1,1'-(4-methyl-1,3-phenylene)bis-1H-pyrrole-2,5-dione

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.64 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):

75

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

123.35 mg/m³

Explanation for the modification of the dose descriptor starting point:

Long term inhalation studies are not available. The long term systemic DNEL for inhalation has been derived from the oral subacute repeated dose toxicity study. A Reproduction/ Developmental toxicity screening study with the maximum dose level of 60 mg/kg bw/day is available in which the highest dose of 60 mg/kg bw/d was applied. Thus, the dervation from the oral repeated dose toxicity study is justified because here the highest dose without observed adverse effects is 100 mg/kg bw /d and toxicity to reproduction is not expected. For derivation of the dose descriptor starting point a factor of 2 has been included for route-to-route extrapolation from oral to inhalative.

AF for dose response relationship:

1

Justification:

Default ECHA AF for NOAEL used as starting point.

AF for differences in duration of exposure:

6

Justification:

Default assessment factor for extrapolation from subacute to chronic.

AF for interspecies differences (allometric scaling):

1

Justification:

Default corrections for respiratory rate and respiratory volume have been included in route-to-route extrapolation.

AF for other interspecies differences:

2.5

Justification:

Default assessment factor for remaining differences.

AF for intraspecies differences:

5

Justification:

Default assessment factor for intraspecies differences.

AF for the quality of the whole database:

1

Justification:

The key study was conducted according to modern regulatory standards and was adequately reported. The database is not considered to contribute uncertainty, no additional factor needed.

AF for remaining uncertainties:

1

Justification:

The key study was conducted according to modern regulatory standards and was adequately reported. Thus, there are no remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

medium 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:

0.467 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):

300

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

140 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Long term studies with dermal exposure are not available. The long term systemic DNEL for dermal exposure has been derived from the oral subacute repeated dose toxicity study.

A Reproduction/ Developmental toxicity screening study with the maximum dose level of 60 mg/kg bw/day is available in which the highest dose of 60 mg/kg bw/d was applied. Thus, the dervation from the oral repeated dose toxicity study is justified because here the highest dose without observed adverse effects is 100 mg/kg bw /d and toxicity to reproduction is not expected.

AF for dose response relationship:

1

Justification:

Default ECHA AF for NOAEL used as starting point.

AF for differences in duration of exposure:

6

Justification:

Default assessment factor for extrapolation from subacute to chronic.

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling rat to humans AF 4 (ECHA 2008).

AF for other interspecies differences:

2.5

Justification:

Default assessment factor for remaining differences.

AF for intraspecies differences:

5

Justification:

Default assessment factor for intraspecies differences.

AF for the quality of the whole database:

1

Justification:

The key study was conducted according to modern regulatory standards and was adequately reported. The quality of the database is not considered to contribute uncertainty, no additional factor needed.

AF for remaining uncertainties:

1

Justification:

The key study was conducted according to modern regulatory standards and was adequately reported. Thus, there are no remaining uncertainties.

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:

medium hazard (no threshold derived)

Additional information - workers

Selection of the relevant dose descriptors:

Oral:

NOAEL =100 mg/kg bw/day: subacute repeated dose toxicity study, rat, oral (gavage)

 

Modification of the relevant dose descriptors to the correct starting point: 

Oral absorption

The physicochemical properties of 2,4-Bismaleimidotoluene (log Kow = -0.036) and the molecular weight of 282.25 g/mol are in a range suggestive of absorption from the gastro-intestinal tract subsequent to oral ingestion (molecular weight < 500 g/mol, log Kow between -1 and 4).

For chemical safety assessment an oral absorption rate of 50% is assumed as a worst case default value in the absence of other data

 

Dermal absorption

In the absence of detailed dermal penetration data it has to be assumed that dermal penetration may occur.

For chemical safety assessment a dermal absorption rate of 50% is assumed as a worst case default value.

 

Inhalation absorption

For chemical safety assessment an inhalation absorption rate of 100% is assumed as a worst case default value due to an acute toxicity by inhalation study according to OECD 403; RL1, GLP. At a concentration of 5.77 mg/L three female animals and all of the animals receiving 28.1 mg/L for 4 h died within the first 24 h after exposure. The results indicate that the adverse effects are caused by local toxicity. Thus, twice as high absorption is assumed compared to oral absorption (Guidance on Information Requirements and Chemical Safety Assessment, R8).

Extrapolation oral to inhalation: AF 2

 

DERIVATION OF DNELs

DNELs derived from subacute repeated dose toxicity NOAEL (OECD guideline 407)

 

Worker-DNEL long-term for inhalation route (systemic): 1.64 mg/m³

Start value: 100 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 123.35 mg/m³

 

For workers the corrected inhalation NOEC is calculated according to the following equation:

corrected inhalation NOAEC  = oral NOAEL x 1/sRVrat x ABSoral-rat/ ABSinh-human x sRVhuman/ wRV

                                             = 100 x 1/0.38 x 50/100 x 6.7/10

The corrected inhalation NOAEC worker (8h) is therefore:

                                             = 88.1 mg/m³ (8h-TWA)

In order to meet the demands already implemented in the default settings of the DNEL-calculator used in IUCLID 6 an additional correction-factor has to be applied with respect to differences between experimental conditions and working conditions. Since the duration of exposure is normally 7 days per week for the experimental conditions and 5 days per week for the working conditions the following factor has to be applied:

7 days per week / 5 days per week = 1.4

The corrected inhalation NOAECworker (8h) is therefore:

                                             = 87.1 mg/m³ (8h-TWA)

and with the additional corrections factor of 1.4:

                                               = 123.35 mg/m³ (8h-TWA)

Overall AF: 1*6*1*2.5*5*1 = 75

 

This DNEL does not address the potential for local irritation. The risk characterisation will consider whether specific risk management measures are necessary to protect against local effects.

 

Worker-DNEL long-term for dermal route (systemic):  0.467 mg/kg bw/d

Start value: 100 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 100 mg/kg bw/d

For workers the corrected inhalation NOEC is calculated according to the following equation:

corrected dermal NOAEL  = oral NOAEL x ABSoral-rat/ ABSderm-human

                                             = 100 x 100/100

The corrected inhalation NOAEC worker (8h) is therefore:

                                             = 100 mg/m³ (8h-TWA)

In order to meet the demands already implemented in the default settings of the DNEL-calculator used in IUCLID 6 an additional correction-factor has to be applied with respect to differences between experimental conditions and working conditions. Since the duration of exposure is normally 7 days per week for the experimental conditions and 5 days per week for the working conditions the following factor has to be applied:

7 days per week / 5 days per week = 1.4

The corrected dermal NOAELworker (8h) is therefore:

                                             = 100 mg/m³ (8h-TWA)

and with the additional corrections factor of 1.4:

                                               = 140 mg/m³ (8h-TWA)

 

Overall AF: 1*6*4*2.5*5*1 = 300

 

 The DNELs for toxicity to reproduction are lower than those for repeated dose toxicity. Since, the dose levels for the high dose group in the reproduction/developemntal study are the maximum dose applied, the repeated dose toxicity-DNELs are also considered to be also protective for development since up to 100 mg/kg bw no adverese effect is expected.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.29 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):

150

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

43.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

Long term inhalation studies are not available. The long term systemic DNEL for inhalation has been derived from the oral subacute repeated dose toxicity study. For derivation of the dose descriptor starting point a factor of 2 has been included for route-to-route extrapolation from oral to inhalative.

AF for dose response relationship:

1

Justification:

Default ECHA AF for NOAEL used as starting point.

AF for differences in duration of exposure:

6

Justification:

Default assessment factor for extrapolation from subacute to chronic.

AF for interspecies differences (allometric scaling):

1

Justification:

Default corrections for respiratory rate and respiratory volume have been included in route-to-route extrapolation.

AF for other interspecies differences:

2.5

Justification:

Default assessment factor for remaining differences.

AF for intraspecies differences:

10

Justification:

Default assessment factor intraspecies differences due to lack of data regarding pathways for metabolism.

AF for the quality of the whole database:

1

Justification:

The key study was conducted according to modern regulatory standards and was adequately reported. The quality of the database is not considered to contribute uncertainty, no additional factor needed.

AF for remaining uncertainties:

1

Justification:

The key study was conducted according to modern regulatory standards and was adequately reported. Thus, there are no remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

DNEL related information

Explanation for the modification of the dose descriptor starting point:

The substance is classified as acute toxic by inhalation Category 2. Thus, according to the Guidance on information requirements and chemical safety assessment, Part E: Risk Characterisation, the substance is of high hazard.

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

medium 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:

0.167 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):

600

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Long term studies with dermal exposure are not available. The long term systemic DNEL for dermal exposure has been derived from the oral subacute repeated dose toxicity study.

A Reproduction/ Developmental toxicity screening study with the maximum dose level of 60 mg/kg bw/day is available in which the highest dose of 60 mg/kg bw/d was applied. Thus, the dervation from the oral repeated dose toxicity study is justified because here the highest dose without observed adverse effects is 100 mg/kg bw /d and toxicity to reproduction is not expected.

AF for dose response relationship:

1

Justification:

Default (DNEL calculator)

AF for differences in duration of exposure:

6

Justification:

Default (DNEL calculator)

AF for interspecies differences (allometric scaling):

4

Justification:

Default (DNEL calculator)

AF for other interspecies differences:

2.5

Justification:

Default (DNEL calculator)

AF for intraspecies differences:

10

Justification:

Default (DNEL calculator)

AF for the quality of the whole database:

1

Justification:

Default (DNEL calculator)

AF for remaining uncertainties:

1

Justification:

The key study was conducted according to modern regulatory standards and was adequately reported. Thus, there are no remaining uncertainties.

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:

0.167 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):

600

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The long term systemic DNEL for oral exposure has been derived from the oral subacute repeated dose toxicity study. A Reproduction/ Developmental toxicity screening study with the maximum dose level of 60 mg/kg bw/day is available in which the highest dose of 60 mg/kg bw/d was applied. Thus, the dervation from the oral repeated dose toxicity study is justified because here the highest dose without observed adverse effects is 100 mg/kg bw /d and toxicity to reproduction is not expected.

AF for dose response relationship:

1

Justification:

Default ECHA AF for NOAEL used as starting point.

AF for differences in duration of exposure:

6

Justification:

Default assessment factor for extrapolation from subacute to chronic.

AF for interspecies differences (allometric scaling):

4

Justification:

Default correction for allometric scaling.

AF for other interspecies differences:

2.5

Justification:

Default correction for remaining differences.

AF for intraspecies differences:

10

Justification:

Default assessment factor for intraspecies differences.

AF for the quality of the whole database:

1

Justification:

The key study was conducted according to modern regulatory standards and was adequately reported.The database is not considered to contribute uncertainty, no additional factor nedded.

AF for remaining uncertainties:

1

Justification:

The key study was conducted according to modern regulatory standards and was adequately reported. Thus, there are no remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Explanation for the modification of the dose descriptor starting point:

No DNEL derived: short-term exposure is controlled by conditions for long-term.

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

Selection of the relevant dose descriptors:

Oral:

NOAEL =100 mg/kg bw/day: subacute repeated dose toxicity study, rat, oral (gavage); OECD 407

Modification of the relevant dose descriptors to the correct starting point: 

Oral absorption

The physicochemical properties of 2,4-Bismaleimidotoluene (log Kow = -0.0036) and the molecular weight of 282.25 g/mol are in a range suggestive of absorption from the gastro-intestinal tract subsequent to oral ingestion (molecular weight < 500 g/mol, log Kow between -1 and 4).

For chemical safety assessment an oral absorption rate of 100% is assumed as a worst case default value in the absence of other data.

Dermal absorption

In the absence of detailed dermal penetration data it has to be assumed that dermal penetration may occur.

For chemical safety assessment a dermal absorption rate of 100% is assumed as a worst case default value.

Inhalation absorption

For chemical safety assessment an inhalation absorption rate of 100% is assumed as a worst case default value due to an acute toxicity by inhalation study according to OECD 403; RL1, GLP.At a concentration of 5.77 mg/L three female animals and all of the animals receiving 28.1 mg/L for 4 h died within the first 24 h after exposure. The results indicate that the adverse effects are caused by local toxicity. Thus, twice as high absorption is assumed compared to oral absorption (Guidance on Information Requirements and Chemical Safety Assessment, R8).

Extrapolation oral to inhalation: AF 2

DERIVATION OF DNELs

DNELs derived from subacute repeated dose toxicity NOAEL (OECD guideline 407)

General population-DNEL long-term for inhalation route (systemic): 0.29 mg/m³

Start value: 100 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 43.5 mg/m³

For general population the corrected inhalation NOEC is calculated according to the following equation:

corrected inhalation NOAEC  = oral NOAEL x 1/sRVrat x ABSoral-rat/ ABSinh-human

                                             = 100 x 1/1.152 x 50/100

The corrected inhalation NOAECgeneral population (24 h) is therefore:

                                             = 43.5 mg/m³ (24 h)

Overall AF: 1*6*1*2.5*10*1 = 150

This DNEL does not address the potential for local irritation. The risk characterisation will consider whether specific risk management measures are necessary to protect against local effects.

general population-DNEL long-term for dermal route (systemic):  0.1667 mg/kg bw/d

Start value: 100 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 100 mg/kg bw/d

Overall AF: 1*6*4*2.5*10*1 = 600

general population-DNEL long-term for oral route (systemic):  0.1667 mg/kg bw/d

Start value: 100 mg/kg bw/d

Route of original study: oral

Overall AF: 1*6*4*2.5*10*1 = 600