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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.39 mg/m³
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
18
Modified dose descriptor starting point:
NOAEC
DNEL value:
7.052 mg/m³
AF for dose response relationship:
1
Justification:
see 'Discussion'
AF for differences in duration of exposure:
6
Justification:
see 'Discussion'
AF for interspecies differences (allometric scaling):
1
Justification:
see 'Discussion'
AF for other interspecies differences:
1
Justification:
see 'Discussion'
AF for intraspecies differences:
3
Justification:
see 'Discussion'
AF for the quality of the whole database:
1
Justification:
see 'Discussion'
AF for remaining uncertainties:
1
Justification:
see 'Discussion'
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.95 mg/m³
DNEL related information
DNEL extrapolated from long term DNEL

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.055 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):
72
Modified dose descriptor starting point:
NOAEL
DNEL value:
4 mg/kg bw/day
AF for dose response relationship:
1
Justification:
see 'Discussion'
AF for differences in duration of exposure:
6
Justification:
see 'Discussion'
AF for interspecies differences (allometric scaling):
4
Justification:
see 'Discussion'
AF for other interspecies differences:
1
Justification:
see 'Discussion'
AF for intraspecies differences:
3
Justification:
see 'Discussion'
AF for the quality of the whole database:
1
Justification:
see 'Discussion'
AF for remaining uncertainties:
1
Justification:
see 'Discussion'
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.27 mg/kg bw/day
DNEL related information
DNEL extrapolated from long term DNEL

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

2-Mercaptomethylbenzimidazole MB2 (CAS 53988-10-6)

and its Na+ salt (CAS 75045-07-7)

DNELs (worker)

Repeated dose toxicity

A subacute oral gavage study rats was evaluated for the derivation of DNELs of 2-mercapto –benzimidazole MB2 (a 1:1 mixture of 4-methyl and 5-methyl isomers) was evaluated

Basis for delineation of the DNEL:

Study (rat study):

Repeated dose study

rat, male, female,

subacute oral gavage study for 28 days

rat: 0 (control), 4, 20 100 mg/kg bw/d – male, female

via gavage

Effects, NOAEL:

NOEL = 4 mg/kg bw/d (male rats)

NOEL = 20 mg/kg bw/d (female rats)

Effects:

Relative organ weights of lung, liver and kidney, and serum cholesterol and phospholipid significantly increased in male rats treated with MB2 at doses of 20 and 100 mg/kg. Male rats administered 100 mg/kg MB2 exhibited a 1.8 fold increase in thyroid weight associated with histopathological changes but not altered serum thyroid hormone levels. Female rats administered 100 mg MB2/kg exhibited significant increases of liver and kidney but not thyroid weights, and serum cholesterol level.

Reference:

Saitoh M, Umemura T, Kawasaki Y, Momma Y, Matsushima Y, Sakemi K, Isama K, Kitajima S, Ogawa Y, Hasegawa R, Suzuki T, Hayashi M, Inoue T, Ohno Y, Sofuni T, Kurokawa Y, Tsuda M

Toxicity study of a rubber antioxidant, mixture of 2-mercaptomethylbenzimidazoles, by repeated oral administration to rats

Food Chem Toxicol 37, 777-787 (1999)

1.) Long-term tocicity – systemic effects (worker)

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

NOEL(rat, male) from a subacute toxicity study: 4 mg/kg bw/day

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

For interspecies rat vs. human: 4

For remaining interspecies differences: 1 (Ecetoc)

For intraspecies differences in workers: 3 (Ecetoc)

For extrapolation of exposure duration subacute to chronic: 6

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 72

Worker DNEL long-term for oral or dermal route-systemic: 0.055 mg/kg bw/day

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

NOAEL(rat) from a subacute oral toxicity study: 4 mg/kg bw/day

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

Corrected inhalatory NOEC = Oral NOEL (4 mg/kg) x 1/0.38 m³/kg x 6.7 m³/10m³

=> NOEC worker = 7.052 mg/m³

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

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

For remaining interspecies differences: 1 (Ecetoc)

For intraspecies differences in workers: 3 (Ecetoc)

For extrapolation of exposure duration subacute to chronic: 6

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 18

Worker DNEL long-term for inhalation exposure: 0.39 mg/m³

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

Concerning the systemic effects an exceeding factor of 5 based on the DNEL for long term exposure seems justified.

Worker DNELshort-term for oral or dermal route-systemic: 0.27 mg/kg bw/day

Worker DNEL short-term for inhalation exposure: 1.95 mg/m³

Conclusion (systemic effects):

Worker DNEL long-term for oral or dermal route-systemic: 0.055 mg/kg bw/day

Worker DNEL long-term for inhalation exposure: 0.39 mg/m³

Worker DNELshort-term for oral or dermal route-systemic: 0.27 mg/kg bw/day

Worker DNEL short-term for inhalation exposure: 1.95 mg/m³

3.) Reproductive Toxicity – systemic effects (worker)

In a dietary combined repeat dose toxicity study with reproduction/development screening test in the rat with 2-mercaptobenzimidazole, zinc salt, reproductive organs from parental animals (testes, epididymides, ovaries) were weighed and evaluated for histological abnormalities. No evidence of toxicity to male or female reproductive organs was reported. Live offspring were evaluated on postnatal days 1 and 4 for changes in sex ratio, body weight and litter number. No significant clinical or macroscopic findings were noted; however the high incidence of mortality in the dams and the limited number of offspring precluded meaningful evaluation, therefore effect levels of for developmental toxicity could not be established. The following LOAEL/NOAEL were determined:

LOAEL (female reproductive toxicity) = 45-50 mg/kg-bw/day (based on increased gestation length)

NOAEL= Not established

NOAEL (male reproductive toxicity) = 275-338 mg/kg-bw/day (based on no effects observed at the highest dose tested)

NOAEL/LOAEL (developmental toxicity) = Not established

As the NOAEL for reproductive toxicity (45-50 mg/kg bw/day) is higher than the NOEL for repeated dose toxicity (4 mg/kg bw/day), the derivation of a separate DNEL for reproductive toxicity is not necessary, because the DNEL for repeated dose toxicity covers reproductive toxicity.

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

In rabbits, 2-mercaptomethylbenzimidazole was not irritating to the skin, and not irritating to the eyes.

5. Sensitization

2-mercaptomethylbenzimidazole was not sensitising in a LLNA.

2-mercaptomethylbenzimidazole is not sensitizing and not irritating to the skin and eyes. Therefore a DNEL for local effects is not applicable.

Conclusion (systemic and local effects - worker):

Route of exposure DNEL;        local effect DNEL;        systemic effect

Oral (long term)                         not applicable               0.055 mg/kg

Oral (short term)                      not applicable               0.27 mg/kg

Dermal (long term)                     not applicable               0.055 mg/kg

Dermal (short term)                    not applicable               0.27 mg/kg

Inhalation (long term)               not applicable               0.39 mg/m³

Inhalation (short term)               not applicable               1.95 mg/m³

References:

• Saitoh M, Umemura T, Kawasaki Y, Momma Y, Matsushima Y, Sakemi K, Isama K, Kitajima S, Ogawa Y, Hasegawa R, Suzuki T, Hayashi M, Inoue T, Ohno Y, Sofuni T, Kurokawa Y, Tsuda M; Toxicity study of rubber antioxidant, mixture of 2-mercaptomethylbenzimidazoles, by repeated oral administration to rats,

Food Chem Toxicol 37, 777-787 (1999)

• Thyssen J, Untersuchungen zur Haut- und Schleimhautvertraeglichkeit - Versuchsprodukt KA 9059 = Vulkanox MB-2/MG, Bayer - Institut fuer Toxikologie Wuppertal-Elberfeld, 1977

• Thyssen J, Untersuchungen zur Haut- und Schleimhautvertraeglichkeit - ZMB-2, Bayer - Institut fuer Toxikologie Wuppertal-Elberfeld, 1979

• SafePharm Laboratories, Vanox ZMTI: Dietary combined repeat dose toxicity study with reproduction/development screening test in the rat (2006)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.11 mg/m³
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
30
Modified dose descriptor starting point:
NOAEC
AF for dose response relationship:
1
Justification:
see 'Discussion'
AF for differences in duration of exposure:
6
Justification:
see 'Discussion'
AF for interspecies differences (allometric scaling):
1
Justification:
see 'Discussion'
AF for other interspecies differences:
1
Justification:
see 'Discussion'
AF for intraspecies differences:
5
Justification:
see 'Discussion'
AF for the quality of the whole database:
1
Justification:
see 'Discussion'
AF for remaining uncertainties:
1
Justification:
see 'Discussion'
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.55 mg/m³
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL
Justification:
see 'Discussion'
Justification:
see 'Discussion'
Justification:
see 'Discussion'
Justification:
see 'Discussion'
Justification:
see 'Discussion'
Justification:
see 'Discussion'

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.033 mg/kg bw/day
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
120
Modified dose descriptor starting point:
NOAEL
DNEL value:
0.33 mg/kg bw/day
AF for dose response relationship:
1
Justification:
see 'Discussion'
AF for differences in duration of exposure:
6
Justification:
see 'Discussion'
AF for interspecies differences (allometric scaling):
4
Justification:
see 'Discussion'
AF for other interspecies differences:
1
Justification:
see 'Discussion'
AF for intraspecies differences:
5
Justification:
see 'Discussion'
AF for the quality of the whole database:
1
Justification:
see 'Discussion'
AF for remaining uncertainties:
1
Justification:
see 'Discussion'
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.16 mg/kg bw/day
DNEL related information
DNEL extrapolated from long term DNEL
Justification:
see 'Discussion'
Justification:
see 'Discussion'
Justification:
see 'Discussion'
Justification:
see 'Discussion'
Justification:
see 'Discussion'
Justification:
see 'Discussion'

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.033 mg/kg bw/day
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
120
Modified dose descriptor starting point:
NOAEL
DNEL value:
4 mg/kg bw/day
AF for dose response relationship:
1
Justification:
see 'Discussion'
AF for differences in duration of exposure:
6
Justification:
see 'Discussion'
AF for interspecies differences (allometric scaling):
4
Justification:
see 'Discussion'
AF for other interspecies differences:
1
Justification:
see 'Discussion'
AF for intraspecies differences:
5
Justification:
see 'Discussion'
AF for the quality of the whole database:
1
Justification:
see 'Discussion'
AF for remaining uncertainties:
1
Justification:
see 'Discussion'
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.16 mg/kg bw/day
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:
no hazard identified

Additional information - General Population

2-Mercaptomethylbenzimidazole MB2 (CAS 53988-10-6)

and its and Na+ salt (CAS 75045-07-7)

DNELs (general population)

Repeated dose toxicity

A subacute oral gavage study rats was evaluated for the derivation of DNELs of 2-mercapto–benzimidazole MB2 (a 1:1 mixture of 4-methyl and 5-methyl isomers) was evaluated

Basis for delineation of the DNEL:

Study (rat study)

Repeated dose study

rat, male, female,

subacute oral gavage study for 28 days

rat: 0 (control), 4, 20 100 mg/kg bw/d – male, female

via gavage

Effects, NOAEL

NOEL = 4 mg/kg bw/d (male rats)

NOEL = 20 mg/kg bw/d (female rats)

Effects:

Relative organ weights of lung, liver and kidney, and serum cholesterol and phospholipid significantly increased in male rats treated with MB2 at doses of 20 and 100 mg/kg. Male rats administered 100 mg/kg MB2 exhibited a 1.8 fold increase in thyroid weight associated with histopathological changes but not altered serum thyroid hormone levels. Female rats administered 100 mg MB2/kg exhibited significant increases of liver and kidney but not thyroid weights, and serum cholesterol level.

Reference

Saitoh M, Umemura T, Kawasaki Y, Momma Y, Matsushima Y, Sakemi K, Isama K, Kitajima S, Ogawa Y, Hasegawa R, Suzuki T, Hayashi M, Inoue T, Ohno Y, Sofuni T, Kurokawa Y, Tsuda M

Toxicity study of a rubber antioxidant, mixture of 2-mercaptomethylbenzimidazoles, by repeated oral administration to rats

Food Chem Toxicol 37, 777-787 (1999)

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

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

NOEL(rat, male) from a subacute toxicity study: 4 mg/kg bw/day

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

For interspecies rat vs. human:                                                  4

For remaining interspecies differences:                                        1 (Ecetoc)

For intraspecies differences in general population:                      5 (Ecetoc)

For extrapolation of exposure duration subacute to chronic:        6

For reliability of dose-response:                                                  1

For quality of whole database:                                                  1

Overall factor:                                                                       120

General population DNEL long-term for oral or dermal route-systemic: 0.033 mg/kg bw/day

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

NOEL(rat) from a subacute oral toxicity study: 4 mg/kg bw/day

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

Corrected inhalatory NOEC = Oral NOEL (4 mg/kg) x 1/1.15 m³/kg x 1.0

=> NOEC general population = 3.47 mg/m³

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

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

For remaining interspecies differences:                                          1 (Ecetoc)

For intraspecies differences in general population:                      5 (Ecetoc)

For extrapolation of exposure duration subacute to chronic:        6

For reliability of dose-response:                                                  1

For quality of whole database:                                                  1

Overall factor:                                                                           30

Worker DNEL long-term for inhalation exposure: 0.11 mg/m³

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

Concerning the systemic effects an exceeding factor of 5 based on the DNEL for long term exposure seems justified.

General population DNEL short-term for oral or dermal route-systemic: 0.16 mg/kg bw/day

General population DNEL short-term for inhalation exposure: 0.55 mg/m³

Conclusion (systemic effects):

General population DNEL long-term for oral or dermal route-systemic: 0.033 mg/kg bw/day

General population DNEL long-term for inhalation exposure: 0.11 mg/m³

General population DNEL short-term for oral or dermal route-systemic: 0.16 mg/kg bw/day

General population DNEL short-term for inhalation exposure: 0.55 mg/m³

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

In a dietary combined repeat dose toxicity study with reproduction/development screening test in the rat with 2-mercaptobenzimidazole, zinc salt, reproductive organs from parental animals (testes, epididymides, ovaries) were weighed and evaluated for histological abnormalities. No evidence of toxicity to male or female reproductive organs was reported. Live offspring were evaluated on postnatal days 1 and 4 for changes in sex ratio, body weight and litter number. No significant clinical or macroscopic findings were noted; however the high incidence of mortality in the dams and the limited number of offspring precluded meaningful evaluation, therefore effect levels of for developmental toxicity could not be established. The following LOAEL/NOAEL were determined:

LOAEL (female reproductive toxicity) = 45-50 mg/kg-bw/day (based on increased gestation length)

NOAEL= Not established

NOAEL (male reproductive toxicity) = 275-338 mg/kg-bw/day (based on no effects observed at the highest dose tested)

NOAEL/LOAEL (developmental toxicity) = Not established

As the NOAEL for reproductive toxicity (45-50 mg/kg bw/day) is higher than the NOEL for repeated dose toxicity (4 mg/kg bw/day), the derivation of a separate DNEL for reproductive toxicity is not necessary, because the DNEL for repeated dose toxicity covers reproductive toxicity.

For developmental/teratogenicity no NOAEL is available – a study according OECD 414 will be conducted.

Therefore the values for reproduction toxicity are preliminary

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

In rabbits, 2-mercaptomethylbenzimidazole was not irritating to the skin, and not irritating to the eyes.

5. Sensitization

2-mercaptomethylbenzimidazole was not sensitising in a LLNA.

2-mercaptomethylbenzimidazole is not sensitizing and not irritating to the skin and eyes. Therefore a DNEL for local effects is not applicable.

Conclusion (systemic and local effects – general population):

Route of exposure DNEL;        local effect DNEL;        systemic effect

Oral (long term)                           not applicable        0.033 mg/kg

Oral (short term)                        not applicable           0.16 mg/kg

Dermal (long term)                     not applicable         0.033 mg/kg

Dermal (short term)                   not applicable        0.16 mg/kg

Inhalation (long term)               not applicable           0.11 mg/m³

Inhalation (short term)               not applicable        0.55 mg/m³

References:

• Saitoh M, Umemura T, Kawasaki Y, Momma Y, Matsushima Y, Sakemi K, Isama K, Kitajima S, Ogawa Y, Hasegawa R, Suzuki T, Hayashi M, Inoue T, Ohno Y, Sofuni T, Kurokawa Y, Tsuda M; Toxicity study of rubber antioxidant, mixture of 2-mercaptomethylbenzimidazoles, by repeated oral administration to rats,

Food Chem Toxicol 37, 777-787 (1999)

• Thyssen J, Untersuchungen zur Haut- und Schleimhautvertraeglichkeit - Versuchsprodukt KA 9059 = Vulkanox MB-2/MG, Bayer - Institut fuer Toxikologie Wuppertal-Elberfeld, 1977

• Thyssen J, Untersuchungen zur Haut- und Schleimhautvertraeglichkeit - ZMB-2, Bayer - Institut fuer Toxikologie Wuppertal-Elberfeld, 1979

• SafePharm Laboratories, Vanox ZMTI: Dietary combined repeat dose toxicity study with reproduction/development screening test in the rat (2006)