Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

19.2 µg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

225

Dose descriptor starting point:

LOAEL

Value:

3.5 mg/kg bw/day

Modified dose descriptor starting point:

LOAEC

Value:

4.32 mg/m³

Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:

3

Justification:

Default (DNEL calculator)

AF for differences in duration of exposure:

6

Justification:

Default (DNEL calculator)

AF for interspecies differences (allometric scaling):

1

Justification:

Default (DNEL calculator)

AF for other interspecies differences:

2.5

Justification:

Default (DNEL calculator)

AF for intraspecies differences:

5

Justification:

Default (DNEL calculator)

AF for the quality of the whole database:

1

Justification:

Default (DNEL calculator)

AF for remaining uncertainties:

1

Justification:

Possible uncertainties are already included in the assessment factors above, so a factor of 1 is applied.

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

repeated dose toxicity

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

repeated dose toxicity

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

repeated dose toxicity

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5.44 µg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

900

Dose descriptor starting point:

LOAEL

Value:

3.5 mg/kg bw/day

Modified dose descriptor starting point:

LOAEL

Value:

4.9 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:

3

Justification:

Default (DNEL calculator)

AF for differences in duration of exposure:

6

Justification:

Default (DNEL calculator)

AF for interspecies differences (allometric scaling):

4

Justification:

Default (DNEL calculator)

AF for other interspecies differences:

2.5

Justification:

Default (DNEL calculator)

AF for intraspecies differences:

5

Justification:

Default (DNEL calculator)

AF for the quality of the whole database:

1

Justification:

Default (DNEL calculator)

AF for remaining uncertainties:

1

Justification:

Possible uncertainties are already included in the assessment factors above, so a factor of 1 is applied.

Hazard assessment conclusion:

medium hazard (no threshold derived)

Hazard assessment conclusion:

medium hazard (no threshold derived)

Hazard assessment conclusion:

medium hazard (no threshold derived)

Hazard assessment conclusion:

medium hazard (no threshold derived)

Selection of Assessment factors for Intra – Inter species variation for workers and the general population (consumers)

ECHA (2012) has produced guidance on the assessment factors to use to derive a DNEL for human exposure based the application of assessment factors (safety factors) to an NOAEL or LOAEL in animal studies.

The guidance proposes that an assessment factor of 2 to be applied when extrapolating from an oral NOAEL to an inhalation DNEL, this is based on an assumption that absorption in the lungs will be 100% compared to 50% by the oral route. However in the case of fatty nitriles and the related derivatives, their low vapour pressure minimises the potential for generating vapour, and thus the risk of inhaling these materials in general. In the unlikely event that particulates are inhaled the relatively large particle size compared to inhalation of a vapour, would be expected to impinge on the nasal passages and the upper respiratory tract. This would result in the particulates being ingested rather than being absorbed after entering the deep lung. Therefore as exposure will be via ingestion with absorption in the stomach and gastrointestinal tract rather than absorption in the lungs, an assessment factor of 1 will be applied rather than the default of 2 when extrapolating from oral NOAEL values to inhalation DNELS.

The ECHA guidance proposes an assessment factor of 4 for the allometric scaling from rats to humans when calculating dermal DNELs. However it then proposes an additional factor of 2.5 to cover remaining differences (uncertainties). There is no clear scientific justification for this additional factor. ECETOC in itsGuidance on Assessment Factors to Derive a DNEL(2010) reviewed the scientific evidence and concluded that the factor of 4 for rats was sufficient to cover the allometric scaling from rats to humans and any remaining differences are of intra-species rather than interspecies variability. Based on this, the additional assessment factor of 2.5 for inter-species variability will not be used.

This ECETOC guidance also reviewed the intra-species assessment factors, which ECHA proposed as 5 for workers and 10 for the general population. ECETOC originally proposed in 2003, based on the scientific evidence, that assessment factors of 3 for workers and 5 for the general population are sufficient for covering any intra-species variability, which includes the remaining differences factor of 2.5. A similar concept was developed for the German Auschuss für Gefahrstoffe - AGS (2006), although arriving at a different factor. Apart from allometric scaling, taking interspecies differences for metabolism and toxicokinetics into account, a separate factor for overall (inter- and intra-species) variability for the workplace of 5 is taken. AGS explicitly did not differentiate between inter- and intra-species variability. They did not specifically propose an assessment factor for the general population. However, following the same principle that the AGS applied for workers, increasing the factor of 5 proposed by ECETOC for the general population also by 2 gives a factor of 7.

After reviewing the three proposals, we have adopted the proposal from ECETOC as our default assessment factors. Where we have limited information or consider there to be the likelihood of addition intra species variation in response, then these factor may be increased for example as suggested by the German Auschuss für Gefahrstoffe of an assessment factor of 5 for workers. Scientifically justified alternative factors for the general public will be selected on a case by case basis, with appropriate modification to the factor of 5 recommended by ECETOC, Examples of modified factors for the general public could be for example a factor of 7 following the approach of the AGS or 10 following the ECHA guidance This is considered a scientifically justified but still conservative approach, although the additional factor of 2.5 for remaining inter species differences as proposed by the ECHA guidance will not be used.

In this case to ensure additional intra-species variability is included the ECETOC assessment factor of 3 for workers will be increased by 2 to give a factor of 5, as described above following the approach of the AGS. For Consumers we have taken the ECETOC recommended factor of 5 and again added an additional 2 to give a factor of 7 to cover any additional variability.

References:

ECHA, 2012 Guidance on information requirements and chemical safety assessment

Chapter R.8: Characterisation of dose [concentration]-response for human health.November 2012

ECETOC, 2010 Guidance on Assessment Factors to Derive a DNEL,Technical Report No.110,ISSN-0773-8072-110 (print),ISSN-2079-1562-110 (online), October 2010

German Auschuss für Gefahrstoffe(AGS) 2006. Technische Regeln für Gefahrstoffe. Begründungen und Erläuterungen zu Grenzwerten in der Luft am Arbeitsplatz. Ausschuss für Gefahrstoffe. TRGS 901, BArbBl. Heft 1/2006.www.baua.de

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.38 µg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

450

Dose descriptor starting point:

LOAEL

Value:

3.5 mg/kg bw/day

Modified dose descriptor starting point:

LOAEC

Value:

1.52 mg/m³

Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:

3

Justification:

Default (DNEL calculator)

AF for differences in duration of exposure:

6

Justification:

Default (DNEL calculator)

AF for interspecies differences (allometric scaling):

1

Justification:

Default (DNEL calculator)

AF for other interspecies differences:

2.5

Justification:

Default (DNEL calculator)

AF for intraspecies differences:

10

Justification:

Default (DNEL calculator)

AF for the quality of the whole database:

1

Justification:

Default (DNEL calculator)

AF for remaining uncertainties:

1

Justification:

Possible uncertainties are already included in the assessment factors above, so a factor of 1 is applied.

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

repeated dose toxicity

Hazard assessment conclusion:

low hazard (no threshold derived)

Hazard assessment conclusion:

low hazard (no threshold derived)

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.94 µg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

other:

Overall assessment factor (AF):

1 800

Dose descriptor starting point:

LOAEL

Value:

3.5 mg/kg bw/day

Modified dose descriptor starting point:

LOAEL

Value:

3.5 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:

3

Justification:

Default (DNEL calculator)

AF for differences in duration of exposure:

6

Justification:

Default (DNEL calculator)

AF for interspecies differences (allometric scaling):

4

Justification:

Default (DNEL calculator)

AF for other interspecies differences:

2.5

Justification:

Default (DNEL calculator)

AF for intraspecies differences:

10

Justification:

Default (DNEL calculator)

AF for the quality of the whole database:

1

Justification:

Default (DNEL calculator)

AF for remaining uncertainties:

1

Justification:

Possible uncertainties are already included in the assessment factors above, so a factor of 1 is applied.

Hazard assessment conclusion:

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