic effects was 60 mg/kg bw (cited from OECD SIDS for 1,2-dichlorobenzene). The NOAEL is independent from the duration of the studies – therefore an AF = 1 is justified.

Justification:

Default factor

Justification:

Default factor

Justification:

Default factor

Justification:

Default factor

Justification:

Default factor

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

Systemic toxicity:

A subchronic gavage study in rats is available for 1,2-dichloro-benzene. Decreased survival time for female rats at 500 mg/kg bw was observed with pathological findings of hepatic centrilobular necrosis and hepatocellular degeneration, depletion of lymphocytes in the thymus and spleen. High-dose male rats showed renal tubular degeneration. A dose of 250 mg/kg bw induced necrosis of individual hepatocytes in both sexes of rats. A dose of 125 mg/kg bw displayed in rats minimal hepatocellular necrosis. Haematological changes were observed at 500 mg/kg bw in rats, which included a slight decrease in haematocrit and haemoglobin, and in the erythrocyte count for male rats. The NOAEL = 60 mg/kg bw (male + female rats) is derived in this study.

Taking into account ECHA default for respiratory volume of rats (0.38 m3/kg), Respiratory volume light activity for worker (10/6.7) and 2 times higher absorption after inhalation exposure compared to oral exposure the corrected inhalatory NOAEC is 52 mg/m3.

Default assessment factors are applied for intra- and inter-species variability and an assessment factor of 1 was applied for time extrapolation. Several oral studies of rats and mice ranging from 10 days to 2 years duration indicate that the adverse effects include increases in liver and kidney weights and hepatotoxicity. From these repeat dose studies, the NOAEL for non-neoplastic effects was 60 mg/kg bw (cited from OECD SIDS for 1,2-dichlorobenzene). The NOAEL is independent from the duration of the studies – therefore an AF = 1 is justified.

Reproductive Toxicity. In an unreliable inhalation 2-generation reproduction study in rats, no fertility effects were observed and reduced pup weight during lactation occurred at doses toxic to adults. The NOAEC and LOAEC (kidney and liver effects) for adult rats were 50 (0.3 mg/L) and 150 ppm (0.6 mg/L) respectively, and for reproductive toxicity and offspring growth and development were 150 ppm (0.6 mg/L) and 400 ppm (2.4 mg/L) respectively.

In developmental studies in rats and rabbits, developmental effects were only seen in rats at maternally toxic doses (400 ppm, 2.4 mg/L). As the NOAEC for reproductive toxicity (50 ppm = 0.3 mg/L = 300 mg/m³ for fertility) and the NOAEC of 400 ppm (2.4 mg/L = 2400 mg/³) for developmental toxicity are higher than the NOAEC for repeated dose toxicity (105.7 mg/m³) that is used as a starting point for the DNEL derivation for the DNEL longterm systemic, the derivation of a separate DNEL for reproductive toxicity (fertility and or developmental toxicity) is not necessary, because the DNEL for repeated dose toxicity covers both endpoints.

Local toxicity:

According to the harmonised classification - Annex VI of Regulation (EC) No 1272/2008 (CLP Regulation), 1,2-dichlorobenzene is classified as H315, H319, and H335. 1,2-dichlorobenzene is allocated to the moderate hazard band based on the irritation properties.

In a LLNA , 1,2-dichlorobenzene was a weak dermal sensitizer. Therefore a classification as GHS: Skin Sens. 1B (H317: May cause an allergic skin reaction) is justified.