Schiff bases, C11-14-tert-alkyl methylene

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2 mg/m³

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

45

Modified dose descriptor starting point:

NOAEC

Value:

88.16 mg/m³

Explanation for the modification of the dose descriptor starting point:

Repeated toxicity studies are available only for the oral route. Effects observed in the acute toxicity studies by oral and inhalation routes are similar, and therefore a route-to-route extrapolation in considered appropriate.

AF for dose response relationship:

1

Justification:

The starting point for the DNEL calculation was a NOAEL, therefore the default assessment factor, as a standard procedure, is 1.

AF for differences in duration of exposure:

6

Justification:

An assessment factor of 6 has been applied in order to consider the differences in the duration of the exposure between the oral reproductive/developmental toxicity study and a chronic exposure.

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling does not apply in case of oral-inhalation route to route extrapolation.

AF for other interspecies differences:

2.5

Justification:

As no allometric factor has been used, an assessment factor for other interspecies differences has been chosen

AF for intraspecies differences:

3

Justification:

Intraspecies AF for workers population, according to ECETOC guidelines

AF for the quality of the whole database:

1

Justification:

The available data are sufficient to correctly derive the inhalation DNEL

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties are foreseen.

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

Justification:

See above.

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

AF for dose response relationship:

1

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.8 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

36

Modified dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Repeated toxicity studies are available only for the oral route. Effects observed in the acute toxicity study by oral route are more severe than effects observed in the acute dermal toxicity study. Therefore a route-to-route extrapolation is considered appropriate and even conservative with respect to the expected hazard for dermal route.

AF for dose response relationship:

1

Justification:

The starting point for the DNEL calculation was a NOAEL, therefore the default assessment factor, as a standard procedure, is 1.

AF for differences in duration of exposure:

6

Justification:

An assessment factor of 6 has been applied in order to consider the differences in the duration of the exposure between the oral reproductive/developmental toxicity study and a chronic exposure.

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling for rats involves a default assessment factor of 4.

AF for other interspecies differences:

1

Justification:

An additional AF for interspecies differences is considered not necessary, because allometric scaling will be conservative enough.

AF for intraspecies differences:

3

Justification:

Intraspecies AF for workers population, according to ECETOC guidelines

AF for the quality of the whole database:

1

Justification:

The available data are sufficient to correctly derive the inhalation DNEL

AF for remaining uncertainties:

0.5

Justification:

Estimated low dermal absorption

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

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)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.2 mg/m³

Most sensitive endpoint:

developmental toxicity / teratogenicity

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:

88 mg/m³

Explanation for the modification of the dose descriptor starting point:

Repeated toxicity studies are available only for the oral route. Effects observed in the acute toxicity studies by oral and inhalation routes are similar, and therefore a route-to-route extrapolation in considered appropriate.

AF for dose response relationship:

1

Justification:

The starting point for the DNEL calculation was a NOAEL, therefore the default assessment factor, as a standard procedure, is 1.

AF for differences in duration of exposure:

6

Justification:

An assessment factor of 6 has been applied in order to consider the differences in the duration of the exposure between the oral reproductive/developmental toxicity study and a chronic exposure.

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling does not apply in case of oral-inhalation route to route extrapolation.

AF for other interspecies differences:

2.5

Justification:

As no allometric factor has been used, an assessment factor for other interspecies differences has been chosen

AF for intraspecies differences:

5

Justification:

Intraspecies AF for general population, according to ECETOC guidelines

AF for the quality of the whole database:

1

Justification:

The available data are sufficient to correctly derive the inhalation DNEL

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties are foreseen.

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)

DNEL related information

AF for remaining uncertainties:

1

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:

1.7 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

60

Modified dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Repeated toxicity studies are available only for the oral route. Effects observed in the acute toxicity study by oral route are more severe than effects observed in the acute dermal toxicity study. Therefore a route-to-route extrapolation is considered appropriate and even conservative with respect to the expected hazard for dermal route.

AF for dose response relationship:

1

Justification:

The starting point for the DNEL calculation was a NOAEL, therefore the default assessment factor, as a standard procedure, is 1.

AF for differences in duration of exposure:

6

Justification:

An assessment factor of 6 has been applied in order to consider the differences in the duration of the exposure between the oral reproductive/developmental toxicity study and a chronic exposure.

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling for rats involves a default assessment factor of 4.

AF for other interspecies differences:

1

Justification:

An additional AF for interspecies differences is considered not necessary, because allometric scaling will be conservative enough.

AF for intraspecies differences:

5

Justification:

Intraspecies AF for general population, according to ECETOC guidelines

AF for the quality of the whole database:

1

Justification:

The available data are sufficient to correctly derive the inhalation DNEL

AF for remaining uncertainties:

0.5

Justification:

Low dermal absorption is predicted with < 50% absorption in view of molecular weight

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

Justification:

The available data are sufficient to correctly derive the inhalation DNEL

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.8 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

120

Modified dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

None.

AF for dose response relationship:

1

Justification:

The starting point for the DNEL calculation was a NOAEL, therefore the default assessment factor, as a standard procedure, is 1.

AF for differences in duration of exposure:

6

Justification:

An assessment factor of 6 has been applied in order to consider the differences in the duration of the exposure between the oral reproductive/developmental toxicity study and a chronic exposure.

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling for rats involves a default assessment factor of 4.

AF for other interspecies differences:

1

Justification:

An additional AF for interspecies differences is considered not necessary, because allometric scaling will be conservative enough.

AF for intraspecies differences:

5

Justification:

Intraspecies AF for general population, according to ECETOC guidelines

AF for the quality of the whole database:

1

Justification:

The available data are sufficient to correctly derive the inhalation DNEL

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties are foreseen.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.8 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

other: ECHA REACH Guidance and ECETOC Guidance on Assessment Factors to Derive a DNEL

Overall assessment factor (AF):

120

DNEL extrapolated from long term DNEL

Modified dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

None.

AF for dose response relationship:

1

Justification:

The starting point for the DNEL calculation was a NOAEL, therefore the default assessment factor, as a standard procedure, is 1.

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling for rats involves a default assessment factor of 4.

AF for other interspecies differences:

1

Justification:

An additional AF for interspecies differences is considered not necessary, because allometric scaling will be conservative enough.

AF for intraspecies differences:

5

Justification:

Intraspecies AF for general population, according to ECETOC guidelines

AF for the quality of the whole database:

1

Justification:

The available data are sufficient to correctly derive the inhalation DNEL

AF for remaining uncertainties:

6

Justification:

An assessment factor of 6 has been applied in order to consider the differences in the duration of the exposure between the oral reproductive/developmental toxicity study and a chronic exposure.

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - General Population

DNELs for inhalation, dermal and oral routes of exposure have been derived. The DNEL derived for inhalation route systemic effects after long term-exposure has been used also to cover the hazards relater to local effects and short-term exposure because it has been considered conservative enough to protect general population also from other hazards related to inhalation exposure. These DNELs derive from the NOAEL observed in the reproduction/developmental toxicity screening test, performed by oral route. Also the DNEL for systemic effects after a dermal repeated exposure has been derived from the same oral toxicity study, therefore a route-to-route extrapolation have been deemed necessary in order to obtain the correct starting point for the derivation of the inhalation and dermal DNELs.

DNELs for local effects after dermal exposure have been derived from the skin sensitization study, in which theEC₃value has been calculatedat 6.51%. As the starting dose descriptor was expressed as a percentage, a correction has been calculated in order to obtain the correct starting point in mg/cm²of skin.

Also DNELs for the oral exposure derive from the reproduction/developmental toxicity screening test but, in this case, no route-to-route extrapolation have been considered necessary.

The correct starting points were then divided by an overall assessment factor, which was a result of various consideration on uncertainties on inter-and intra-species variations, and on differences in the duration of exposure between test animals and humans. Moreover also the whole quality of the database was considered.

No DNEL was derived for systemic effects after short-term dermal exposure, because no hazard has been identified (i.e. the studies performed for the skin irritation/corrosion endpoint gave non-irritant results) and no DNEL have been derived for the eye irritation effects, for which a qualitative approach has been followed, leading to a low hazard for this endpoint.