Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.7 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:
2.7 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 zinc methacrylate: zinc has a molecular weight of 86.06 g/mol. ZDMA has a molecular weight of 235.57 g/mol. A proportional rule is applied: DNELinhal = 1 mg Zn/m3/day x 2.7 = 2.7 mg ZDMA/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:
1.2 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:
59 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 zinc methacrylate: methyl methacrylate has a molecular weight of 100.12 g/mol. Zinc methacrylate has a molecular weight of 235.57 g/mol. A proportional rule is applied. Then, as zinc methacrylate can potentially release 2 molecules of methacrylic acid, the starting point is divided by 2. Thus, the corrected starting point for inhalation is : 50 mg/kg bw/d x 235.57 / 100.12 / 2 = 59 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:
medium 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 zinc methacrylate because the basic assumption is that after intake of zinc methacrylate, 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 zinc methacrylate. DNEL were calculated from toxicological data on zinc and methacrylate compounds. 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:
3.4 mg/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):
25
Modified dose descriptor starting point:
NOAEC
Value:
86 mg/m³
Explanation for the modification of the dose descriptor starting point:
A correction factor is applied to take into account the modification of exposure (rat exposure condition (6h – 5/7 days) vs. general population exposure condition (24 h – 7/7 days)). Then, an additional correction factor needs to be applied to take into account the difference in molecular weights between methacrylic acid and zinc methacrylate: methacrylic acid has a molecular weight of 86.09 g/mol. Zinc methacrylate has a molecular weight of 235.57 g/mol. A proportional rule is applied. Then, as zinc methacrylate can potentially release 2 molecules of methacrylic acid, the starting point is divided by 2. Thus, the corrected starting point for inhalation is: 352 mg/m3 x (6/24) x (5/7) x 235.57 / 86.09 / 2 = 86 mg/m3
AF for dose response relationship:
1
Justification:
Starting point is a NOAEC
AF for differences in duration of exposure:
1
Justification:
Results from chronic studies lead to comparable or higher NOAEC
AF for interspecies differences (allometric scaling):
1
Justification:
AF not used for oral to inhalation route extrapolation
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:
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:
0.25 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):
100
Modified dose descriptor starting point:
NOAEL
Value:
25 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Methacrylate compounds are 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, an additional correction factor needs to be applied for the difference in molecular weights between methacrylic acid and zinc methacrylate: methacrylic acid has a molecular weight of 86.09 g/mol. Zinc methacrylate has a molecular weight of 235.57 g/mol. A proportional rule is applied. Then, as zinc methacrylate can potentially release 2 molecules of methacrylic acid, the starting point is divided by 2. Thus, the corrected starting point for dermal exposure is : 352 mg/m3 x 0.29 m3/kg bw x (6/24) x (5/7) x 235.57 / 86.09 / 2 = 25 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 studies lead to comparable or higher NOAEC
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:
0.6 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:
59 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 zinc methacrylate: methyl methacrylate has a molecular weight of 100.12 g/mol. ZDMA has a molecular weight of 235.57 g/mol. A proportional rule is applied. Then, as zinc methacrylate can potentially release 2 molecules of methacrylic acid, the starting point is divided by 2. Thus, the corrected starting point is : 50 mg/kg bw/d x 235.57 / 100.12 / 2 = 59 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:
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:
medium hazard (no threshold derived)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

Data on zinc compounds (mainly zinc chloride and zinc sulphate) and methacrylic acid (with methyl methacrylate) have been used to deduce the toxicologic properties of zinc methacrylate because the basic assumption is that after intake of zinc methacrylate, 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 zinc methacrylate.

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 DNEL 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:

- DNEL by inhalation: the lowest NOAEC found in sub chronic and chronic studies is 100 ppm for systemic effects, found in the 90-day study by inhalation on methacrylic acid, which is equivalent to 352 mg/m3. As NOAEC comparable or higher than this value were found in chronic studies, this value was used as the point of departure for DNEL calculation as a worst case, but no assessment factor was used for duration extrapolation (from sub-chronic to chronic exposure).

- DNEL by dermal route:

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 (352 mg/m3 from a 90-day study on methcrylic acid) 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.