Reaction products of tetraethylenepentamine and maleic anhydride

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

23.51 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

Modified dose descriptor starting point:

NOAEC

Value:

1 763.16 mg/m³

Explanation for the modification of the dose descriptor starting point:

Relevant inhalation study is not available

AF for dose response relationship:

1

Justification:

adequate data available

AF for differences in duration of exposure:

6

Justification:

subacute to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

covered in route-to-route extrapolation

AF for other interspecies differences:

2.5

Justification:

rat to human

AF for intraspecies differences:

5

Justification:

worker population

AF for the quality of the whole database:

1

Justification:

no need for a further assessment factor

AF for remaining uncertainties:

1

Justification:

no need for a further assessment factor

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:

3.33 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

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Relevant study via dermal application is not available

AF for dose response relationship:

1

Justification:

adequate data available

AF for differences in duration of exposure:

6

Justification:

subacute to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

rat to human

AF for other interspecies differences:

2.5

Justification:

rat to human

AF for intraspecies differences:

5

Justification:

worker population

AF for the quality of the whole database:

1

Justification:

no need for a further assessment factor

AF for remaining uncertainties:

1

Justification:

no need for a further assessment factor

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:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

Acute/short term exposure (systemic and local effects):

- No data are available for acute toxicity via the inhalation route. A key study is available for the oral route of exposure and for the dermal route of exposure. According to the REACH Regulation, only one additional route of exposure other than the oral route of exposure should be tested for acute toxicity (column 2, annex VIII, section 8.5). Therefore it is not necessary to perform an acute toxicity study via the inhalation route of exposure.

- An acute dermal toxicity study has been performed in rats. The LD50 was determined to be > 2000 mg/kg (based on active ingredient). Therefore the substance is not classified based on CLP Regulation. As no peak exposure is anticipated for this substance, it is considered that the long-term DNEL is sufficiently protective for acute exposure.

- According to the criteria of the CLP Regulation, the substance is classified as skin sensitizing (category 1B, H317). According to ECHA’s Guidance on Information Requirements and Chemical Safety Assessment, part E, Table E.3-1 the substance should be considered to cause moderate hazard.

Long-term exposure (systemic effects):

- Dermal: No long-term dermal toxicity studies are available for the substance. An oral combined repeated dose toxicity study with reproduction/developmental toxicity screening (OECD 422) with the substance could be used after extrapolation to the dermal route. Exposures were daily via oral gavage during 42 days (females) and 43 or 44 days for males (Rashid, 2015). Wistar rats (12 per sex and per dose) were treated at dose levels of 100, 300 and 1000 mg/kg/day (active ingredient). A control group of 12 males and 12 females received concurrent vehicle treatment. The NOAEL was considered to be the high dose of 1000 mg/kg/day. For route-to-route extrapolation (oral to dermal) no factor needs to be applied as it is assumed that oral and dermal absorption will be similar (assumed to be 50%). The dose descriptor starting point is 1000 mg/kg/day. The long-term dermal systemic DNEL is derived with an overall assessment factor of 300 : 4 (allometric scaling) x 2.5 (interspecies differences) x 6 (difference in duration subacute to chronic) x 5 (intraspecies differences). A long-term systemic DNEL of 1000 mg/kg/day/300 = 3.33 mg/kg/day is derived.

- Inhalation: the NOAEL observed in the combined repeated dose toxicity study with reproduction/developmental screening toxicity with the substance was used to derive a DNEL long-term, systemic effects via the inhalation route. For the route-to-route extrapolation from oral to inhalation, the dose descriptor starting point = 1000 mg/kg/day x 1/(0.38 m³/kg/day) x 6.7 m³/10m³ = 1763.16 mg/m³. The oral dose for rats was converted to the corresponding air concentration using a standard breathing volume for the rat (0.38 m³/kg for 8 hours exposure for workers). For workers the resulting air concentration needs to be additionally corrected for the difference between basal caloric demand and caloric demand under light activity. This correction factor is derived from the inhaled volumes in 8 hours under the respective conditions (6.7 m³for base level, 10 m³for light activity). The bioavailability via the inhalation route is considered to be similar to bioavailability after oral exposure, i.e. 50%. With an overall assessment factor of 75: 6 (difference in duration subacute to chronic) x 5 (intraspecies differences) x 2.5 (interspecies – remaining differences), the long-term DNEL, inhalation for systemic effects of 1763.16 mg/m³/75 = 23.51 mg/m³.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.54 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

Modified dose descriptor starting point:

NOAEC

Value:

230 mg/m³

Explanation for the modification of the dose descriptor starting point:

Relevant inhalation study is not available

AF for dose response relationship:

1

Justification:

adequate data available

AF for differences in duration of exposure:

6

Justification:

subacute to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

rat to human

AF for other interspecies differences:

2.5

Justification:

rat to human

AF for intraspecies differences:

10

Justification:

general population

AF for the quality of the whole database:

1

Justification:

no need for further assessment factor

AF for remaining uncertainties:

1

Justification:

no need for further assessment factor

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:

1.67 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

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Relevant study via dermal application is not available

AF for dose response relationship:

1

Justification:

adequate data available

AF for differences in duration of exposure:

6

Justification:

subacute to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

rat to human

AF for other interspecies differences:

2.5

Justification:

rat to human

AF for intraspecies differences:

10

Justification:

general population

AF for the quality of the whole database:

1

Justification:

no need for further assessment factor

AF for remaining uncertainties:

1

Justification:

no need for further assessment factor

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)

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:

1.67 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:

1 000 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:

adequate data available

AF for differences in duration of exposure:

6

Justification:

subacute to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

rat to human

AF for other interspecies differences:

2.5

Justification:

rat to human

AF for intraspecies differences:

10

Justification:

general population

AF for the quality of the whole database:

1

Justification:

no need for further assessment factor

AF for remaining uncertainties:

1

Justification:

no need for further assessment factor

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

Acute/short-term exposure (systemic and local effects):

- An acute oral toxicity test has been performed in rats. The LD50 was >1000 mg/kg (active ingredient) and > 2000 mg/kg (test item). According to the criteria of the CLP regulation, the substance is not to be classified. As no peak exposure is anticipated for this substance, it is considered that the long-term DNEL is sufficiently protective for acute exposure.

- An acute dermal toxicity test has been performed in rats. The LD50 was > 2000 mg/kg (active ingredient). According to the criteria of the CLP Regulation, the substance is not to be classified via dermal application. As no peak exposure is anticipated for this substance, it is considered that the long-term DNEL is sufficiently protective for acute exposure.

- No data are available for acute toxicity via the inhalation route. A key study is available for the oral route of exposure and for the dermal route of exposure. According to the REACH Regulation, only one additional route of exposure should be tested other than the oral route of exposure for acute toxicity (column 2, annex VIII, section 8.5). Therefore, it is not necessary to perform an acute toxicity study via the inhalation route of exposure.

- According to the criteria of the CLP Regulation, the substance is classified as skin sensitizing (category 1B, H317). According to ECHA’s Guidance on Information Requirements and Chemical Safety Assessment, part E, Table E.3-1 the substance should be considered to cause moderate hazard.

Long-term exposure (systemic effects)

- Inhalation:The NOAEL observed in the combined repeated dose toxicity study with reproduction/developmental toxicity screening with the substance was used to derive a DNEL long-term, systemic effects via the inhalation route. For the route-to-route extrapolation from oral to inhalation, the dose descriptor starting point = 1000 mg/kg bw/day x 1/(1.15 m³/kg/day)= 230 mg/m³.The dermal dose for rats was converted to the corresponding air concentration using a standard breathing volume for the rat (1.15 m³/kg for 24 hours exposure).The bioavailability via the inhalation route is considered 50%, similar to that after oral exposure No correction for the exposure duration was added as the animals in the reference study were exposed daily. With an overall assessment factor of 150: 6 (difference in duration subacute to chronic) x 10 (intraspecies differences) x 2.5 (interspecies - remaining differences), the long-term DNEL inhalation for systemic effects of 230 mg/m³/150 = 1.54 mg/m³ is derived.

- Dermal: The long-term systemic DNEL for the dermal route was derived based on the combined repeated dose toxicity study with reproduction/developmental toxicity screening with the substance. No correction for the exposure duration was added as the animals in the reference study were exposed daily. The dose descriptor starting point = 1000 mg/kg/day. The NOAEL does not needed to be multiplied by a factor as the bioavailability via the dermal route is considered 50%, similar to the oral bioavailability (50%). With an overall assessment factor of 600: 6 (difference in duration subacute to chronic) x 4 (interspecies differences allometric scaling) x 2.5 (remaining differences) x 10 (intraspecies differences), the long-term DNEL, dermal for systemic effects of 1000 mg/kg/day/600 = 1.67 mg/kg/day is derived.

- Oral: The long-term systemic DNEL for the oral route was derived based on the combined repeated dose toxicity study with reproduction/developmental toxicity screening with the substance. No correction for the exposure duration was added as animals in the reference study were dosed daily, so the dose descriptor starting point = 1000 mg/kg/day. The long-term oral systemic DNEL is derived with an overall assessment factor of 600: 4 (allometric scaling) x 2.5 (remaining interspecies differences) x 6 (difference in duration subchronic to chronic) x 10 (intraspecies differences). A long-term systemic DNEL of 1000 mg/kg/day/600 = 1.67 mg/kg/day is derived.