Hydroxy(2-methylprop-2-enoato-O)zinc

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.9 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):

1

Modified dose descriptor starting point:

NOAEC

Value:

1.9 mg/m³

Explanation for the modification of the dose descriptor starting point:

The DNEL derived from zinc compounds is the most conservative. OELs for soluble zinc compounds represented by zinc chloride are available. While a detailed scientific justification for the OELs is not available, these values have ensured workers safety for decades which correlates with the DNELs derived from the human volunteer studies. Taking a conservative approach it is proposed that for inhalatory exposure, the existing OEL values are used as the respective DNEL (1 mg/m3/day). Then, a correction factor needs to be applied to take into account the difference in molecular weights between zinc and the registered substance (ZMMA): zinc has a molecular weight of 86.06 g/mol vs. 167 g/mol for ZMMA. A proportional rule is applied: DNELinhal = 1 mg Zn/m3/day x 1.9 = 1.9 mg ZMMA/m3/day

AF for dose response relationship:

1

Justification:

Starting point is a NOAEL

AF for differences in duration of exposure:

1

Justification:

No AF required; NOAEL has been derived from human experience through food supplementation

AF for interspecies differences (allometric scaling):

1

Justification:

No AF required; NOAEL has been derived from human experience

AF for other interspecies differences:

1

Justification:

No AF required; NOAEL has been derived from human experience

AF for intraspecies differences:

1

Justification:

No AF required; NOAEL has been derived from human volunteer studies therefore intraspecies differences are already taken into account

AF for the quality of the whole database:

1

Justification:

Appropriate database

AF for remaining uncertainties:

1

Justification:

None

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

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:

1.7 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:

85 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No factor is needed when performing oral to dermal extrapolation. Then, a correction factor needs to be applied to take into account the difference in molecular weights between methyl methacrylate and the registered substance (ZMMA): methyl methacrylate has a molecular weight of 100.12 g/mol vs. 167 g/mol for ZMMA. A proportional rule is applied: 50 mg/kg bw/d x 167 / 100.12 = 85 mg/kg bw/d

AF for dose response relationship:

1

Justification:

Starting point is a NOAEL

AF for differences in duration of exposure:

1

Justification:

In a chronic study, higher NOAEL was found; therefore the NOAEL selected to derive DNEL is considered as already conservative enough for long term exposure

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling from rat to human

AF for other interspecies differences:

2.5

Justification:

Toxicodynamic and toxicokinetic remaining differencies

AF for intraspecies differences:

5

Justification:

Default factor for workers

AF for the quality of the whole database:

1

Justification:

Appropriate database

AF for remaining uncertainties:

1

Justification:

None

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - workers

Data on zinc compounds (soluble compounds such as zinc chloride and zinc sulphate) and methacrylic acid (mainly methyl methacrylate) have been used to deduce the toxicological properties of Hydroxy(2-methylprop-2-enoato-O)zinc because the basic assumption is that after intake of Hydroxy(2-methylprop-2-enoato-O)zinc, it is mainly transformed into the ionic species and zinc cation and the methacrylic part of the substance are the determining factors of the toxicological properties of Hydroxy(2-methylprop-2-enoato-O)zinc. DNEL were calculated from toxicological data on zinc compounds and on methyl methacrylate. Also, for dermal systemic DNEL using methyl methacrylate data, route-to-route extrapolation was done from inhalation and oral toxicity studies in order to compare DNEL from both methods. The most conservative DNEL between zinc compound and methyl methacrylate was selected for each route of exposure. DNEL calculations are detailed in the file attached.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.5 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):

1

Modified dose descriptor starting point:

NOAEC

Value:

2.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

The oral NOAEL of 50 mg Zn/day derived from the 10 week oral human volunteer study by Yadrick et al., (1989) is used as the starting point for deriving DNELs for worker and general population. Derivation of the systemic exposure reflecting the oral NOAEL considering the bioavailability of soluble zinc compounds which have been used in the human volunteer studies: NOAELsyst = 50 mg Zn/day x 20% = 10 mg Zn/day. Calculation of the inhalatory exposure that results in a systemic exposure of 10 mg Zn/day, with bioavailability by inhalation of 40%: NOAELinhal = 10 mg Zn/day / 40% = 25 mg Zn/day. Corrected dose descriptor for consumers considering a breathing volume of 20 m3 per day: NOAELinhal = 25 mg Zn/day / 20m3/day = 1.3 mg/m3. Then, a correction factor needs to be applied to take into account the difference in molecular weights between zinc and the registered substance (ZMMA): zinc has a molecular weight of 86.06 g/mol vs. 167 g/mol for ZMMA. A proportional rule is applied: DNELinhal = 1.3 mg Zn/m3/day x 1.9 = 2.5 mg ZMMA/m3/day

AF for dose response relationship:

1

Justification:

Starting point is a NOAEC

AF for differences in duration of exposure:

1

Justification:

In a chronic study, higher NOAEL was found; therefore the NOAEL selected to derive DNEL is considered as already conservative enough for long term exposure

AF for interspecies differences (allometric scaling):

1

Justification:

No AF required; NOAEL has been derived from human experience

AF for other interspecies differences:

1

Justification:

No AF required; NOAEL has been derived from human experience

AF for intraspecies differences:

1

Justification:

o AF required; NOAEL has been derived from human volunteer studies therefore intraspecies differences are already taken into account

AF for the quality of the whole database:

1

Justification:

Appropriate database

AF for remaining uncertainties:

1

Justification:

None

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

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:

0.35 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):

100

Modified dose descriptor starting point:

NOAEL

Value:

35 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Methyl methacrylate is almost completely absorbed by oral route therefore no correction factor between inhalation and oral routes is needed; in a conservative approach, absorption by dermal route is also considered as 100%. A correction factor is applied to take into account the difference in respiratory rate in rats (sRV rats = 0.29 m3/kg bw for 6 h). Also, modification of exposure (rat exposure condition (6h – 5/7 days) vs. general population exposure condition (24 h – 7/7 days)) is taken into account. Then, a correction factor needs to be applied to take into account the difference in molecular weights between methyl methacrylate and the registered substance (ZMMA): methyl methacrylate has a molecular weight of 100.12 g/mol vs. 167 g/mol for ZMMA. A proportional rule is applied. Thus, the corrected starting point for dermal exposure is: 400 mg/m3 x 0.29 m3/kg bw x (6/24) x (5/7) x 167 / 100.12 = 35 mg/kg bw/d

AF for dose response relationship:

1

Justification:

Starting point is a NOAEL

AF for differences in duration of exposure:

1

Justification:

Results from chronic exposure

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling from rat to human

AF for other interspecies differences:

2.5

Justification:

Toxicodynamic and toxicokinetic remaining differencies

AF for intraspecies differences:

10

Justification:

Default factor for general population

AF for the quality of the whole database:

1

Justification:

Appropriate database

AF for remaining uncertainties:

1

Justification:

None

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:

0.85 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:

85 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No factor is needed when performing oral to dermal extrapolation. Then, a correction factor needs to be applied to take into account the difference in molecular weights between zinc and the registered substance (ZMMA): zinc has a molecular weight of 86.06 g/mol vs. 167 g/mol for ZMMA. A proportional rule is applied. Thus, the corrected starting point is: DNELoral = 0.83 mg Zn/kg bw/day x 1.9 = 1.6 mg ZMMA/kg bw/day

AF for dose response relationship:

1

Justification:

Starting point is a NOAEL

AF for differences in duration of exposure:

1

Justification:

In a chronic study, higher NOAEL was found; therefore the NOAEL selected to derive DNEL is considered as already conservative enough for long term exposure

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling from rat to human

AF for other interspecies differences:

2.5

Justification:

Toxicodynamic and toxicokinetic remaining differencies

AF for intraspecies differences:

10

Justification:

Default factor for general population

AF for the quality of the whole database:

1

Justification:

Appropriate database

AF for remaining uncertainties:

1

Justification:

None

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - General Population

Data on zinc compounds (soluble compounds such as zinc chloride and zinc sulphate) and methacrylic acid (mainly methyl methacrylate) have been used to deduce the toxicological properties of Hydroxy(2-methylprop-2-enoato-O)zinc because the basic assumption is that after intake of Hydroxy(2-methylprop-2-enoato-O)zinc, it is mainly transformed into the ionic species and zinc cation and the methacrylic part of the substance are the determining factors of the toxicological properties of Hydroxy(2-methylprop-2-enoato-O)zinc.

DNEL were calculated from toxicological data on zinc compounds and on methyl methacrylate. Also, for dermal systemic DNEL using methyl methacrylate data, route-to-route extrapolation was done from inhalation and oral toxicity studies in order to compare DNEL from both methods. The most conservative DNEL between zinc compound and methyl methacrylate was selected for each route of exposure.

Choice of points of depatures of DNEL calculation:

- For zinc compounds, the DNELs were derived from the studies on human volunteers; the starting point identified was 50 Zn mg/day (equivalent to 0.83 mg/kg bw/day). See endpoint summary 7.10 for more details.

- For the methacrylate compounds:

A carcinogenicity study and a two-generation reproduction study were available on methyl methacrylate by oral route. The lowest NOAEL identified was found in the two-generation reproduction study; as the NOAEL found in the chronic study was higher than in the two-generation reproduction study (125 mg/kg bw/day), no assessment factor was used for duration extrapolation (from sub-chronic to chronic exposure).

As studies by inhalation (400 mg/m3 from a carcinogenicity study on methyl methacrylate) and oral route (50 mg/kg bw/day found in a two-generation reproduction study on methyl methacrylate) were available, DNELs were derived by route-to-route extrapolation from both values and the most conservative value was selected.

DNEL calculations are detailed in the file attached.