Reaction products of 1,4-cyclohexanedimethanol with propylene oxide and ammonia

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.49 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):

18

Dose descriptor starting point:

NOAEL

Value:

10 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

8.82 mg/m³

Explanation for the modification of the dose descriptor starting point:

No long-term toxicity study via the inhalation route of exposure is available for the test substance. Route-to-route extrapolation has been performed.

The NOAEL (oral) observed in the combined repeated dose toxicity study with reproduction/developmental toxicity screening study (Betancourt Martell A, 2014) was used to derive a DNEL long-term, systemic effects via the inhalation route. This study was performed according to the OECD 422 guideline and in compliance with GLP. The NOAEL was considered to be 10 mg/kg bw/day. After route-to-route extrapolation from oral to inhalation, the dose descriptor starting point = 10 mg/kg bw/d x 1/(0.38 m3/kg/d)) x 6.7 m3/10 m3 x 0.5 = 8.82 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 m3 for base level, 10m3 for light activity). In addition, the NOAEL needs to be divided by 2 as the bioavailability via the inhalation route is considered as 100% while for oral exposure this is assumed to be 50%.

AF for dose response relationship:

1

Justification:

NOAEL is used as starting point, no additional assessment factor is required

AF for differences in duration of exposure:

6

Justification:

difference in duration, subacute to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

differences in allometry are assumed to be compensated by differences in respiration rate, and thus covered by the route-to-route extrapolation

AF for other interspecies differences:

1

Justification:

ECETOC assessment factor, included in total allometry

AF for intraspecies differences:

3

Justification:

ECETOC assessment factor for worker population

AF for the quality of the whole database:

1

Justification:

default assessment factor

AF for remaining uncertainties:

1

Justification:

default 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:

0.14 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):

72

Dose descriptor starting point:

NOAEL

Value:

10 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

10 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No long-term toxicity study via dermal exposure was available for the test substance. Route-to-route extrapolation has been performed.

The NOAEL (oral) observed in the combined repeated dose toxicity study with reproduction/developmental toxicity screening study (Betancourt Martell A, 2014) was used to derive a DNEL long-term, systemic effects via the dermal route. This study was performed according to the OECD 422 guideline and in compliance with GLP. The NOAEL was considered to be 10 mg/kg bw/day. After route-to-route extrapolation (oral to demal) the dose descriptor starting point is 10 mg/kg bw/day as no additional factor should be applied (it is assumed that there is no difference between oral and dermal absorption; see toxicokinetic assessment).

AF for dose response relationship:

1

Justification:

NOAEL is used as starting point, no additional assessment factor is required

AF for differences in duration of exposure:

6

Justification:

difference in duration, subacute to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

differences allometry, rat to human

AF for other interspecies differences:

1

Justification:

ECETOC assessment factor, included in total allometry

AF for intraspecies differences:

3

Justification:

ECETOC assessment factor for worker population

AF for the quality of the whole database:

1

Justification:

default assessment factor

AF for remaining uncertainties:

1

Justification:

default assessment factor

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Dermal

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

medium 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:

0.15 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):

30

Dose descriptor starting point:

NOAEL

Value:

10 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

4.35 mg/m³

Explanation for the modification of the dose descriptor starting point:

No long-term toxicity study via the inhalation route of exposure is available for the test substance. Routeto-route extrapolation has been performed.

The NOAEL (oral) observed in the combined repeated dose toxicity study with reproduction/ developmental toxicity screening study (Betancourt Martell A, 2014) was used to derive a DNEL longterm, systemic effects via the inhalation route. This study was performed according to the OECD 422 guideline and in compliance with GLP. The NOAEL was considered to be 10 mg/kg bw/day. After routeto-route extrapolation from oral to inhalation, the dose descriptor starting point = 10 mg/kg bw/d x 1/(1.15 m3/kg/d)) x 0.5 = 4.35 mg/m3. The oral 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). In addition, the NOAEL needed to be divided by 2 as the bioavailability via the inhalation route is considered 100%, while for oral exposure this is only 50%.

AF for dose response relationship:

1

Justification:

NOAEL is used as starting point, no additional assessment factor is required

AF for differences in duration of exposure:

6

Justification:

differences in duration, subacute to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

covered by calculation for route-to-route extrapolation

AF for other interspecies differences:

1

Justification:

ECETOC assessment factor, included in total allometry

AF for intraspecies differences:

5

Justification:

ECETOC assessment factor for general population

AF for the quality of the whole database:

1

Justification:

default assessment factor

AF for remaining uncertainties:

1

Justification:

default 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:

0.083 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):

120

Dose descriptor starting point:

NOAEL

Value:

10 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

10 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No long-term toxicity study via dermal exposure was available for the test substance. Route-to-route extrapolation has been performed.

The NOAEL (oral) observed in the combined repeated dose toxicity study with reproduction/ developmental toxicity screening study (Betancourt Martell A, 2014) was used to derive a DNEL longterm, systemic effects via the dermal route. This study was performed according to the OECD 422 guideline and in compliance with GLP. The NOAEL was considered to be 10 mg/kg bw/day. After route-to-route extrapolation (oral to demal) the dose descriptor starting point is 10 mg/kg bw/day as no additional factor should be applied (it is assumed that there is no difference between oral and dermal absorption; see toxicokinetic assessment).

AF for dose response relationship:

1

Justification:

NOAEL is used as starting point, no additional assessment factor is required.

AF for differences in duration of exposure:

6

Justification:

difference in duration, subacute to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

difference in allometry, rat to human

AF for other interspecies differences:

1

Justification:

ECETOC assessment factor, included in total allometry

AF for intraspecies differences:

5

Justification:

ECETOC assessment factor for general population

AF for the quality of the whole database:

1

Justification:

default assessment factor

AF for remaining uncertainties:

1

Justification:

default assessment factor

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Dermal

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.083 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):

120

Dose descriptor starting point:

NOAEL

Value:

10 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

10 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The NOAEL (oral) observed in the combined repeated dose toxicity study with reproduction/ developmental toxicity screening study (Betancourt Martell A, 2014) was used to derive a DNEL longterm, systemic effects via the oral route. This study was performed according to the OECD 422 guideline and in compliance with GLP. The NOAEL was considered to be 10 mg/kg bw/day.

AF for dose response relationship:

1

Justification:

NOAEL is used as starting point, no additional assessment factor is required

AF for differences in duration of exposure:

6

Justification:

difference in duration, subacute to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

difference in allometry, rat to human

AF for other interspecies differences:

1

Justification:

ECETOC assessment factor, included in total allometry

AF for intraspecies differences:

5

Justification:

ECETOC assessment factor for general population

AF for the quality of the whole database:

1

Justification:

default assessment factor

AF for remaining uncertainties:

1

Justification:

default assessment factor

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

No consumer use is expected.