N-[3-(dimethylamino)propyl]methacrylamide

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

26.45 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):

10

Modified dose descriptor starting point:

NOAEC

Value:

264.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

Oral to inhalation route-to-route extrapolation (ECHA, 2008). Correction for rat standard breathing volume (ECHA R8

guidance p. 63, ECHA 2008) -Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (10 m³/6.7 m³) is required (ECHA 2008).

AF for dose response relationship:

1

Justification:

The NOAEC is reliable. No adjustment is required. (see also discussion below).

AF for differences in duration of exposure:

2

Justification:

The NOAEC is based on a 13-week study. AF for extrapolation from sub-chronic to chronic (ECHA 2008).

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scalling rat to humans as inhalation (ECHA 2008). 2.5 for remaining differences not justified (ECETOC, 2010) There is no good reason for an additional factor of 2.5. ECETOC has shown that, as a default mechanism, this is not justified. Taking differences in toxicokinetic into account a normal intraspecies factor is justified but beyond that there is no scientific basis for additional safety factors.

AF for other interspecies differences:

1

Justification:

No other factor required, ubiquitous metabolic pathways, equally present in rodents and humans.

AF for intraspecies differences:

5

Justification:

Default AF for Worker (ECHA R.8, 2012)

AF for the quality of the whole database:

1

Justification:

The key study (being rated K1) as well as the database in general are comprehensive and high quality. No adjustment is required.

AF for remaining uncertainties:

1

Justification:

No further adjustment necessary.

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

7.5 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):

40

Modified dose descriptor starting point:

NOAEL

Value:

300 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No adjustment is necessary (oral to dermal).

AF for dose response relationship:

1

Justification:

The starting point is fully reliable. No adjustment required.

AF for differences in duration of exposure:

2

Justification:

The NOAEL is based on a subchronic study, default AF.

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling rat to humans AF 4 (ECHA 2008). 2.5 for remaining differences not justified (ECETOC, 2010), see comment below.

AF for other interspecies differences:

1

Justification:

No other factor required, ubiquitous metabolic pathways, equally present in rodents and humans.

AF for intraspecies differences:

5

Justification:

Default AF for Worker (ECHA R.8, 2012)

AF for the quality of the whole database:

1

Justification:

The key study (being rated K1) as well as the database in general are comprehensive and of high quality. No adjustment is required.

AF for remaining uncertainties:

1

Justification:

No further adjustment necessary.

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

high 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

Acute, short-term exposure

Acute systemic effects

Since the acute toxicity of N-[3-Dimethylamino)propyl]methacrylamide is low and the vapour pressure is only 0.4 Pa at 20 °C an acutely toxic exposure is not expected.

Acute local effects

N-[3-Dimethylamino)propyl]methacrylamide is strongly irritating to the eyes and irritating and sensitising to skin. DNELs for eye irritation cannot be derived. Also for sensitisation, where all EC3 values in the LLNA are above 3, a DNEL cannot be derived. For both end points only a qualitative risk assessment is required.

The substance is a skin sensitiser, hence, use of dermal protection is indicated whenever a chance for direct dermal contact exists.

Long-term exposure (dermal) - systemic effects

In an OECD 422 Combined repeated dose toxicity study with reproduction/developmental toxicity by oral dosage up to 400 mg/kg bw/d absolute and relative increase in spleen weight were noted in females and a dose related increase of relative kidneys and liver weights in males. Also at 400 mg/kg bw unilateral, slight to moderate tubular atrophy was observed in the testes of 3/5 male animals. All these findings were not seen in a 90 d oral sub-chronic repeated dose toxicity study, OECD 408, where the animals were tested up to 300 mg/kg bw/d with no observed adverse effects. Under the results of the 90 day study the overall NOAEL male/female will be 300 mg/kg bw/d.

On the assumption, that in general, dermal absorption will not be higher than the absorption in the oral study no default factor (factor 1) should be used when performing oral to dermal exposure. Therefore no correction of the NOAEL oral for the dermal route will be necessary.

Calculation of the oral/dermal DNEL for DMAPMA - Workers

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 300 mg/kg bw	NOAEL for rats in a subchronic study
Step 2) Modification of starting point	1	No adjustment is necessary (oral to dermal)
Step 3) Assessment factors
Interspecies	4	Allometric scaling rat to humans AF 4 (ECHA 2008). 2.5 for remaining differences not justified (ECETOC, 2010), see comment below.
Intraspecies	5	Default AF for Worker (ECHA R.8, 2012)
Exposure duration	2	The NOAEL is based on a subchronic study, default AF
Dose response	1	The NOAEL is reliable. No adjustment is required.
Quality of database	1	The key study (being rated K1) as well as the database in general are comprehensive and of high quality. No adjustment is required.
DNEL	Value
based on NOAELratof 300 mg/kg bw	Using a total factor (Allometric scaling and AF) of 40 ( 4 x 5 x 2 x 1) a DNELlong-term,workerof 7.5 mg/kg bw/d is derived.

 

Long-term exposure (inhalation) - systemic effects

Based on POD modifiers for route-to-route extrapolation, rat breathing volume and slight exercise, the corrected NOAEC_inhalbased on a systemic NOAEL of 300 mg/kg bw/d by oral route is 264.5 mg/m³ for inhalation.

 

Calculation of the inhalation DNEL for DMAPMA- Workers

Description	Value	Remark
Step 1) Relevant dose-descriptor	300 mg/kg bw/d	NOAEL in a subchronic study in rats
Step 2) Modification of starting point	2   0.38 m³/kg bw   10 m3/6.7 m3	Oral to inhalation route-to-route extrapolation (ECHA, 2008) Correction for rat standard breathing volume (ECHA R8 guidance p. 63, ECHA 2008) -Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (10 m3/6.7 m3) is required (ECHA 2008).
Modified starting point	264.5 mg/m³
Step 3) Assessment factors	1	No allometric scaling rat to humans as intraspecies adjustment is accounted for in relative breathing volumes. 2.5 for remaining differences not justified (ECETOC, 2010).
Interspecies	1	No allometric scaling rat to humans as inhalation (ECHA 2008). 2.5 for remaining differences not justified (ECETOC, 2010, in press) *
Intraspecies	5	Default AF for Worker (ECHA R.8, 2012)
Exposure duration	2	The NOAEC is based on a 13-week study. AF for extrapolation from Sub-chronic to chronic (ECHA 2008).
Dose response	1	The NOAEC is reliable. No adjustment is required. (see also discussion below)
Quality of database	1	The key study (being rated K1) as well as the database in general are comprehensive and of high quality. No adjustment is required.
DNEL	Value
Based on NOAEL of 300 mg/kg bw in a subchronic study in rats	Using a POD modifier of 1.13 (2 x 0.38 x 10/6.7) and an AF of 10 (5 x 2) a DNELlong-term,workerof 26.45 mg/m^3is derived.

* There is no good reason for an additional factor of 2.5. ECETOC has shown that, as a default mechanism, this is not justified. Taking differences in toxicokinetics into account a normal intraspecies factor is justified but beyond that there is no scientific basis for additional safety factors.

Long-term exposure (dermal) - local effects

As indicated in the acute section, the substance is a skin sensitiser, hence, use of dermal protection is indicated whenever a chance for direct dermal contact exists.

ECHA, 2008/2012, Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health

ECETOC, 2010 Guidance on Assessment Factors to Derive a DNEL, Technical Report No. 110, ISSN-0773-8072-110.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

6.5 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):

20

Modified dose descriptor starting point:

NOAEC

Value:

130.4 mg/m³

Explanation for the modification of the dose descriptor starting point:

Oral to inhalation route-to-route extrapolation (ECHA, 2008). Correction for rat standard breathing volume vs. humans,

24 h exposure (ECHA R8 guidance p. 63, ECHA 2008) -No correction for activity driven differences of respiratory volumes required for general population (ECHA 2008).

AF for dose response relationship:

1

Justification:

The NOAEC is reliable. No adjustment is required. (see also discussion below).

AF for differences in duration of exposure:

2

Justification:

The NOAEC is based on a 13-week study. AF for extrapolation from Sub-chronic to chronic (ECHA 2008).

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling rat to humans as inhalation (ECHA 2008). 2.5 for remaining differences not justified (ECETOC, 2010). ECHA, 2008, Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health.

AF for other interspecies differences:

1

Justification:

No other factor required, ubiquitous metabolic pathways, equally present in rodents and humans.

AF for intraspecies differences:

10

Justification:

Default AF for General Population (ECHA R.8, 2012)

AF for the quality of the whole database:

1

Justification:

The key study (being rated K1) as well as the database in general are comprehensive and of high quality. No adjustment is required.

AF for remaining uncertainties:

1

Justification:

No further adjustment necessary.

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.75 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):

80

Modified dose descriptor starting point:

NOAEL

Value:

300 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No adjustment is necessary (oral to dermal).

AF for dose response relationship:

1

Justification:

The NOAEL is reliable. No adjustment is required.

AF for differences in duration of exposure:

2

Justification:

The NOAEL is based on a subchronic study, default AF.

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling rat to humans AF 4 (ECHA 2008). 2.5 for remaining differences not justified (ECETOC, 2010).

AF for other interspecies differences:

1

Justification:

No other factor required, ubiquitous metabolic pathways, equally present in rodents and humans.

AF for intraspecies differences:

10

Justification:

Default AF for General Population (ECHA R.8, 2012)

AF for the quality of the whole database:

1

Justification:

The key study (being rated K1) as well as the database in general are comprehensive and of high quality. No adjustment is required.

AF for remaining uncertainties:

1

Justification:

No further adjustment necessary.

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.75 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):

80

Modified dose descriptor starting point:

NOAEL

Value:

300 mg/kg bw/day

AF for dose response relationship:

1

Justification:

The starting point is fully reliable. No adjustment required.

AF for differences in duration of exposure:

2

Justification:

The NOAEL is based on a subchronic study, default AF.

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling rat to humans AF 4 (ECHA 2008). 2.5 for remaining differences not justified (ECETOC, 2010), see comment below.

AF for other interspecies differences:

1

Justification:

No other factor required, ubiquitous metabolic pathways, equally present in rodents and humans.

AF for intraspecies differences:

10

Justification:

Default AF for General Population (ECHA R.8, 2012)

AF for the quality of the whole database:

1

Justification:

The key study (being rated K1) as well as the database in general are comprehensive and of high quality. No adjustment is required.

AF for remaining uncertainties:

1

Justification:

No further adjustment necessary.

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - General Population

Acute, short-term exposure

Acute systemic effects

Since the acute toxicity of N-[3-Dimethylamino)propyl]methacrylamide is low and the vapour pressure is only 0.4 Pa at 20 °C an acutely toxic exposure is not expected for the general population.

Acute local effects

N-[3-Dimethylamino)propyl]methacrylamide is strongly irritating to the eyes and sensitising to skin. DNELs for eye irritation cannot be derived. Also for sensitisation, where all EC3 values in the LLNA are above 3, a DNEL cannot be derived. For both end points only a qualitative risk assessment is required.

The substance is a skin sensitiser, hence, use of dermal protection is indicated whenever a chance for direct dermal contact exists and the potential for irreversible eye damage has to be taken into account devising handling recommendations for the general public.

Long-term exposure (dermal) - systemic effects

As in the case of workers the NOAEL of 300 mg/kg bw/d for systemic effects in a 90 d oral sub-chronic repeated dose toxicity study, OECD 408, was chosen as the point of departure for the derivation of the DNEL.

Calculation of the oral/dermal DNEL for DMAPMA – General population

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 300 mg/kg bw	NOAEL for rats in a subchronic study
Step 2) Modification of starting point	1	No adjustment is necessary (oral to dermal)
Step 3) Assessment factors
Interspecies	4	Allometric scaling rat to humans AF 4 (ECHA 2008). 2.5 for remaining differences not justified (ECETOC, 2010), see comment above.
Intraspecies	10	Default AF for General Population (ECHA R.8, 2012)
Exposure duration	2	The NOAEL is based on a subchronic study, default AF
Dose response	1	The NOAEL is reliable. No adjustment is required. (see also discussion above)
Quality of database	1	The key study (being rated K1) as well as the database in general are comprehensive and of high quality. No adjustment is required.
DNEL	Value
based on NOAELratof 300 mg/kg bw	Using a total factor (Allometric scaling and AF) of 80 ( 4 x 10 x 2 x 1) a DNELlong-term,general pop.of 3.75 mg/kg bw/d is derived.

 

Long-term exposure (inhalation) - systemic effects

As in the case of workers the NOAEL of 300 mg/kg bw/d in a 90 d oral sub-chronic repeated dose toxicity study, OECD 408, was chosen as the point of departure for the derivation of the DNEL

Based on POD modifiers for route-to-route extrapolation and rat breathing volume the corrected NOAEC_inhalbased on a systemic NOAEL of 300 mg/kg bw/d by oral route is 130.4 mg/m³ for inhalation.

 

Calculation of the inhalation DNEL for DMAPMA- General Population

Description	Value	Remark
Step 1) Relevant dose-descriptor	300 mg/kg bw/d	NOAEL in a subchronic study in rats
Step 2) Modification of starting point	2   1.15 m³/kg bw   -	Oral to inhalation route-to-route extrapolation (ECHA, 2008) Correction for rat standard breathing volume vs. humans, 24 h exposure (ECHA R8 guidance p. 63, ECHA 2008) -No correction for activity driven differences of respiratory volumes required for general population (ECHA 2008).
Modified starting point	130.4 mg/m³
Step 3) Assessment factors
Interspecies	1	No allometric scaling rat to humans as inhalation (ECHA 2008). 2.5 for remaining differences not justified (ECETOC, 2010, in press) *
Intraspecies	10	Default AF for General Population (ECHA R.8, 2012)
Exposure duration	2	The NOAEC is based on a 13-week study. AF for extrapolation from Sub-chronic to chronic (ECHA 2008).
Dose response	1	The NOAEC is reliable. No adjustment is required. (see also discussion below)
Quality of database	1	The key study (being rated K1) as well as the database in general are comprehensive and of high quality. No adjustment is required.
DNEL	Value
Based on NOAEL of 300 mg/kg bw in a subchronic study in rats	Using a total factor (POD modifier and AF) of 46 (2 x 1.15 x 10 x 2) a DNELlong-term,general pop.of 6.5 mg/m^3is derived.

* ECHA, 2008/2012, Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration] response for human health