Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.52 mg/m³
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
28.1 mg/m³
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.52 mg/m³
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
28.1 mg/m³
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.42 mg/kg bw/day
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
11.3 mg/kg bw/day
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available

Workers - Hazard for the eyes

Additional information - workers

Repeated dose toxicity

Basis for delineation of the DNEL:

Study:

Repeated dose study

dog, male, female,

Subchronic capsule study over 90 days

dog: 0 (control), 5, 20 or 80 mg/kg bw/d – males + females

Effects, NOAEL:

NOEL > 20 mg/kg bw/day (male + female dogs)

effects:

In all dose groups there were no treatment related

effects on behaviour, survival, hematology, clinical chemistry, histopathology,

eyes and bone marrow. Occasional episodes of vomiting in 1/4 females and red blood in

the feces of this animal given 80 mg/kg bw is regarded to be the physiological response to

the treatment with the slightly irritating compound.

Reference:

Gibson WE, Gossett FO, Koenig GR, Marroquin F (1974)

The toxicity of daily oral doses of o-chlorotoluene in the dog

Toxicology Division Lilly Research Laboratories

Study D-4433

1.) Long-term toxixity – systemic effects (workers)

Long-term oral or dermal route-systemic effects (worker) using default extrapolation factors:

NOEL (dog) from a subchronic toxicity study: 20 mg/kg bw/day

Penetration oral compared to dermal (both assumed 100%) 1

For interspecies differences rat vs. human: 1.4

For remaining interspecies differences: 1*

For intraspecies differences in workers: 5

For extrapolation of exposure duration subchronic to chronic: 2

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 14

Worker DNEL long-term for oral or dermal route-systemic: 1.42 mg/kg bw/day

* In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor of 2.5 is scientifically unjustified as a default factor. This view is supported by data generated by the ERASM project (Batke et al, 2010).

Long-term inhalation route-systemic effects (worker):

NOEL (dog) from a subchronic toxicity study: 20 mg/kg bw/day

Correction of the starting point according TGD Figure R.8-3:

Corrected inhalatory NOEC = Oral NOEL (20 mg/kg) x 1/0.38 m³/kg x 6.7 m³/10m³ x 1.0

=> NOAEC worker = 35.26 mg/m³

For interspecies differences dog vs. human: 1 (according TGD Table

R.8-4. already covered by correction of starting point)

For remaining interspecies differences: 1*

For intraspecies differences in workers: 5

For extrapolation of exposure duration subchronic to chronic: 2

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 10

Worker DNEL long-term for inhalation exposure: 3.52 mg/m³

* In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor of 2.5 is scientifically unjustified as a default factor. This view is supported by data generated by the ERASM project (Batke et al, 2010).

2.) Short-term toxicity – systemic effects (worker)

Concerning the systemic effects an exceeding factor of 8 based on the DNEL for long term exposure seems justified.

Therefore the

Worker DNELshort-term for oral or dermal route-systemic: 11.3 mg/kg bw/day

Worker DNEL short-term for inhalation exposure: 28.1 mg/m³

Conclusion (systemic effects):

Worker DNEL long-term for oral or dermal route-systemic: 1.42 mg/kg bw/day

Worker DNEL long-term for inhalation exposure: 3.52 mg/m³

Worker DNELshort-term for oral or dermal route-systemic: 11.3 mg/kg bw/day

Worker DNEL short-term for inhalation exposure: 28.1 mg/m³

3.) Reproductive Toxicity – systemic effects (workers)

A 2-generation toxicity study (OECD TG 422) or a prenatal developmental toxicity study (OECD 414) are not available. However, no treatment related changes regarding gross examination on reproductive organs were observed in the capsule study for 95-96 days in dogs.

Also in this study the histological examination of the testes, ovaries, prostatate, uterus showed no pathological alteration.

The NOEL for reproductive toxicity concerning fertility in dogs is therefore > 80 mg/kg bw/day as the lower limit. Additional or higher assessment factors than those used for the delineation of the DNEL from the repeated dose toxicity study are not necessary. As the NOEL for reproductive toxicty (> 80 mg/kg bw/day for fertility) is higher than the NOEL for repeated dose toxicity (20 mg/kg bw/day), the derivation of a separate DNEL for reproductive toxicity (fertility) is not necessary, because the DNEL for repeated dose toxicty covers both endpoints.

4. Long-term and short-term dermal or inhalation route - local effects (worker)

2-Chlorotoluene, tested according to OECD Guideline 404, is not irritating to the skin.

2-Chlorotoluene, tested according to OECD Guideline 405, was not irritating to the eye.

The findings were not sufficient for classification.

5. Sensitization

2-Chlorotoluene, tested according to OECD Guideline 406, is not sensitizing to the skin of guinea pigs.

Therefore the DNEL for systemic effects also applies to local effects:

Conclusion (systemic + local effects):

Worker DNEL long-term for oral or dermal route:      1.42 mg/kg bw/day

Worker DNEL long-term for inhalation exposure:       3.52 mg/m³

Worker DNELshort-term for oral or dermal route:     11.3 mg/kg bw/day

Worker DNEL short-term for inhalation exposure:      28.1 mg/m³

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.86 mg/m³
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.88 mg/m³
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.86 mg/m³
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.88 mg/m³
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.71 mg/kg bw/day
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5.68 mg/kg bw/day
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.71 mg/kg bw/day
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5.58 mg/kg bw/day
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

Repeated dose toxicity

Basis for delineation of the DNEL:

Study:

Repeated dose study

dog, male, female,

Subchronic capsule study over 90 days

dog: 0 (control), 5, 20 or 80 mg/kg bw/d – males + females

Effects, NOAEL:

NOEL > 20 mg/kg bw/day (male + female dogs)

effects:

In all dose groups there were no treatment related

effects on behaviour, survival, hematology, clinical chemistry, histopathology,

eyes and bone marrow. Occasional episodes of vomiting in 1/4 females and red blood in

the feces of this animal given 80 mg/kg bw is regarded to be the physiological response to

the treatment with the slightly irritating compound.

Reference

Gibson WE, Gossett FO, Koenig GR, Marroquin F (1974)

The toxicity of daily oral doses of o-chlorotoluene in the dog

Toxicology Division Lilly Research Laboratories

Study D-4433

1.) Long-term toxixity – systemic effects (general population)

Long-term oral or dermal route-systemic effects (general population) using default extrapolation factors:

NOEL (dog) from a subchronic toxicity study: 20 mg/kg bw/day

Penetration oral compared to dermal (both assumed 100%) 1

For interspecies differences dog vs. human: 1.4

For remaining interspecies differences: 1*

For intraspecies differences in general population: 10

For extrapolation of exposure duration subchronic to chronic: 2

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 28

Worker DNEL long-term for oral or dermal route-systemic: 0.71 mg/kg bw/day

* In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor of 2.5 is scientifically unjustified as a default factor. This view is supported by data generated by the ERASM project (Batke et al, 2010).

Long-term inhalation route-systemic effects (general population):

NOEL (dog) from a subchronic toxicity study: 20 mg/kg bw/day

Correction of the starting point according TGD Figure R.8-3:

Corrected inhalatory NOEC = Oral NOEL (20 mg/kg) x 1/1.15 m³/kg x 1.0

=> NOAEC general population = 17.39 mg/m³

For interspecies differences dog vs. human: 1 (according TGD Table

R.8-4. already covered by correction of starting point)

For remaining interspecies differences: 1*

For intraspecies differences in general population: 10

For extrapolation of exposure duration subchronic to chronic: 2

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 20

general population DNEL long-term for inhalation exposure: 0.86 mg/m³

* In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor of 2.5 is scientifically unjustified as a default factor. This view is supported by data generated by the ERASM project (Batke et al, 2010).

2.) Short-term toxicity – systemic effects (general population)

Concerning the systemic effects an exceeding factor of 8 based on the DNEL for long term exposure seems justified.

Therefore the

General population DNELshort-term for oral or dermal route-systemic: 5.68 mg/kg bw/day

General population DNEL short-term for inhalation exposure: 6.88 mg/m³

Conclusion (systemic effects):

General population DNEL long-term for oral or dermal route-systemic: 0.71 mg/kg bw/day

General population DNEL long-term for inhalation exposure: 0.86 mg/m³

General population DNELshort-term for oral or dermal route-systemic: 5.68 mg/kg bw/day

General population DNEL short-term for inhalation exposure: 6.88 mg/m³

3.) Reproductive Toxicity – systemic effects (general population)

A 2-generation toxicity study (OECD TG 422) or a prenatal developmental toxicity study (OECD 414) are not available. However, no treatment related changes regarding gross examination on reproductive organs were observed in the capsule study for 95-96 days in dogs.

Also in this study the histological examination of the testes, ovaries, prostatate, uterus showed no pathological alteration.

The NOEL for reproductive toxicity concerning fertility in dogs is therefore > 80 mg/kg bw/day as the lower limit. Additional or higher assessment factors than those used for the delineation of the DNEL from the repeated dose toxicity study are not necessary. As the NOEL for reproductive toxicty (> 80 mg/kg bw/day for fertility) is higher than the NOEL for repeated dose toxicity (20 mg/kg bw/day), the derivation of a separate DNEL for reproductive toxicity (fertility) is not necessary, because the DNEL for repeated dose toxicty covers both endpoints.

4. Long-term and short-term dermal or inhalation route - local effects (worker)

2-Chlorotoluene, tested according to OECD Guideline 404, is slightly irritating to the skin.

2-Chlorotoluene, tested according to OECD Guideline 405, was not irritating to the eye.

The findings were not sufficient for classification.

5. Sensitization

2-Chlorotoluene, tested according to OECD Guideline 406, is not sensitizing to the skin of guinea pigs.

Therefore the DNEL for systemic effects also applies to local effects:

Conclusion (systemic + local effects):

General population DNEL long-term for oral or dermal route-systemic: 0.71 mg/kg bw/day

General population DNEL long-term for inhalation exposure:               0.86 mg/m³

General population DNELshort-term for oral or dermal route-systemic: 5.68 mg/kg bw/day

General population DNEL short-term for inhalation exposure: 6.88 mg/m³