Reaction mass of copper oxide and manganese dioxide

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

160 µg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

2

Dose descriptor starting point:

BMCL10

Value:

320 µg/m³

AF for dose response relationship:

1

Justification:

default

AF for differences in duration of exposure:

1

Justification:

default for chronic exposure (average exposure length in the key study (geometric mean) of 5.3 years (range: 0.2–17.7 years); the most reliable long-term study in humans and also in other studies with longer exposure no effect enhancement observed)

AF for interspecies differences (allometric scaling):

1

Justification:

not required as basis are human data

AF for other interspecies differences:

1

Justification:

not required as basis are human data

AF for intraspecies differences:

2

Justification:

reduction from default - high number of study objects revealing the effects all in the same exposure height

AF for the quality of the whole database:

1

Justification:

quality of database is considered good

AF for remaining uncertainties:

1

Justification:

default

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

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:

4.5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

2

Dose descriptor starting point:

BMCL10

Value:

320 µg/m³

Modified dose descriptor starting point:

BMDL10

Value:

9 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

There are no reliable and applicable studies available using the dermal exposure route for DNEL derivation.

Route-to-route extrapolation was performed using the most adequate data obtained when workers were exposed to MnO2 dust.

For adjustment of the differences of fractions becoming bioavailable via the different routes the following assumptions are made.

Inhalation bioavailability = 100 %

Dermal Bioaccessibility = 0.5 % (assumption based on data of solubility study, see IUCLID section 4.8, dermal absorption might even be lower as not all bioaccessible Mn will be absorbed into the skin and become bioavailable)

POD = BMCL₁₀= 320μg hopcalite/m³/ 0.005 = 64000 µg hopcalite/m³

With human body weight being assumed 70 kg and a respiratory volume of 10 m³ in one shift the adjusted POD = 9140 µg hopcalite/kg bw/day ≈ 9 mg hopcalite/kg bw/day

AF for dose response relationship:

1

Justification:

default

AF for differences in duration of exposure:

1

Justification:

chronic exposure

AF for interspecies differences (allometric scaling):

1

Justification:

not required as basis are human data

AF for other interspecies differences:

1

Justification:

not required as basis are human data

AF for intraspecies differences:

2

Justification:

reduction from default - high number of study objects revealing the effects all in the same exposure height

AF for the quality of the whole database:

1

Justification:

quality of database is considered good

AF for remaining uncertainties:

1

Justification:

default

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

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

There are no adequate and reliable studies available for the registration substance, hopcalite, itself. However adequate and reliable studies performed with each of the two constituents of this reaction mass are at hand. For each relevant hazard the DNELs provided are based on the more critical value obtained using the critical studies for each of the two constituents as POD, respectively. Thus the hazard assessment conclusions are thought to be a conservative approach.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

20 µg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

4

Dose descriptor starting point:

BMCL10

Value:

320 µg/m³

Modified dose descriptor starting point:

BMCL10

Value:

76.2 µg/m³

Explanation for the modification of the dose descriptor starting point:

PBPK modeling demonstrates that the relationship between ambient Mn exposures and dose-to-target tissue is not linear due to normal tissue background levels and homeostatic controls. This application of PBPK modeling for an essential element clearly demonstrates that the conventional application of default factors to “convert” an occupational exposure to an equivalent continuous environmental exposure, followed by the application of safety factors, would be not appropriate in the case of Mn.(Gentry et al., 2017)

However in a conservative approach and according to ECHA guidance the following adjustment of POD would have to be made for different exposure pattern of workers compared to continuous exposure of the general population.

*5 day exposure workers / 7 days exposure general population

*8 h/day exposure workers /24 h/day exposure general population

leading to an approximately 4 times lower POD (BMCL₁₀= 76.2 μg hopcalite/m³) than the one that could be used for assessment here.

AF for dose response relationship:

1

Justification:

default

AF for differences in duration of exposure:

1

Justification:

default for chronic exposure (average exposure length in the key study (geometric mean) of 5.3 years (range: 0.2–17.7 years); the most reliable long-term study in humans and also in other studies with longer exposure no effect enhancement observed)

AF for interspecies differences (allometric scaling):

1

Justification:

not required as basis are human data

AF for other interspecies differences:

1

Justification:

not required as basis are human data

AF for intraspecies differences:

4

Justification:

reduction from default - high number of study objects revealing the effects all in the same exposure height

AF for the quality of the whole database:

1

Justification:

quality of database is considered good

AF for remaining uncertainties:

1

Justification:

default

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

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:

2.25 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

4

Dose descriptor starting point:

BMCL10

Value:

320 µg/m³

Modified dose descriptor starting point:

BMDL10

Value:

9 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

There are no reliable and applicable studies available using the dermal exposure route for DNEL derivation.

Route-to-route extrapolation was performed using the most adequate data obtained when workers were exposed to MnO2 dust.

For detailed explanation on modification of the dose descriptor starting point please see explanation provided at worker dermal DNEL systemic effects long-term exposure.

(Note - no adjustment of the worker ihalation exposure to continuous exposure of the general population was performed, as this would be overly conservative for such a strictly controled essential element - see also discussion above from Gentry et al., 2017).

AF for dose response relationship:

1

Justification:

default

AF for differences in duration of exposure:

1

Justification:

chronic exposure

AF for interspecies differences (allometric scaling):

1

Justification:

not required as basis are human data

AF for other interspecies differences:

1

Justification:

not required as basis are human data

AF for intraspecies differences:

4

Justification:

reduction from default - high number of study objects revealing the effects all in the same exposure height

AF for the quality of the whole database:

1

Justification:

quality of database is considered good

AF for remaining uncertainties:

1

Justification:

default

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

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:

0.23 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

4

Dose descriptor starting point:

BMCL10

Value:

320

Modified dose descriptor starting point:

BMDL10

Value:

910 µg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

As there are no reliable and applicable studies available using the oral exposure route for DNEL derivation a route-to-route extrapolation was performed using the most adequate data obtained when workers were exposed to MnO2 dust (Roels et al., 1992).

For adjustment of the differences of fractions becoming bioavailable via the different routes the following assumptions are made.

Inhalation bioavailability = 100 %

Oral bioavailability = 5 % (assumption based on data of limited absorption after oral administration of manganese in various forms)

POD =BMCL₁₀= 320 μg hopcalite/m³/ 0.05 = 6400 µg hopcalite/m³

With human body weight being assumed 70 kg and a respiratory volume of 10 m³ in one shift the adjusted POD =910 µg hopcalite/kg bw/day

AF for dose response relationship:

1

Justification:

default

AF for differences in duration of exposure:

1

Justification:

chronic exposure

AF for interspecies differences (allometric scaling):

1

Justification:

not required as basis are human data

AF for other interspecies differences:

1

Justification:

not required as basis are human data

AF for intraspecies differences:

4

Justification:

reduction from default - high number of study objects revealing the effects all in the same exposure
height

AF for the quality of the whole database:

1

Justification:

quality of database is considered good

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

There are no adequate and reliable studies available for the registration substance, hopcalite, itself. However adequate and reliable studies performed with each of the two constituents of this reaction mass are at hand. For each relevant hazard the DNELs provided are based on the more critical value obtained using the critical studies for each of the two constituents as POD, respectively. Thus the hazard assessment conclusions are thought to be a conservative approach.