4,4'-methylenebis(cyclohexylamine)

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.13 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):

10

Dose descriptor starting point:

NOAEL

Value:

1.5 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

1.3 mg/m³

Explanation for the modification of the dose descriptor starting point:

No repeated dose toxicity study by inhalation is available. For derivation of the DNEL the EOGRTS study (OECD 443) of the structural analogue DM-PACM (CAS 6864-37-5) was used. PACM and DM-PACM are considered read-across analogues based on structural similarity and similar physico-chemical and toxicological properties. The common structural features of the two substances are: a common functional primary amine group; the amines are bound to a cyclic aliphatic organic substituent; there are no elements other than carbon, hydrogen and nitrogen; identical structures except for a methyl group on each cyclohexane, ortho to the amine on DM-PACM similar molecular weights, both under 500 daltons, qualifying as “low molecular weight” compounds. For a detailed read across justification see also the attached justification document (IUCLID chapter 13). An oral-to-inhalation extrapolation is done. The default factor of 2 for differences in bioavailability oral/inhalative exposure is included.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

1

Justification:

The default allometric scaling factor is not needed, since it is already included in the route-to-route extrapolation.

AF for other interspecies differences:

1

Justification:

The most prominent effect after repeated inhalation is the induction of local effects. However, interspecies differences were already included to address the differences in metabolism between humans and 4 rats. To address systemic effects also, there is no need to use an additional factor for other inter
species differences. The worst case has therefore already been considered.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The repeated dose oral toxicity study was conducted according to 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:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

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:

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:

0.053 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):

40

Dose descriptor starting point:

NOAEL

Value:

1.5 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

2.1 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No repeated dose toxicity study by dermal exposure is available. For derivation of the DNEL the EOGRT study (OECD 443) of the structural analogue DM-PACM (CAS 6864-37-5) was used. PACM and DM-PACM are considered read-across analogues based on structural similarity and similar physico-chemical and toxicological properties. The common structural features of the two substances are: a common functional primary amine group; the amines are bound to a cyclic aliphatic organic substituent; there are no elements other than carbon, hydrogen and nitrogen; identical structures except for a methyl group on each cyclohexane, ortho to the amine on DM-PACM similar molecular weights, both under 500 daltons, qualifying as “low molecular weight” compounds. For a detailed read across justification see also the attached justification document (IUCLID chapter 13). An oral-to-dermal extrapolation is done. The bioavailability is assumed to be 100% for both exposure routes. An additional factor for the correction of treatment days (7 days) to working days (5 days) was also included.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

1

Justification:

The most prominent effect after skin contact is the induction of local corrosion. However, interspecies differences were already included to address the differences in metabolism between humans and rats. To address systemic effects also, there is no need to use an additional factor for other interspecies differences. The worst case has therefore already been considered.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The repeated dose oral toxicity study was conducted according to 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:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

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:

medium hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

Worker DNELs

For PACM, the mode-of-action is a threshold toxicant. This determination is based on the findings that, in repeated dose oral toxicity studies, systemic toxicity has a NOAEL. Furthermore, PACM is not mutagenic nor is it predicted to be carcinogenic, characteristics which are associated with non-threshold modes of action.

Assessment factors were adopted according to ECETOC's Technical Report No. 86 (2003) and according to the REACH guidance R.8 (Table R.8-6).

Short-term exposure worker (systemic effects)

Inhalation and dermal

It is not possible to derive a DNEL for acute effects based on the available data. The acute toxicity of PACM is moderate with respect to the oral route of exposure. Concerning the dermal and inhalative exposure routes the acute toxicity is rather low. There is no acute risk to be expected from inhalation since an inhalation hazard test showed no mortality and no clinical signs after 6h exposure to saturated vapor.

Long/short term exposure worker (local effects)

Inhalationand dermal

As PACM is a corrosive substance, local dermal effects are qualitatively assessed, due to lack of dose-response information and the irritating and sensitising properties of the substance. According to the REACH guidance on information requirements and chemical safety assessment, Part E: Risk Characterisation, a qualitative risk characterisation should be performed for this endpoint. In order to guarantee ‘adequate control of risks’, it is necessary to stipulate risk management measures that prevent skin and eye corrosion.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Additional information - General Population

There is no known or anticipated direct exposure of the general population to this industrial chemical. The calculation of DNELs is waived based on negligible risk due to lack of exposure.