Tetramethylene dimethacrylate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

14.5 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

Overall assessment factor (AF):

18

Modified dose descriptor starting point:

NOAEC

Value:

261.72 mg/m³

Explanation for the modification of the dose descriptor starting point:

no repeated dose toxicity study via inhalation route is available

AF for dose response relationship:

1

Justification:

The NOAEL is reliable. No adjustment is required.

AF for differences in duration of exposure:

6

Justification:

The NOAEL is based on a 33-40 day study. AF for extrapolation from sub-acute to chronic (ECHA 2008).

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling rat to humans as inhalation; differences in respiratory volume already included in route-to-route extrapolation (ECHA 2008).

AF for other interspecies differences:

1

Justification:

The substances are metabolised via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.

AF for intraspecies differences:

3

Justification:

Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricaboxylic acid cycle) makes a lower variability likely, hence the AF of 3 by ECETOC (2010) is sufficiently conservative for workers.

AF for the quality of the whole database:

1

Justification:

The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

AF for remaining uncertainties:

1

Justification:

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

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.2 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

Overall assessment factor (AF):

72

Modified dose descriptor starting point:

NOAEL

Value:

300 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

no dermal repeated dose toxicity study is available

AF for dose response relationship:

1

Justification:

The NOAEL is reliable. No adjustment is required.

AF for differences in duration of exposure:

6

Justification:

The NOAEL is based on a 33-40 day study. AF for extrapolation from sub-acute to chronic (ECHA 2008).

AF for interspecies differences (allometric scaling):

4

Justification:

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

AF for other interspecies differences:

1

Justification:

The substances are metabolised via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.

AF for intraspecies differences:

3

Justification:

Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricaboxylic acid cycle) makes a lower variability likely, hence the AF of 3 by ECETOC (2010) is sufficiently conservative for workers.

AF for the quality of the whole database:

1

Justification:

The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

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:

no hazard identified

Additional information - workers

Route-to-route extrapolation:

Oral to inhalatory

Only oral studies are available.

Extrapolation oral to inhalation: AF 2

  

Oral to dermal

Only oral studies are available. In the absence of data on dermal uptake, 100% dermal absorption is assumed.

Extrapolation oral to dermal: AF 1

DNEL derivation is based on an OECD 422 guideline study (dose levels: 100, 300 and 1000 mg/kg bw/d).

6/10 females of the high dose group were not pregnant. Reduced litter and mean pup weights were found in the high dose group

Body weight/body weight gain and food consumption were low in the high dose group. A dose-dependent increase in bile acids was noted in males.

Upon microscopic examination in the high dose group the following was noted:

- non-glandular stomach: mild diffused hyperplasia of the squamous epithelium, associated with mild hyperkeratosis (however, no indication of inflammation and/or ulceration)

- liver: minimal degree of multifocal perilobular hepatocytic vacuolation (no inflammation and/or necrosis)

  

-> NOAEL (repeated dose, reproduction) = 300 mg/kg bw/d

  

  

DNEL worker, chronic dermal systemic: 4.2 mg/kg bw/d

Start value: 300 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 300 mg/kg bw/d

Overall AF: 4*1*3*6*1*1 = 72

  

DNEL worker, chronic inhalative systemic: 14.5 mg/m³

Start value: 300 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 261.72 mg/m³

  

inhalatory NOEC (8 h)            = oral NOAEL x 1/sRV_ratx ABS_oral-rat/ ABS_inh-humanx sRV_human/ wRV

                                             = 300 x 1/0.384 x 50/100 x 6.7/10

  

Overall AF: 1*1*3*6*1*1 = 18

Relevance and robustness of the dataset:

The slight effects observed in the study of subacute duration at a limit dose of 1000 mg/kg bw/d suggest a relatively high inherent robustness of the NOAEL used in the assessment. Furthermore, in terms of repeated dose systemic toxicity the members of the category of multifunctional methacrylates demonstrate non-specific toxicity, i.e. effects on body weight gain, organ weight changes and slight histopathological changes thus supporting the findings for 1,4-BDDMA. Also, the current DNELs for the primary metabolites (methacrylic acid and 1,4-butanediol) have been derived from subchronic studies of longer duration and in the case of both metabolites they are in the same order of magnitude or up to several fold higher, indicating that the standard assessment factor is sufficient to compensate for effects of study duration.

The dataset is considered to be robust and reliable and further studies are not required.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.3 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

Overall assessment factor (AF):

30

Modified dose descriptor starting point:

NOAEC

Value:

130.21 mg/m³

Explanation for the modification of the dose descriptor starting point:

no repeated dose toxicity study via inhalation route is available

AF for dose response relationship:

1

Justification:

The NOAEL is reliable. No adjustment is required.

AF for differences in duration of exposure:

6

Justification:

The NOAEL is based on a 33-40 day study. AF for extrapolation from sub-acute to chronic (ECHA 2008).

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling rat to humans as inhalation; differences in respiratory volume already included in route-to-route extrapolation (ECHA 2008).

AF for other interspecies differences:

1

Justification:

The substances are metabolised via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.

AF for intraspecies differences:

5

Justification:

Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of 5 by ECETOC (2010) is sufficiently conservative for the general population.

AF for the quality of the whole database:

1

Justification:

The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

AF for remaining uncertainties:

1

Justification:

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

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.5 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

Overall assessment factor (AF):

120

Modified dose descriptor starting point:

NOAEL

Value:

300 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

no dermal repeated dose toxicity study is available

AF for dose response relationship:

1

Justification:

The NOAEL is reliable. No adjustment is required.

AF for differences in duration of exposure:

6

Justification:

The NOAEL is based on a 33-40 day study. AF for extrapolation from sub-acute to chronic (ECHA 2008).

AF for interspecies differences (allometric scaling):

4

Justification:

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

AF for other interspecies differences:

1

Justification:

The substances are metabolised via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.

AF for intraspecies differences:

5

Justification:

Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of 5 by ECETOC (2010) is sufficiently conservative for the general population.

AF for the quality of the whole database:

1

Justification:

The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

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)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.5 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

Overall assessment factor (AF):

120

Modified dose descriptor starting point:

NOAEL

Value:

300 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

no route-to-route extrapolation required

AF for dose response relationship:

1

Justification:

The NOAEL is reliable. No adjustment is required.

AF for differences in duration of exposure:

6

Justification:

The NOAEL is based on a 33-40 day study. AF for extrapolation from sub-acute to chronic (ECHA 2008).

AF for interspecies differences (allometric scaling):

4

Justification:

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

AF for other interspecies differences:

1

Justification:

The substances are metabolised via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.

AF for intraspecies differences:

5

Justification:

Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of 5 by ECETOC (2010) is sufficiently conservative for the general population.

AF for the quality of the whole database:

1

Justification:

The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

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

Route-to-route extrapolation:

Oral to inhalatory

Only oral studies are available.

Extrapolation oral to inhalation: AF 2

 

Oral to dermal

Only oral studies are available. In the absence of data on dermal uptake, 100% dermal absorption is assumed.

Extrapolation oral to dermal: AF 1

DNEL derivation is based on an OECD 422 guideline study (dose levels: 100, 300 and 1000 mg/kg bw/d).

6/10 females of the high dose group were not pregnant.Reduced litter and mean pup weights were found in the high dose group

Body weight/body weight gain and food consumption were low in the high dose group. A dose-dependent increase in bile acids was noted in males.

Upon microscopic examination in the high dose group the following was noted:

- non-glandural stomach: mild diffused hyperplasia of the squamous epithelium, associated with mild hyperkerathosis (however, no indication of inflammation and/or ulceration)

- liver: minimal degree of multifocal perilobular hepatocytic vacuolation (no inflammation and/or necrosis)

 

-> NOAEL (repeated dose, reproduction) = 300 mg/kg bw/d

DNEL general population, chronic dermal systemic: 2.5 mg/kg bw/d

Start value: 300 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 300 mg/kg bw/d

Overall AF: 4*1*5*6*1*1 = 120

 

DNEL general population, chronic inhalative systemic: 4.3 mg/m³

Start value: 300 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 130.21 mg/m³

inhalatory NOEC (24 h) = oral NOAEL x 1/sRV_ratx ABS_oral-rat/ ABS_inh-human

                                          = 300 x 1/1.152 x 50/100

 

Overall AF: 1*1*5*6*1*1 = 30

 

DNEL general population, chronic oral systemic: 2.5 mg/kg bw/d

Start value: 300 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point: 300 mg/kg bw/d

Overall AF: 4*1*5*6*1*1 = 120

Relevance and robustness of the dataset:

The slight effects observed in the study of subacute duration at a limit dose of 1000 mg/kg bw/d suggest a relatively high inherent robustness of the NOAEL used in the assessment. Furthermore, in terms of repeated dose systemic toxicity the members of the category of multifunctional methacrylates demonstrate non-specific toxicity, i.e. effects on body weight gain, organ weight changes and slight histopathological changes thus supporting the findings for 1,4-BDDMA. Also, the current DNELs for the primary metabolites (methacrylic acid and 1,4-butanediol) have been derived from subchronic studies of longer duration and in the case of both metabolites they are in the same order of magnitude or up to several fold higher, indicating that the standard assessment factor is sufficient to compensate for effects of study duration.

The dataset is considered to be robust and reliable and further studies are not required.