Propanoic acid, 2-hydroxy-, compd. with 7-[[4,6-bis[[3-(diethylamino)propyl]amino]-1,3,5-triazin-2-yl]amino]-3-[2-(2,3-dihydro-2-oxo-1H-benzimidazol-6-yl)diazenyl]-4-hydroxy-2-naphthalenesulfonic acid (1:1)

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

29.4 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:

1 763 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:

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:

13.9

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECETOC technical report 110

Overall assessment factor (AF):

72

Modified dose descriptor starting point:

NOAEL

Value:

1 000 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 (i.e. 100%)

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:

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 CSR characterizes the hazards and risks associated with the manufacturing and formulation of the registration substance. The only use of the substance is the manufacture of dyed paper.

The following section summarizes DNEL values derived for workers for which the main route of exposure would be dermal. Although less likely to occur, inhalation exposure is also considered. In a conservative approach, long-term systemic DNEL were calculated. As the substance is a dye and coloration during handling cannot be excluded, appropriate protection measures are in place to avoid exposure to high doses.

The most relevant study for DNEL derivation is the oral subacute study on the registration 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:

DNEL long-term systemic effects, inhalation:

The relevant dose descriptor selected to derive the inhalation DNEL was the subacute oral rat NOAEL of 1000 mg/kg bw/day. This dose descriptor, which is the starting point, 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}) = 1000 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 = 1000 mg/kg bw/day ÷ 0.38 m³/kg bw x (6.7 m³÷ 10 m³)

Corrected NOEC =1763 mg/m³

According to the ECHA REACH Guidance as presented in Section R.8.4.3 of REACH guidance document R.8, Table R. 8-6 and ECETOC (2010)., 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 of 6 was 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 of5is 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 assumption.

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 1is 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 29.4 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.

DNEL long-term systemic effects, dermal:

A dermal systemic DNEL was derived from the oral subacute study, which revealed a NOAEL of 1000 mg/kg bw/d which is used as stating point. According to the ECHA REACH Guidance as presented in Section R.8.4.3 of REACH guidance document R.8, Table R. 8-6 and ECETOC (2010)., 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 sca ling 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 3 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 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 13.9 mg/m²/day.

Short-term systemic effects, 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 not dermal acute toxic, not irritant to the skin and not a skin sensitizer. The existing risk management measures in place are considered adequate and sufficient to ensure safe use of the substance.

Local DNELs

No DNEL for inhalation local effectswas established. 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.

No DNEL long-term dermal for local effects was calculated for the registration substance. The long term systemic dermal DNEL is considered to be sufficient to ensure that no effects occur. The substance is not to be classified as irritating to the eye or irritating to skin, nor is the registration substance a sensitizer. Therefore, in this respect no DNEL derivation for long-term local effects is necessary.

No DNEL short-term dermal for local effects was calculated for the registration substance. The substance is not to be classified as irritating to the eye or irritating to skin, nor is the registration substance a sensitizer. Therefore, in this respect no DNEL derivation for long-term local effects is necessary.

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:

8.3 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:

1 000 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

AF for differences in duration of exposure:

6

Justification:

extrapolating subacute study to chronic study

AF for interspecies differences (allometric scaling):

4

Justification:

adjusting metbolic 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:

25 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):

40

DNEL extrapolated from long term DNEL

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

General comment to DNEL derivation:

The substance registered 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. It will not be bioavailable. Exposure of the general population to the dye is anticipated negligible. Based on this the general population is not getting in contact with the material in relevant amounts. Still the oral long-term DNEL was being derived for covering a theoretically possible exposure of the population with the substance. Derivation of inhalation and dermal DNELs are not applicable based on exposure grounds. There is no use resulting in direct exposure of the general population. 

The most relevant study for DNEL derivation is the oral subacute study. 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 1000 mg/kg bw/d.

Long-term oral systemic effects: A DNEL was derived from the oral subacute study, which revealed a NOAEL of 1000 mg/kg bw/d and is used as starting 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 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 120 (6 x 4 x 5 x 1 x 1), resulting in a DNEL "long-term oral exposure - systemic effects" of 8.3 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: Based on ECHA's " Guidance on information requirements and chemical safety assessment - Chapter R.8: Characterisation of dose [concentration]-response for human health" the (oral) acute DNEL for systemic effects can by default be set as 1-5 times the long-term DNEL derived from the (oral) long-term exposure DNEL for systemic effects. Further guidance is provided by ECETOC Technical Report 110. Thus, the DNEL is calculated by multiplying the long term systemic oral DNEL of 8.3 mg/kg bw/day with a factor of 3, which leads to an oral short-term exposure DNEL for systemic effects of  25 mg/kg bw/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 dying process the molecules are fixed to the paper fibres. Thus the general population is not getting in direct contact with the registration substance, and no DNEL for long-term dermal local effect is derived.

Short-term dermal DNEL for local effects

No DNEL for short-term dermal local effects has been quantified. As the substance registered is used for the manufacturing of paper, the general population is not involved in such a direct exposure scenario and thus resulting in no hazard for the skin or the eyes of the general population.