Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.48 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

12.5

Dose descriptor starting point:

NOAEL

Value:

15 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

18.5 mg/m³

AF for dose response relationship:

1

AF for differences in duration of exposure:

1

Justification:

The adverse effects at the next higher dose (40 mg/kg) is dystocia. No other adverse effects are observed in the OECD TG 443 study. Since the animals are exposed during 10 weeks before mating, during mating and during gestation, exposure covers the entire reproductive period and consequently a time extrapolation factor of 1 is appropriate for fertility effects, including dystocia, observed in an EOGRTS.

AF for interspecies differences (allometric scaling):

1

Justification:

default value (ECHA)

AF for other interspecies differences:

2.5

Justification:

default value (ECHA)

AF for intraspecies differences:

5

Justification:

default value (ECHA)

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

7.4 mg/m³

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

DNEL derivation method:

ECHA REACH Guidance

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.42 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Dose descriptor starting point:

NOAEL

Value:

15 mg/m³

AF for dose response relationship:

1

AF for differences in duration of exposure:

1

Justification:

The adverse effects at the next higher dose (40 mg/kg) is dystocia. No other adverse effects are observed in the OECD TG 443 study. Since the animals are exposed during 10 weeks before mating, during mating and during gestation, exposure covers the entire reproductive period and consequently a time extrapolation factor of 1 is appropriate for fertility effects, including dystocia, observed in an EOGRTS.

AF for interspecies differences (allometric scaling):

4

Justification:

default value (ECHA)

AF for other interspecies differences:

2.5

Justification:

default value (ECHA)

AF for intraspecies differences:

5

Justification:

default value (ECHA)

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

DNEL derivation method:

ECHA REACH Guidance

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

DNEL derivation method:

ECHA REACH Guidance

Hazard assessment conclusion:

no hazard identified

Vulkanox ZMB2 (CAS 61617-00-3)

DNELs (worker)

Extended one generation reproductive toxicity study

In an extended one generation reproductive toxicity study according to OECD TG 443, Vulkanox ZMB2 was administered orally, by gavage, to CD rats at dose levels of 5, 15 or 40 mg/kg bw/day. The evaluation included assessment of the integrity and performance of the adult male and female reproductive tract, and systemic toxicity in pregnant and lactating females and in young and adult offspring. In addition, developmental neurotoxicity and developmental immunotoxicity assessments were included, along with an evaluation of the maturing reproductive tract and its integrity and function.

Based on this OECD TG 443 study the starting point is the NOAEL = 15 mg/kg bw/day.

Basis for delineation of the DNEL:

Study (rat study):

EOGRTS

rat, male, female,

rat: 0 (control), 5, 15, 40 mg/kg bw/day – male, female

via gavage

Effects, NOAEL:

NOAEL = 15 mg/kg bw/day (male + female rats)

Effects:

Based on the results obtained in this study it was concluded that the No-Observed-Adverse-Effect-Level (NOAEL) for reproductive performance of the F0 and F1 Cohort 1B animals was 15 mg/kg/day due to the incidences of prolonged parturition/dystocia in females of both generations receiving 40 mg/kg/day.

Aside from the above mentioned instances of prolonged parturition/dystocia among females at 40 mg/kg/day, increased incidences of liver hypertrophy, thyroid gland hypertrophy and involution/atrophy of the thymus were observed at 40 mg/kg/day, therefore the NOAEL for systemic toxicity in the F0 and F1 adult animals was concluded to be 15 mg/kg/day.

The NOAEL for the F1 and F2 offspring up to weaning was concluded to be 15 mg/kg/day due to reduced early post-partum survival at 40 mg/kg/day in both generations.

There was no evidence of developmental neurotoxicity or developmental immunotoxicity on this study, therefore the NOAEL for these endpoints was concluded to be 40 mg/kg/day.

Reference:

Stannard D, Vulkanox ZMB2: Extended One Generation Reproductive Toxicity Study in the CD Rat by Oral Gavage Administration, Covance CRS Limited, Report no. QG31PJ, 19 January 2020

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

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

NOAEL(rat, male) from a EOGRTs: 15 mg/kg bw/day

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

For interspecies rat vs. human: 4 (default value ECHA)

For remaining interspecies differences: 2.5 (default value ECHA)

For intraspecies differences in workers: 5 (default value ECHA)

For extrapolation of exposure duration subacute to chronic: 1*

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 50

*Since the animals are exposed during 10 weeks before mating, during mating and during gestation, exposure covers the entire reproductive period and consequently a time extrapolation factor of 1 is appropriate for fertility effects, including dystocia, observed in an EOGRTS.

Worker DNEL long-term for oral or dermal route-systemic: 0.42 mg/kg bw/day

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

NOAEL(rat) from a subacute oral toxicity study: 15 mg/kg bw/day

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

Corrected inhalatory NOAEC = Oral NOAEL (15 mg/kg) x 1/0.38 m³/kg x 6.7 m³/10m³ x x 50/100 x 7/5

=> NOAEC worker = 18.5 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: 2.5 (default value ECHA)

For intraspecies differences in workers: 5 (default value ECHA)

For extrapolation of exposure duration subacute to chronic: 1*

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 12.5

*Since the animals are exposed during 10 weeks before mating, during mating and during gestation, exposure covers the entire reproductive period and consequently a time extrapolation factor of 1 is appropriate for fertility effects, including dystocia, observed in an EOGRTS.

Worker DNEL long-term for inhalation exposure: 1.48 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 for inhalation toxicity.

Worker DNEL short-term for inhalation exposure: 7.4 mg/m³

Worker DNEL short-term for dermal route-systemic: no hazard (LD50 > 2000 mg/kg (acute toxicity study)

Conclusion (systemic effects):

Worker DNEL long-term for oral or dermal route-systemic: 0.42 mg/kg bw/day

Worker DNEL long-term for inhalation exposure: 1.48 mg/m³

Worker DNEL short-term for dermal route-systemic: no hazard identified

Worker DNEL short-term for inhalation exposure: 7.4 mg/m³

3.) Reproductive Toxicity – systemic effects (worker)

The extended one generation reproductive toxicity study according to OECD TG 443 (EOGRTS) is used as starting point for the derivation of the systemic DNELs. For fertility no separate DNEL is derived.

In an OECD Guideline 414 (Prenatal Developmental Toxicity Study) four groups of 20 females received Vulkanox ZMB2 at doses of 8, 25 or 70 mg/kg bw/day by oral gavage administration, from Day 6 to 19 after mating, at a volume dose of 5mL/kg body weight. A similarly constituted Control group received the vehicle, dried corn oil at the same volume dose as treated groups. Animals were killed on Day 20 after mating for reproductive assessment and fetal examination.

Based on the results of this study, the No-Observed-Adverse-Effect-Level (NOAEL) for maternal toxicity and embryo-fetal survival and development was concluded to be 70 mg/kg bw/day.

The derivation of a separate DNEL for reproductive toxicity is not necessary, because the NOAEL for repeated dose toxicity is equal or higher than the NOAEL used as stating point for the derivation of systemic DNELs and covers reproductive toxicity.

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

In rabbits, ZMB2 (1,3-dihydro-4(or 5)-methyl-2H-benzimidazole-2-thione, zinc salt, CAS 61617-00-3) is not irritating to the skin, and not irritating to the eyes. ZMB2 is not classified for skin and eye irritation.

5. Sensitization

ZMB2 (1,3-dihydro-4(or 5)-methyl-2H-benzimidazole-2-thione, zinc salt, CAS 61617-00-3) was sensitising in a GPMT. ZMB2 is classified as Skin Sens. 1B (H317: May cause an allergic skin reaction).

ZMB2 (1,3-dihydro-4(or 5)-methyl-2H-benzimidazole-2-thione, zinc salt, CAS 61617-00-3) is sensitizing and not irritating to the skin and eyes. For local effects the following hazard assessment conclusion applies:

Local oral (short and long-term): no hazard

Local inhalation (short and long-term): no hazard

Local dermal (short and long-term): medium hazard band (Skin Sens. 1B)

Conclusion (systemic and local effects - worker):

Route of exposure DNEL: local effect DNEL systemic effect

Oral (long term) - -

Oral (short term) - -

Dermal (long term) medium hazard band 0.42 mg/kg bw/day

Dermal (short term) medium hazard band no hazard identified

Inhalation (long term) no hazard identified 1.48 mg/m³

Inhalation (short term) no hazard identified 7.4 mg/m³

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.26 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Dose descriptor starting point:

NOAEL

Value:

15 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

6.5 mg/m³

AF for dose response relationship:

1

Justification:

see 'discussion'

AF for differences in duration of exposure:

1

Justification:

The adverse effects at the next higher dose (40 mg/kg) is dystocia. No other adverse effects are observed in the OECD TG 443 study. Since the animals are exposed during 10 weeks before mating, during mating and during gestation, exposure covers the entire reproductive period and consequently a time extrapolation factor of 1 is appropriate for fertility effects, including dystocia, observed in an EOGRTS.

AF for interspecies differences (allometric scaling):

1

Justification:

default value (ECHA)

AF for other interspecies differences:

2.5

Justification:

default value (ECHA)

AF for intraspecies differences:

10

Justification:

default value (ECHA)

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.3 mg/m³

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

Hazard assessment conclusion:

no hazard identified

DNEL derivation method:

ECHA REACH Guidance

Hazard assessment conclusion:

no hazard identified

DNEL derivation method:

ECHA REACH Guidance

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.15 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Dose descriptor starting point:

NOAEL

Value:

15 mg/kg bw/day

AF for dose response relationship:

1

AF for differences in duration of exposure:

1

Justification:

The adverse effects at the next higher dose (40 mg/kg) is dystocia. No other adverse effects are observed in the OECD TG 443 study. Since the animals are exposed during 10 weeks before mating, during mating and during gestation, exposure covers the entire reproductive period and consequently a time extrapolation factor of 1 is appropriate for fertility effects, including dystocia, observed in an EOGRTS.

AF for interspecies differences (allometric scaling):

4

Justification:

defalutl value (ECHA)

AF for other interspecies differences:

2.5

Justification:

defalutl value (ECHA)

AF for intraspecies differences:

10

Justification:

defalutl value (ECHA)

AF for the quality of the whole database:

1

Justification:

1

AF for remaining uncertainties:

1

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

medium hazard (no threshold derived)

DNEL derivation method:

ECHA REACH Guidance

Hazard assessment conclusion:

medium hazard (no threshold derived)

DNEL derivation method:

ECHA REACH Guidance

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.15 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Dose descriptor starting point:

NOAEL

Value:

15 mg/kg bw/day

AF for dose response relationship:

1

AF for differences in duration of exposure:

1

Justification:

The adverse effects at the next higher dose (40 mg/kg) is dystocia. No other adverse effects are observed in the OECD TG 443 study. Since the animals are exposed during 10 weeks before mating, during mating and during gestation, exposure covers the entire reproductive period and consequently a time extrapolation factor of 1 is appropriate for fertility effects, including dystocia, observed in an EOGRTS.

AF for interspecies differences (allometric scaling):

4

Justification:

default value (ECHA)

AF for other interspecies differences:

2.5

Justification:

default value (ECHA)

AF for intraspecies differences:

10

Justification:

default value (ECHA)

AF for remaining uncertainties:

1

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.75 mg/kg bw/day

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

Hazard assessment conclusion:

no hazard identified

Vulkanox ZMB2 (CAS 61617-00-3)

DNELs (general population)

Extended one generation reproductive toxicity study:

In an extended one generation reproductive toxicity study according to OECD TG 443, Vulkanox ZMB2 was administered orally, by gavage, to CD rats at dose levels of 5, 15 or 40 mg/kg bw/day. The evaluation included assessment of the integrity and performance of the adult male and female reproductive tract, and systemic toxicity in pregnant and lactating females and in young and adult offspring. In addition, developmental neurotoxicity and developmental immunotoxicity assessments were included, along with an evaluation of the maturing reproductive tract and its integrity and function.

Based on this OECD TG 443 study the starting point is the NOAEL = 15 mg/kg bw/day. The adverse effects at the next higher dose (40 mg/kg bw/day) is dystocia.

Basis for delineation of the DNEL:

Study (rat study):

EOGRTS

rat, male, female,

rat: 0 (control), 5, 15, 40 mg/kg bw/day – male, female

via gavage

Effects, NOAEL:

NOAEL = 15 mg/kg bw/day (male + female rats)

Effects:

Based on the results obtained in this study it was concluded that the No-Observed-Adverse-Effect-Level (NOAEL) for reproductive performance of the F0 and F1 Cohort 1B animals was 15 mg/kg/day due to the incidences of prolonged parturition/dystocia in females of both generations receiving 40 mg/kg/day.

Aside from the above mentioned instances of prolonged parturition/dystocia among females at 40 mg/kg/day, increased incidences of liver hypertrophy, thyroid gland hypertrophy and involution/atrophy of the thymus were observed at 40 mg/kg/day, therefore the NOAEL for systemic toxicity in the F0 and F1 adult animals was concluded to be 15 mg/kg/day.

The NOAEL for the F1 and F2 offspring up to weaning was concluded to be 15 mg/kg/day due to reduced early post-partum survival at 40 mg/kg/day in both generations.

There was no evidence of developmental neurotoxicity or developmental immunotoxicity on this study, therefore the NOAEL for these endpoints was concluded to be 40 mg/kg/day.

Reference:

Stannard D, Vulkanox ZMB2: Extended One Generation Reproductive Toxicity Study in the CD Rat by Oral Gavage Administration, Covance CRS Limited, Report no. QG31PJ, 19 January 2020

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

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

NOAEL(rat, male) from a EOGRTs: 15 mg/kg bw/day

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

For interspecies rat vs. human: 4 (default value ECHA)

For remaining interspecies differences: 2.5 (default value ECHA)

For intraspecies differences in general populations: 10 (default value ECHA)

For extrapolation of exposure duration subacute to chronic: 1*

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 100

*Since the animals are exposed during 10 weeks before mating, during mating and during gestation, exposure covers the entire reproductive period and consequently a time extrapolation factor of 1 is appropriate for fertility effects, including dystocia, observed in an EOGRTS.

General population DNEL long-term for oral or dermal route-systemic: 0.15 mg/kg bw/day

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

NOAEL(rat) from a subacute oral toxicity study: 15 mg/kg bw/day

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

Corrected inhalatory NOAEC = Oral NOAEL (15 mg/kg) x 1/1.15 m³/kg x 50/100

=> NOAEC worker = 6.5 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: 2.5 (default value ECHA)

For intraspecies differences in general population: 10 (default value ECHA)

For extrapolation of exposure duration subacute to chronic: 1*

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 25

*Since the animals are exposed during 10 weeks before mating, during mating and during gestation, exposure covers the entire reproductive period and consequently a time extrapolation factor of 1 is appropriate for fertility effects, including dystocia, observed in an EOGRTS.

General population DNEL long-term for inhalation exposure: 0.26 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 for inhalation toxicity.

General population DNEL short-term for inhalation exposure: 1.3 mg/m³ (classified as Acute Tox. 4, H332: Harmful if inhaled, no local effects).

General population DNEL short-term for oral route-systemic: 0.75 mg/kg (classified as Acute Tox. 4, H302: Harmful if swallowed, no local effects).

General population DNEL short-term for dermal route-systemic: no hazard (LD50 > 2000 mg/kg (acute toxicity study).

Conclusion (systemic effects):

General population DNEL long-term for oral or dermal route-systemic: 0.15 mg/kg bw/day

General population DNEL long-term for inhalation exposure: 0.75 mg/m³

General population DNEL short-term for dermal route-systemic: no hazard identified

General population DNEL short-term for inhalation exposure: 1.3 mg/m³

3.) Reproductive Toxicity – systemic effects (worker)

The extended one generation reproductive toxicity study according to OECD TG 443 (EOGRTS) is used as starting point for the derivation of the systemic DNELs. For fertility no separate DNEL is derived.

In an OECD Guideline 414 (Prenatal Developmental Toxicity Study) four groups of 20 females received Vulkanox ZMB2 at doses of 8, 25 or 70 mg/kg bw/day by oral gavage administration, from Day 6 to 19 after mating, at a volume dose of 5mL/kg body weight.

A similarly constituted Control group received the vehicle, dried corn oil at the same volume dose as treated groups. Animals were killed on Day 20 after mating for reproductive assessment and fetal examination.

Based on the results of this study, the No-Observed-Adverse-Effect-Level (NOAEL) for maternal toxicity and embryo-fetal survival and development was concluded to be 70 mg/kg bw/day.

The derivation of a separate DNEL for reproductive toxicity is not necessary, because the NOAEL for repeated dose toxicity is equal or higher than the NOAEL used as stating point for the derivation of systemic DNELs and covers reproductive toxicity.

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

In rabbits, ZMB2 (1,3-dihydro-4(or 5)-methyl-2H-benzimidazole-2-thione, zinc salt, CAS 61617-00-3) is not irritating to the skin, and not irritating to the eyes. ZMB2 is not classified for skin and eye irritation.

5. Sensitization

ZMB2 (1,3-dihydro-4(or 5)-methyl-2H-benzimidazole-2-thione, zinc salt, CAS 61617-00-3) was sensitising in a GPMT. ZMB2 is classified as Skin Sens. 1B (H317: May cause an allergic skin reaction).

ZMB2 (1,3-dihydro-4(or 5)-methyl-2H-benzimidazole-2-thione, zinc salt, CAS 61617-00-3) is sensitizing and not irritating to the skin and eyes. For local effects the following hazard assessment conclusion applies:

Local oral (short and long-term): no hazard

Local inhalation (short and long-term): no hazard

Local dermal (short and long-term): medium hazard band (Skin Sens. 1B)

Conclusion (systemic and local effects - general population):

Route of exposure DNEL: local effect DNEL systemic effect

Oral (long term) - 0.15 mg/kg bw/day

Oral (short term) - 0.75 mg/kg

Dermal (long term) medium hazard band 0.15 mg/kg bw/day

Dermal (short term) medium hazard band no hazard identified

Inhalation (long term) no hazard identified 0.26 mg/m³

Inhalation (short term) no hazard identified 1.3 mg/m³

Registration Dossier

Registration Dossier

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Diss Factsheets

1,3-dihydro-4(or 5)-methyl-2H-benzimidazole-2-thione, zinc salt

Toxicological Summary

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

Acute/short term exposure

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

Workers - Hazard for the eyes

Local effects

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

General Population - Hazard for the eyes

Local effects

Additional information - General Population