1,3,5-Triazine-2,4-diamine, N2-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-yl]-6-(1-fluoroethyl)-

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.536 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):

12.5

Dose descriptor starting point:

NOAEL

Value:

2 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

6.7 mg/m³

Explanation for the modification of the dose descriptor starting point:

NOAECcorr = NOAELoral*(1/0.14 m³/kg bw/day)*(ABSoral-rat/ABSinh-human)*(6.7 m³ (8h)/10 m³ (8h))*(7 days exposure/ 5 days exposure) = 2 mg/kg bw/day*(1/0.14 m³/kg bw/day)*(1/2)*0.67*1.4 = 6.7 mg/m³.

ABS(oral/rat) = oral absorption rate in rats, ABS(inh./human) = inhalation absorption rate in humans

Starting point for the DNEL derivation is the human NAEC for inhalation exposure of workers over 8 hours of 6.7 mg/m³. This value is based on the conversion of the chronic oral NOAEL of 2 mg/kg bw/day for dogs from the 1-year study to the corresponding air concentration for workers. Route-to-route extrapolation within the Beagle dog was based on the respiratory volume of 0.3 L/min/kg bw, leading to an inhalation volume of 0.14 m³/kg bw for a time period of 8 hours, reflecting the normal duration of an 8-hour work shift. The resulting air concentration of 14.29 mg/m³ has been corrected by a factor of 0.67 considering the ratio of the normal inhalation volume of 6.7 m³/person over 8 hours and the increased inhalation volume of 10 m³/person of workers during light activity at work. Moreover, the NOAEL was corrected for the differences in the experimental and human exposure conditions. The animals (dog) were exposed to the test substance 7 days/week, whereas workers are in general exposed 5 days/week (factor 7 days/5 days). As worst case as recommended in the ECHA Guidance R.8 (2012), it is assumed that oral absorption rate is 50% of that of inhalation absorption.

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL.

AF for differences in duration of exposure:

1

Justification:

The DNEL is based on a chronic study.

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation route

AF for other interspecies differences:

2.5

Justification:

Default value according to ECHA REACH Guidance.

AF for intraspecies differences:

5

Justification:

Default value for workers according to ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

The DNEL is based on a high-quality study.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

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:

3.33 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

300

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Dermal NOAELcorr = dermal NOAEL*ABS(derm-rat)/ABS(derm-human) = 1000 mg/kg bw/day *(1/1) = 1000 mg/kg bw/day

Starting point for DNEL derivation is the subacute dermal NOAEL of 1000 mg/kg bw/day from the 29/30-day study in rats. The dermal NOAEL value is not corrected for differences in penetrability of human and rat skin. In an in vitro flow-through diffusion cell system, it was demonstrated that the permeability (re-evaluation according to EFSA Guidance on dermal absorption (2017) considered) of human skin is equal to rat skin at the highest applied dose. Thus no conversion factor for absorption of human vs rat skin was derived.

The corrected dermal NOAEL is then adapted by an AF of 6 for the conversion of the subacute study to a chronic exposure, an AF of 10 (2.5 x 4) to correct for interspecies differences between rat and man, followed by a factor of 5 to cover for individual variations among the workers.

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL.

AF for differences in duration of exposure:

6

Justification:

The DNEL is based on a subacute study.

AF for interspecies differences (allometric scaling):

4

Justification:

The experimental animal was the rat.

AF for other interspecies differences:

2.5

Justification:

Default value according to ECHA REACH Guidance.

AF for intraspecies differences:

5

Justification:

Default value for workers according to ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

The DNEL is based on a high-quality study.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

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

Since there is no dose descriptor for every exposure route, dose descriptors were converted into a correct starting point by route-to-route extrapolation based on the ECHA Guidance document "Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health", November 2012.

 

Starting point for the dermal DNEL derivation is a NOAEL for dermal exposure of 1000 mg/kg bw/day. In order to convert a dermal NOAEL derived from rats into a dermal NAEL, the differences in absorption between species have to be accounted for.The percutaneous absorption of the test substance was measured in vitro in a comparative dermal absorption study using human and rat skin in a flow-through diffusion cell system. In this study doses of 0.5, 2, 10 and 5000 µg/cm² of the test substance were applied to dermatomed human and rat skin for an exposure period of 8 hours, and dermal penetration was assessed until 24 hours after application. The absorption rates after re-evaluation according to EFSA Guidance on dermal absorption (2017) determined for human skin ranged from 2.4% up to 14%; for rat skin absorption rates of 13% to 39% were measured. At the highest dose (5000 µg/cm²) the absorption rate after EFSA re-evaluation (2017) was 12% for human and 14% for rat skin. Thus, based on these values no conversion factor for absorption of human vs rat skin was derived and considered in the derivation of the corrected NOAEL.

Starting point for the inhalation DNEL derivation is the NAEC for workers of 6.7 mg/m³ for exposure durations of 8 hours. Basis for the derivation of the NAECworker (8h) is the oral NOAEL of 2 mg/kg bw/day, derived from a 1-year feeding study in dogs, which was used for the route-to-route extrapolation from oral to inhalation exposure.

As worst case as recommended in the ECHA Guidance R.8 (2012), it is assumed that oral absorption rate is 50% of that of inhalation absorption.

Route-to route extrapolation within the dog was based on the respiratory volume of 0.3 L/min/kg bw, leading to an inhalation volume of 0.14 m³/kg bw for a time period of 8 hours, reflecting the duration of an 8-hour shift. The resulting value was further adjusted to compensate for the increased inhalation volume of workers during light activities at work and for differences in the experimental and human exposure conditions in order to obtain the NAEC.

 

Short-term exposure scenarios will not be assessed due to hazard characteristics and exposure considerations, only long-term DNELs for workers and the general population are derived. The oral route is not relevant for workers. In addition it is assumed that only workers might come into contact with the test substance as it is not intended for general use. The test substance is neither irritating nor sensitising.Levels of control including appropriate risk management measures and personal protective equipment are in place at sites producing and using the substance. Therefore, effects by dermal and inhalative exposure are unlikely, and considering acute and/or local DNELs can be omitted.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.093 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):

25

Dose descriptor starting point:

NOAEL

Value:

2 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

2.3 mg/m³

Explanation for the modification of the dose descriptor starting point:

NOAECcorr = NOAELoral*(1/0.43 m³/kg bw/day (24h)) *(ABSoral-rat/ABSinh-human) = 2 mg/kg bw/day*(1/0.43 m³/kg bw/day)*(1/2) = 2.3 mg/m³.

ABS(oral/rat) = oral absorption rate in rats, ABS(inh./human) = inhalation absorption rate in humans

Starting point for the DNEL derivation is the human NAEC for inhalation exposure over 24 hours of 2.3 mg/m³. This value is based on the conversion of the chronic oral NOAEL of 2 mg/kg bw/day for dogs from the 1-year study to the corresponding air concentration over a period of 24 hours. Route-to-route extrapolation within the Beagle dog was based on the respiratory volume of 0.3 L/min/kg bw, leading to an inhalation volume of 0.43 m³/kg bw for a time period of 24 hours, reflecting continuous exposure via the environment. As worst case as recommended in the ECHA Guidance R.8 (2012), it is assumed that oral absorption rate is 50% of that of inhalation absorption.

An assessment factor 10 was included to take care of possible intraspecies differences within the general population and an assessment factor of 2.5 for other interspecies differences was considered. However, the substance is not intended for use by the general population, therefore exposure is unlikely.

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL.

AF for differences in duration of exposure:

1

Justification:

The DNEL is based on a chronic study.

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation route

AF for other interspecies differences:

2.5

Justification:

Default value according to ECHA REACH Guidance.

AF for intraspecies differences:

10

Justification:

Default value for general population according to ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

The DNEL is based on a high-quality study.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

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:

1.67 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

600

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Dermal NOAELcorr = dermal NOAEL*ABS(derm-rat)/ABS(derm-human) = 1000 mg/kg bw/day *(1/1) = 1000 mg/kg bw/day

Starting point for DNEL derivation is the subacute dermal NOAEL of 1000 mg/kg bw/day from the 29/30-day study in rats. The dermal NOAEL value is not corrected for differences in penetrability of human and rat skin. In an in vitro flow-through diffusion cell system, it was demonstrated that the permeability (EFSA reevaluation considered) of human skin is equal to rat skin at the highest applied dose. Thus no conversion factor for absorption of human vs rat skin was derived.

The corrected dermal NOAEL is then adapted by an AF of 6 for the conversion of the subacute study to a chronic exposure, an AF of 10 (2.5 x 4) to correct for interspecies differences between rat and man, followed by a factor of 10 to cover for individual variations within the general population. However, the substance is not intended for use by the general population, therefore exposure is unlikely.

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL.

AF for differences in duration of exposure:

6

Justification:

The DNEL is based on a subacute study.

AF for interspecies differences (allometric scaling):

4

Justification:

The experimental animal was the rat.

AF for other interspecies differences:

2.5

Justification:

Default value according to ECHA REACH Guidance.

AF for intraspecies differences:

10

Justification:

Default value for general population according to ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

The DNEL is based on a high-quality study.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

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:

0.057 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):

35

Dose descriptor starting point:

NOAEL

Value:

2 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

2 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

There is no route to route extrapolation necessary.

Starting point for the DNEL derivation is the chronic oral NOAEL of 2 mg/kg bw/day from the 1-year study in dogs as most sensitive species. An assessment factor (AF) of 1.4 is included for correction of interspecies differences between dogs and humans, an AF of 2.5 for other interspecies differences and a factor of 10 to take care of possible intraspecies differences within the general human population. However, the substance is not intended for use by the general population, therefore exposure is unlikely.

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL.

AF for differences in duration of exposure:

1

Justification:

The DNEL is based on a chronic study.

AF for interspecies differences (allometric scaling):

1.4

Justification:

The experimental animal was the dog.

AF for other interspecies differences:

2.5

Justification:

Default value according to ECHA REACH Guidance.

AF for intraspecies differences:

10

Justification:

Default value for general population according to ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

The DNEL is based on a high-quality study.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

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:

no hazard identified

Additional information - General Population

Since there is no dose descriptor for every exposure route, dose descriptors were converted into a correct starting point by route-to-route extrapolation based on the ECHA Guidance document "Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health", November 2012.

 

Starting point for the dermal DNEL derivation is a NOAEL for dermal exposure of 1000 mg/kg bw/day. In order to convert a dermal NOAEL derived from rats into a dermal NAEL, the differences in absorption between species have to be accounted for.The percutaneous absorption of the test substance was measured in vitro in a comparative dermal absorption study using human and rat skin in a flow-through diffusion cell system. In this study doses of 0.5, 2, 10 and 5000 µg/cm² of the test substance were applied to dermatomed human and rat skin for an exposure period of 8 hours, and dermal penetration was assessed until 24 hours after application. The absorption rates after re-evaluation according to EFSA Guidance on dermal absorption (2017) determined for human skin ranged from 2.4% up to 14%; for rat skin absorption rates of 13% to 39% were measured. At the highest dose (5000 µg/cm²) the absorption rate after EFSA re-evaluation (2017) was 12% for human and 14% for rat skin. Thus, based on these values no conversion factor for absorption of human vs rat skin was derived and considered in the derivation of the corrected NOAEL.

 

Starting point for the inhalation DNEL derivation is the NAEC for the general population of 2.3 mg/m³ for exposure durations of 24 hours. Basis for the derivation of the NAEChuman (24h) is the oral NOAEL of 2 mg/kg bw/day, derived from a 1-year feeding study in dogs, which was used for the route-to-route extrapolation from oral to inhalation exposure.

As worst case as recommended in the ECHA Guidance R.8 (2012), it is assumed that oral absorption rate is 50% of that of inhalation absorption.

Route-to route extrapolation within the dog was based on the respiratory volume of 0.3 L/min/kg bw, leading to an inhalation volume of 0.43 m³/kg bw for a time period of 24 hours, reflecting continuous exposure via the environment.

 

Short-term exposure scenarios will not be assessed due to hazard characteristics and exposure considerations, only long-term DNELs for workers and the general population are derived. In addition it is assumed that only workers might come into contact with the test substance as it is not intended for general use. The test substance is neither irritating nor sensitising. Therefore, effects by dermal and inhalative exposure are unlikely, and considering acute and/or local DNELs can be omitted.