N-isopropylmethacrylamide

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.89 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA REACH Guidance and ECETOC 2010

Overall assessment factor (AF):

18

Modified dose descriptor starting point:

LOAEC

Value:

88.1 mg/m³

Explanation for the modification of the dose descriptor starting point:

Route to route extraploation required for oral to inhalation route and modification of the starting point performed (see discussion section).

AF for dose response relationship:

3

Justification:

For the minimal adverse effects observed in the OECD 422 study, an AF of 3 for extrapolation of LOAEC to NOAEC is considered sufficient.

AF for differences in duration of exposure:

2

Justification:

Extrapolation for subchronic to chronic study durations (OECD 422 is considered as a subchronic study as standard)

AF for interspecies differences (allometric scaling):

1

Justification:

AF for allometric scaling not required as the differences in allometry (respiration rate and rat to human body sizes) were considered in the conversion from oral to inhalation starting point (see discussion section).

AF for other interspecies differences:

1

Justification:

An extra AF for additional toxicodynamic differences was not applied, as inhalation absorption to oral absorption was assessed in the modificatio of starting point.

AF for intraspecies differences:

3

Justification:

In analogy to the structurally closely related methacrylamide, a standard mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases) is expected and makes a lower variability likely, hence the AF of 3 by ECETOC (2010) for workers is sufficiently conservative.

AF for the quality of the whole database:

1

Justification:

The key study is of high quality (reliability 1) and no further adjustment is required.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties identified.

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:

1.39 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA REACH Guidance and ECETOC 2010

Overall assessment factor (AF):

72

Modified dose descriptor starting point:

LOAEL

Value:

100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No adjustment of starting dose descriptor required for oral to dermal extrapolation.

AF for dose response relationship:

3

Justification:

For the minimal adverse effects observed in the OECD 422 study, an AF of 3 for extrapolation of LOAEL to NOAEL is considered sufficient.

AF for differences in duration of exposure:

2

Justification:

Extrapolation for subchronic to chronic study durations (OECD 422 is considered as a subchronic study as standard).

AF for interspecies differences (allometric scaling):

4

Justification:

Default AF for allometric scaling based on rat to human (ECHA)

AF for other interspecies differences:

1

Justification:

An extra AF for additional toxicodynamic differences was not applied, as dermal absorption is expected to be lower in humans as in rats.

AF for intraspecies differences:

3

Justification:

In analogy to the structurally closely related methacrylamide, a standard mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases) is expected and makes a lower variability likely, hence the AF of 3 by ECETOC (2010) for workers is sufficiently conservative.

AF for the quality of the whole database:

1

Justification:

The key study is of high quality (reliability 1) and no further adjustment is required.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties identified.

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

The substance is classified for human health as STOT Rep. Exp. 2.

Inhalation:

Inhalation is not considered to be a significant route of exposure. However, a long-term DNEL for systemic effects have been derived, based on the results obtained OECD 422 Oral (Gavage) Combined Repeat Dose Toxicity Study With Reproduction / Developmental Toxicity Screening Test in the Rat conducted on the substance.

Long-term systemic effects:

A modification of the dose dsecrptior starting point (oral to inhalation) was conducted. It is assumed as a worst case assumption that the oral absorption rate is 50% of that of the inhalation absorption. In practice this is unlikely to be the case based on the particle size distribution 0.165% of particles being less than 100μm and substance being considered to be essentially non-inhalable).

The corrected dose descriptor (LOAEC) for inhalation was calculated in accordance with the ECHA Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health.

The conversion of an oral rat LOAEL into a corrected inhalatory LOAEC to assess human inhalatory exposure was performed using the modification of starting point equation as given in Figure R. 8-3 (see below) for workers (in the case of 8 hour exposure/day).

Default parameters for rats and humans (for 8 hour exposure) were used for the modification of starting point under the allometric scaling principle as given in Table R. 8-2 of the above ECHA guidance.

Conversion of an oral rate N(L) OAEL into a correct inhalatory N(L) OAEC to assess human inhalatory exposure:

For workers (in case of 8h exposure/day):

Corrected inhalatory N(L) OAEC = oral N(L) OAEL x (1 / sRVrat) x (ABSoral-rat / ABSinh-human) x (sRVhuman / wRV)

Corrected inhalatory N(L) OAEC= 100 mg/kg bw/day x (1 / 0.38 m³/kg/d) x (0.5) x (6.7 m³(8h) / 10 m³(8h))= 88.1 mg/m³

^Where:

^{ABS: Absorption}

^{sRV: standard Respiratory Volume}

^{wRV: worker Respiratory Volume (light activity)}

^{Default parametrs:}

sRVrat (8 h) : 0.38m³/kg bw

sRVhuman (8 h) : 6.7 m³/ person

wRV (8 h): 10 m³/ person

The appropriate assessment factors were then applied to give an overall assessment factor of 18.

Long-term systemic DNEL (inhalation) = 4.89 mg/m³

This long-term inhalation systemic effect DNEL is used in the quantitative assessment of risk for systemic toxicity to workers via the inhalation route.

A 90 -day inhalation study has been conducted on a structurally closely related substance (methacrylamide), but this study has not been used for DNEL derivation, as it was considered more appropriate to derive DNELs from study results on the substance (NIPMAA) itself.

Dermal:

A DNEL has been derived for long-term systemic effects by the dermal route, based on the results obtained OECD 422 Oral (Gavage) Combined Repeat Dose Toxicity Study With Reproduction / Developmental Toxicity Screening Test in the Rat conducted on the substance.

Long-term systemic DNEL (dermal) = 1.39 mg/kg bw/day

This long-term inhalation systemic effect DNEL is used in the quantitative assessment of risk for systemic toxicity to workers via the dermal route.

DNELs for local effects have not been derived since the substance is not classified as an irritant or sensitiser, and studies showed only minimal irritation effects, all of which were fully reversible.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

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:

no hazard identified

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:

0.83 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA REACH Guidance and ECETOC 2010

Overall assessment factor (AF):

120

Modified dose descriptor starting point:

LOAEL

Value:

100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Not required as key result from an oral OECD 422 study.

AF for dose response relationship:

3

Justification:

For the minimal adverse effects observed in the OECD 422 study, a AF of 3 for extrapolation of LOAEL to NOAEL is considered sufficient.

AF for differences in duration of exposure:

2

Justification:

Extrapolation for subchronic to chronic study durations (OECD 422 is considered as a subchronic study as standard).

AF for interspecies differences (allometric scaling):

4

Justification:

Default AF for allometric scaling based on rat to human (ECHA)

AF for other interspecies differences:

1

Justification:

An extra AF for additional toxicodynamic differences was not applied as route to route extrapolation not required.

AF for intraspecies differences:

5

Justification:

In analogy to the structurally closely related methacrylamide, a standard mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases) is expected and makes a lower variability likely, hence the AF of 5 by ECETOC (2010) for general population is sufficiently conservative.

AF for the quality of the whole database:

1

Justification:

The key study is of high quality (reliability 1) and no further adjustment is required.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties identified.

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

DNELs have not been derived for the general public (apart from via the oral route for systemic effects) as there will be no exposure to the general public/consumers.

A DNEL for long term systemic effects via the oral route has been derived, in order to assess indirect exposure of humans via the environment. The DNEL derived is based on the LOAEL result of 100 mg/kg bw/day. The DNEL is therefore 0.83 mg/kg bw/day based on use of an overall assessment factor of 120.