Reaction mass of 5,5'-{(phenylmethanediyl)bis[benzene-4,1-diyl-diazene-2,1-diyl]}bis{1-[3-(dimethylamino)propyl]-4-methyl-6-oxo-3-(pyridinium-1-yl)-1,6-dihydropyridin-2-olate} hydrochloride and 5,5’-[3,4’-(phenylmethanediyl)diphenylene]bis(diazene-2,1-diyl)bis{1-[3-(dimethylamino)propyl]-4-methyl-6-oxo-3-(pyridinium-1-yl)-1,6-dihydropyridin-2-olate} hydrochloride

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

13.2 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA REACH guidance & ECETOC

Overall assessment factor (AF):

60

Modified dose descriptor starting point:

NOAEC

Value:

793.4 mg/m³

Explanation for the modification of the dose descriptor starting point:

As there is no inhalation study available an extrapolation using default assessment factors was performed. There was no information indicating other methods as more suitable.

AF for dose response relationship:

1

Justification:

default, no information indicating otherwise is available

AF for differences in duration of exposure:

6

Justification:

extrapolating subacute study to chronic study

AF for interspecies differences (allometric scaling):

1

Justification:

not used for inhalation, ECHA Practical Guide 14, 2012

AF for other interspecies differences:

1

Justification:

default, no information indicating otherwise is available

AF for intraspecies differences:

5

Justification:

AF modified from Ecetoc TG 110 and German AGS 2006

AF for the quality of the whole database:

1

Justification:

default, no information indicating otherwise is available

AF for remaining uncertainties:

2

Justification:

ECHA Guidance, route to route extrapolation (oral to inhalation), conservative assumption

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

6.25 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

other: ECETOC technical report 110

Overall assessment factor (AF):

72

Modified dose descriptor starting point:

NOAEL

Value:

450 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

As worst case scenario it was assumed that the dermal bioavailability is equal to the oral bioavailability

AF for dose response relationship:

1

Justification:

not required, starting point is NOAEL

AF for differences in duration of exposure:

6

Justification:

extrapolating subacute study to chronic study

AF for interspecies differences (allometric scaling):

4

Justification:

adjusting metabolic rates rat to human

AF for other interspecies differences:

1

Justification:

not required according to ECETOC technical report 110

AF for intraspecies differences:

3

Justification:

according to ECETOC technical report 110

AF for the quality of the whole database:

1

Justification:

not required

AF for remaining uncertainties:

1

Justification:

not required

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

General comment to DNEL derivation:

The DNELs derived for the substance registered, mostly have been derived based on studies read-across from the analogue substance (refer to IUCLID section 13). A full justification for appropriateness of the performed read-across approach is given as na appendix in chapter13, "Assessment Reports", of this dossier. The most relevant study for DNEL derivation is the oral subacute study on the source substance. Therefore, route-route extrapolation had to be applied for deriving certain DNELs. Derivation of inhalation DNEL is based on subacute oral study results. Derivation of assessment factors are based on ECETOC Technical Report 110 and ECHA Reach guidance. Modification was used according to German AGS 2010.

Systemic DNELs:

The long-term systemic inhalation DNELis considered to be sufficient to ensure that no effects occur. The starting point is the subacute study by oral gavage dosing in rats, resulting to a NOAEL of 450 mg/kg bw/day. This dose descriptor was corrected for route to route extrapolation in accordance with the procedure recommended in Chapter R8 of the REACH Technical Guidance documents (May 2008) as follows:

NOAEL oral rat (NOAEL_{oral rat}) = 450 mg/kg bw/day

Standard respiratory volume of a rat during 8 h exposure (SRv_rat) =0.38 m³

Standard respiratory volume of a human during 8 h exposure (SRv_human) = 6.7 m³/8hr

Standard respiratory volume of a human during light activity for a worker -8 h (WSRv_human) =10 m³/8hr - light activity

NOEC_corrfor workers = NOAEL_{oral rat}÷ SRv_ratx (SRv_human÷ WSRv_human)

Corrected NOEC = 450 mg/kg bw/day ÷ 0.38 m³/kg bw x (6.7 m³÷ 10 m³)

Corrected NOEC = 793.4 mg/m³

According to the ECHA REACH Guidance, the DNEL was then obtained by applying assessment factors to the starting point:

-Dose response relationship: An assessment factor of1is considered. There is no reason to consider special concern, because the starting point for the DNEL calculation is a NOAEL.

-Differences in duration of exposure:A default assessment factor of6was applied based on the extrapolation from subacute to chronic.

-interspecies differences (allometric scaling): No allometric scaling is considered in the derivation of the inhalation DNEL (ECHA Practical Guide 14, 2012). Differences in the allometry are assumed to be compensated by differences in the respiration rate.

-intraspecies differences: Taking into account the overall toxicity profile of the submission substance and the read across approach, a somewhat more conservative approach is taken and a combined inter-/intraspecies assessment factor of 5 is considered. This is in line with a similar concept developed by the German Committee for Hazardous Substances (AGS 2010).

-Remaining uncertainties: According to ECHA Guidance document, an assessment factor of 2 is considered for route to route extrapolation (oral to inhalation) as a conservative approach.

Since the available data are adequate for labelling and classification purposes of the submission substance, the quality of the data base is judged sufficient for evaluation. Thus, an assessment factor of 1 is applied.

The resulting overall Assessment Factor is 60 (1x 6 x 5 x 2 x1) resulting in a DNEL" long-term inhalation exposure – systemic effects” of 13.2 mg/m³/day.

Acute short-term systemic effects, inhalation:Due to the physico-chemical characteristics of the registration substance and the low vapor pressure, inhalation is not an exposure route of significant concern.The long term systemic inhalation DNEL is considered to be sufficient to ensure that no effects occur. Further,the existing technical and personal risk management measures in place are considered adequate and sufficient to ensure safe use of the substance.

Long-term dermal systemic effects: A DNEL was derived from the oral subacute study, which revealed a NOAEL of 450 mg/kg bw/d, which is used as staring point.According to the ECHA REACH Guidance, the DNEL was then obtained by applying assessment factors to the starting point.

-Differences in duration of exposure:A default assessment factor of 6 was applied based on the extrapolation from subacute to chronic.

-interspecies differences (allometric scaling): An allometric scaling factor of 4 as default is used (ECHA Guidance, ECETOC 2010) (correction for differences in metabolic rate: rat to humans).

-intraspecies differences: According to ECETOC technical Report 110 an assessment Factor of3is considered.

-Dose response relationship: as no conspicious behavior is observed an AF of 1 is taken.

Since the available data are adequate for labelling and classification purposes of the submission substance, the quality of the data base is judged sufficient for evaluation. Thus the assessment factor of 1 is applied.

The resulting overall Assessment Factor is 72 (6 x 4 x 3 x 1 x 1), resulting in a DNEL "long-term dermal exposure - systemic effects" of 6.25 mg/m2/day.

Short-term dermal DNELis not considered applicable. The long-term systemic dermal DNEL is considered to be sufficient to ensure that no effects occur. The registration substance is a skin sensitizer and based hereupon, no dermal exposure is allowed. The existing risk management measures in place are considered adequate and sufficient to ensure safe use of the substance.

Local DNELs:

No DNEL was establishedfor inhalation local effects.The long term systemic inhalation DNEL is considered to be sufficient to ensure that no effects occur.The existing technical and personal risk management measures in place are considered adequate and sufficient to ensure safe use of the substance.

Nolong-term dermal DNEL for local effectswas calculated for the registration substance. The substance is considered to be a skin sensitizer but is not irritating to the skin, thus dermal exposure is strictly to avoid. Therefore, appropriate technical and personal measures to avoid exposure, is mandatory. The technical and personal risk management measures are considered adequate and sufficient to ensure safe use of the registration substance.Long-term local exposure is not anticipated for the worker. Therefore, a qualitative risk assessment was performed.

Short-term dermal DNEL for local effects has not been quantified. Beside the sensitizing property of the substance, it is also causing "irreversible effects to the eye", thus, during handling and use of the material wearing of protective gear has to be considered as absolutely mandatory for workers.The existing technical and personal risk management measures in place are considered adequate and sufficient to ensure safe use of the substance.

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

Value:

10

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:

3.75 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: Assessment factors based on ECETOC Technical Report No. 110

Overall assessment factor (AF):

120

Modified dose descriptor starting point:

NOAEL

Value:

450 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

not required

AF for dose response relationship:

1

Justification:

not required if NOAEL is starting point

AF for differences in duration of exposure:

6

Justification:

extrapolating subacute study to chronic study

AF for interspecies differences (allometric scaling):

4

Justification:

adjusting metabolic rates rat to human

AF for other interspecies differences:

1

Justification:

not required based on ECETOC Technical Report No. 110

AF for intraspecies differences:

5

Justification:

based on ECETOC Technical Report No. 110

AF for the quality of the whole database:

1

Justification:

not required

AF for remaining uncertainties:

1

Justification:

not required

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

11.25 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

other: Assessment factors based on ECETOC Technical Report No. 110

Overall assessment factor (AF):

40

DNEL extrapolated from long term DNEL

Modified dose descriptor starting point:

NOAEL

Value:

450 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

not required

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

General comment to DNEL derivation:

The registration substance is used as paper dye at paper manufacturing sites, and based on available information after the paper dyeing process the dye molecules are fixed to the paper fibres. Based on this the general population is not getting in contact with the material in relevant amounts. Still the oral long term DNEL is being derived for covering a theoretically possible exposure of the population with the substance. Derivation of inhalation and dermal DNELs not applicable based on exposure grounds.

The DNELs derived for the registration substance, mostly have been derived based on studies read-across from the analogue substance (refer to IUCLID section 13). A full justification for the appropriateness of the performed read-across approach is given as an appendix in chapter 13 "Assessment Reports"of this dossier. The most relevant study for DNEL derivation is the oral subacute study on the source substance. Therefore, route-route extrapolation had to be applied for deriving certain DNELs. Derivation of assessment factors are based on ECETOC Technical Report 110.

Systemic DNELs:

No DNELs for inhalation- or dermal exposure to the registration substance are established as there is no use resulting in direct exposure of the general population. Long-term and acute oral systemic DNELs were derived from the oral subacute study, which revealed a NOAEL of 450 mg/kg bw/d.

Long-term oral systemic effects: A DNEL was derived from the oral subacute study, which revealed a NOAEL of 450 mg/kg bw/d and is used as staring point. According to the ECHA REACH Guidance, the DNEL was then obtained by applying assessment factors to the starting point.

-Differences in duration of exposure: A default assessment factor of 6 was applied based on the extrapolation from subacute to chronic.

-interspecies differences (allometric scaling): An allometric scaling factor of 4 as default is used (ECHA Guidance, ECETOC 2010) (correction for differences in metabolic rate: rat to humans).

-intraspecies differences: According to ECETOC technical Report 110 an assessment Factor of 5 is considered.

-Dose response relationship: As no conspicuous behavior is observed an AF of 1 is taken.

Since the available data are adequate for labelling and classification purposes of the submissionsubstance, the quality of the data base is judged sufficient for evaluation. Thus, an assessment factor of 1 is applied.

The resulting overall Assessment Factor is 120 (6 x 4 x 5 x 1 x 1), resulting in a DNEL "long-term oral exposure - systemic effects" of 3.75 mg/kg/day.

The short-term systemic dermal DNEL is not considered applicable, as the registration substance is considered to be fixed to the paper fibres of paper articles and thus resulting in no direct exposure to the general population.

The short-term systemic oral DNEL is calculated by multiplying the long term oral systemic DNEL with a factor of 3 (based on ECETOC Technical Report 110).The resulting DNEL for short-term systemic oral is calculated to be 11.25mg/kg/day.

Local DNELs:

Long-term dermal DNEL for local effects: No long-term local exposure to the registration substance is anticipated for the general population, i.e. based on the paper dyeing process the dye molecules are fixed to the paper fibres and thus the general population is not getting in direct contact with the registration substance, thus, no DNEL for long-term dermal local effects is derived.

 

Short-term dermal DNEL for local effects has not been quantified. Beside the sensitizing property of the substance, it is also causing "irreversible effects to the eye". Thus, during handling and use of the material wearing of protective gear has to be considered as absolutely mandatory for workers. As the substance registered however is used for the manufacturing of paper, the general population is not involved in such a direct exposure scenario, in this way resulting in no hazard for the eyes of the general population.