1-(2,6-bis(4-tolyl)-1,3-dioxano(5,4-d)-1,3-dioxan-4-yl)ethane-1,2-diol

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.46 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:

LOAEC

Value:

634.4 mg/m³

Explanation for the modification of the dose descriptor starting point:

Route to route extrapolation required for oral to inhalation route as no long-term inhalation study available.

AF for dose response relationship:

3

Justification:

An AF of 3 is considered reasonable based on the use of a precautionary LOAEL.

AF for differences in duration of exposure:

2

Justification:

Default AF for sub-chronic (90 day study) to chronic studies.

AF for interspecies differences (allometric scaling):

1

Justification:

AF for allometric scaling not required as the differences in allometry (respiration rate and rat to human body sizes) were considered in the conversion from oral to inhalation starting point.

AF for other interspecies differences:

2.5

Justification:

Default AF for remaining interspecies differences.

AF for intraspecies differences:

5

Justification:

Default AF for worker population

AF for the quality of the whole database:

1

Justification:

Relevant studies conducted in accordance with generally accepted scientific principles.

AF for remaining uncertainties:

1

Justification:

None considered applicable.

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:

2.4 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:

LOAEL

Value:

720 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Route to route extrapolation required for oral to inhalation route as no long term dermal study available.

AF for dose response relationship:

3

Justification:

An AF of 3 is considered reasonable based on the use of a precautionary LOAEL.

AF for differences in duration of exposure:

2

Justification:

Default AF for sub-chronic (90 day study) to chronic studies.

AF for interspecies differences (allometric scaling):

4

Justification:

Default AF for rats

AF for other interspecies differences:

2.5

Justification:

Default AF for remaining interspecies differences.

AF for intraspecies differences:

5

Justification:

Default AF for worker population

AF for the quality of the whole database:

1

Justification:

Relevant studies conducted in accordance with generally accepted scientific principles.

AF for remaining uncertainties:

1

Justification:

None considered applicable.

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

The substance is not classified for human health.

However, DNELs for long-term systemic effects for inhalation and dermal routes have been derived.

These DNELs have been derived based on the results of the 90 day oral feeding study. Based on the findings of this study, a precautionary LOAEL of 700 - 750 mg/kg bw/day was recommended. The starting point for the DNEL derivations was chosen as 720 mg/kg bw/day, as this was the lowest dose used in the study (for males).

The recommended LOAEL of 700 - 750 mg/kg bw/day is a precautionary result, as the effects observed in the 90 day study could be considered not to be significant/ adverse, and no adverse effects were seen in a 28 -day study or 1 -generation reproduction study.

The DNELs should therefore also be considered precautionary and a worst case assessment.

Inhalation:

Inhalation is not considered to be a significant route of exposure. However, a long-term DNEL for systemic effects have been derived

Long-term systemic effects:

A modification of the dose descriptor starting point (oral to inhalation) was conducted. It is assumed as a worst case assumption that the oral absorption rate is 50% of that of the inhalation absorption. In practice this is unlikely to be the case based on the particle size distribution.

The corrected dose descriptor (NOAEC) for inhalation was calculated in accordance with the ECHA Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health.

The conversion of an oral rat NOAEL into a corrected inhalatory NOAEC to assess human inhalatory exposure was performed using the modification of starting point equation as given in Figure R. 8-3 (see below) for workers (in the case of 8 hour exposure/day).

Default parameters for rats and humans (for 8 hour exposure) were used for the modification of starting point under the allometric scaling principle as given in Table R. 8-2 of the above ECHA guidance.

Conversion of an oral rate LOAEL into a correct inhalatory LOAEC to assess human inhalatory exposure:

For workers (in case of 8h exposure/day):

Corrected inhalatory LOAEC = oral LOAEL x (1 / sRVrat) x (ABSoral-rat / ABSinh-human) x (sRVhuman / wRV)

Corrected inhalatory LOAEC= 720 mg/kg bw/day x (1 / 0.38 m³/kg/d) x (0.5) x (6.7 m³(8h) / 10 m³(8h))= 634.4 mg/m³

^Where:

^{ABS: Absorption}

^{sRV: standard Respiratory Volume}

^{wRV: worker Respiratory Volume (light activity)}

^{Default parametrs:}

sRVrat (8 h) : 0.38m³/kg bw

sRVhuman (8 h) : 6.7 m³/ person

wRV (8 h): 10 m³/ person

The appropriate assessment factors were then applied to give an overall assessment factor of 75

Long-term systemic DNEL (inhalation)= 8.46 mg/m³

Local inhalation effects are not considered to be of concern due to inhalation not being a significant route of exposure and the lack of local effects seen in an acute inhalation study.

Dermal:

A DNEL has been derived for long-term systemic effects by the dermal route.

Long-term systemic DNEL (dermal) = 2.4 mg/kg bw/day

DNELs for local effects have not been derived since the substance is not a skin irritant or sensitiser.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

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:

no hazard identified

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

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.2 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:

LOAEL

Value:

720 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Not required

AF for dose response relationship:

3

Justification:

An AF of 3 is considered reasonable based on the use of a precautionary LOAEL.

AF for differences in duration of exposure:

2

Justification:

Default AF for sub-chronic (90 day study) to chronic studies.

AF for interspecies differences (allometric scaling):

4

Justification:

Default AF for rats

AF for other interspecies differences:

2.5

Justification:

Default AF for remaining interspecies differences.

AF for intraspecies differences:

10

Justification:

Default AF fro general population

AF for the quality of the whole database:

1

Justification:

Relevant studies conducted in accordance with generally accepted scientific principles.

AF for remaining uncertainties:

1

Justification:

None considered applicable.

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

The substance is used solely in industry in the manufacture of polyolefin compounds. The substance has no general population/consumer uses so exposure to the general population from use is not anticipated. Once the substance is bound into polyolefin compounds there should be no release, so exposure to the general population from release of the substance from final products is not anticipated.

A DNEL for long term systemic effects via the oral route has been derived, in order to assess indirect exposure of humans via the environment.