Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.94 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: according to ECHA TGD
Overall assessment factor (AF):
30
Dose descriptor starting point:
NOAEL
DNEL value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
88.2 mg/m³
Explanation for the modification of the dose descriptor starting point:

in accordance with ECHA REACH TGD R8 and ECETOC technical report 110

Inhalation long-term systemic DNEL based on NOAEL (OECD 407, oral) in rats:

- NOAEC (inhalation derived according to ECHA Guidance TGD R8: "Guidance on information requirements and chemical safety assessment", Chapter R.8.4.2, Figure R.8-3)

corrected NOAEC(inhalation) = NOAEL(oral,rat) *1 / sRVrat * ABS(oral-rat)/ABS(inhalation-human) * sRVhuman / wRV

= 100mg/kg * 1/0.38 m3/kg/d + 50% /100% * 6.7 m3 /10 m3

= 88.2 mg/ m3

(with sRV: standard respiratory volume; ABS: Absorption; wRV: worker respiratory Volume)

AF for dose response relationship:
1
Justification:
according to ECETOC technical report 110
AF for differences in duration of exposure:
6
Justification:
According to ECHA TGD and ECETOC technical report 110. Increasing exposure duration does not result in an increase in incidence and severity of adverse effects, based on comparable results from animal studies after repeated oral treatment lasting 14 days, 28 days and up to about 54 days.
AF for interspecies differences (allometric scaling):
1
Justification:
according to ECETOC technical report 110; ECHA REACH TGD; Allometric scaling is not applied. Factor of 2,5 for interspecies difference is included in the calculation by correcting the respiratory volumes of rat and
man.
AF for other interspecies differences:
1
Justification:
according to ECETOC technical report 110; ECHA REACH TGD; Factor of 2,5 for interspecies difference is included in the calculation by correcting the respiratory volumes of rat and
man.
AF for intraspecies differences:
5
Justification:
ECHA REACH TGD
AF for the quality of the whole database:
1
Justification:
ECHA REACH TGD and ECETOC technical report 110
AF for remaining uncertainties:
1
Justification:
ECHA REACH TGD and ECETOC technical report 110
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
other: VCI inhalation DNEL for irritating substances (Messinger H, 2014.Regulatory Toxicology and Pharmacology 68 (2014) 317–324)

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
other: VCI inhalation DNEL for irritating substances (Messinger H, 2014.Regulatory Toxicology and Pharmacology 68 (2014) 317–324)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
DNEL related information
DNEL extrapolated from long term DNEL

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.83 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH TGD and ECETOC technical report 10
Overall assessment factor (AF):
120
Modified dose descriptor starting point:
NOAEL
DNEL value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

in accordance with ECHA REACH TGD R8 and ECETOC technical report 110

Worker: Dermal long-term systemic DNEL based on NOAEL (OECD 407, oral) in rats:

- NOAEL (dermal) derived according to ECHA Guidance TGD R8: "Guidance on information requirements and chemical safety assessment", Appendix R.8-2, Example B.5

corrected NOAEL(dermal) = NOAEL(oral,rat) * Absorption(oral, rat)/Absorption (dermal, human)

= 100 mg/kg bw * 100% / 100%

= 100 mg/kg bw

AF for dose response relationship:
1
Justification:
according to ECHA REACH TGD R8 and ECETOC technical report 110
AF for differences in duration of exposure:
6
Justification:
according to ECHA REACH TGD R8 and ECETOC technical report 110. Increasing exposure duration does not result in an increase in incidence and severity of adverse effects, based on comparable results from animal studies after repeated oral treatment lasting 14 days, 28 days and up to about 54 days.
AF for interspecies differences (allometric scaling):
4
Justification:
according to ECHA REACH TGD R8 and ECETOC technical report 110; Allometric scaling from rat to human => factor of 2.5 for remaining interspecies differences not taken but included into intraspecies variability consideration
AF for other interspecies differences:
1
Justification:
according to ECHA REACH TGD R8 and ECETOC technical report 110: factor of 2.5 for remaining interspecies differences not taken but included into intraspecies variability consideration
AF for intraspecies differences:
5
Justification:
according to ECHA REACH TGD R8 and ECETOC technical report 110; German Ausschuss für Gefahrstoffe- AGS 2010
AF for the quality of the whole database:
1
Justification:
according to ECHA REACH TGD R8 and ECETOC technical report 110: Good /standard quality of database
AF for remaining uncertainties:
1
Justification:
according to ECHA REACH TGD
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
DNEL extrapolated from long term DNEL

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:
medium hazard (no threshold derived)

Additional information - workers

Worker DNEL: Long-term/short term for inhalation route, local effects

The German VCI ("Verband der chemischen Industrie") established an inhalation DNEL for local effects for corrosive substances of 1 mg/m3that should be applied for long- and short-term exposure equally. The derivation of this value is fully described in Messinger (2013). Briefly, the DNEL is a generic cut-off value based on an extensive analysis of the German occupational exposure limit (OEL) values as published in TRGS 900 (“Technische Regeln für Gefahrstoffe”) for substances that are legally classified as corrosive. Substances identified as corrosive in self-classifications only were not considered, since they lack a peer review of the classification assigned. After exclusion of some (groups of) substances, such as CMR substances, the evaluation retrieved 40 corrosive substances with OEL values effective in Germany. In addition to the dermal effects, corrosive substances often display pronounced acute toxicity when administered by other pathways, especially via inhalation. When all very toxic (R26 or R27 or R28) and all sensitizing (R42 or R43) substances were removed from the set of 40 corrosive substances, only 2/24 (8%) substances had an OEL below 1 mg/m3. The two substances are 1) sulfuric acid, a very strong acid vigorously reacting with water and b) barium hydroxide, for which the low OEL was derived on the basis of systemic effects (Messinger, 2013).

Overall, the applicability domain of the DNEL of 1 mg/m3for corrosive substances is defined as follows (Messinger, 2013):

- The substance is not a CMR substance, a heavy metal derivative, a sensitizer and does not hydrolyse to strong acids/bases

- The substance is not very toxic by ingestion, dermal contact or inhalation.

The submission substance fulfils these criteria and the DNEL of 1 mg/m3can be applied.

With this DNEL for local effects, any potential systemic effects are covered as well.

Reference 

Messinger, H.: An approach for the delineation of a generic cut-off value for local respiratory tract irritation by irritating or corrosive substances, 2013.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.72 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH TGD and ECETOC technical report 10
Overall assessment factor (AF):
30
Dose descriptor starting point:
NOAEL
DNEL value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
43.5 mg/m³
Explanation for the modification of the dose descriptor starting point:

in accordance with ECHA R8 and ECETOC technical report 110,

- NOAEC(inhalation) derived according to “Guidance on information requirements and chemical safety assessment”, Chapter R.8.4.2, Figure R. 8-3.
corrected NOAEC(inhalation)
        

= NOAEL(oral, rat) x 1/sRVratxABS(oral-rat)/ABS(inh-human)

= 100 mg/kg x 1/1.15 m3/kg/d x 50%/100%
= 43.5 mg/m3
(with: sRV: standard respiratory volume; ABS: Absorption; wRV: worker respiratory volume)

AF for dose response relationship:
1
Justification:
according to ECETOC technical report 110
AF for differences in duration of exposure:
6
Justification:
According to ECHA TGD and ECETOC technical report 110.
AF for interspecies differences (allometric scaling):
1
Justification:
Interspecies difference is included in the calculation by correcting the respiratory volumes of rat and man. No allometric scaling from rat to human is chosen resulting in an AF of 1 which is appropriate due to TGD.
AF for other interspecies differences:
1
Justification:
In accordance with ECHA R8 and ECETOC technical report 110, interspecies difference is included in the calculation by correcting the respiratory volumes of rat and man. A factor of 2.5 for remaining interspecies differences not taken but included into intraspecies variability consideration.
AF for intraspecies differences:
10
Justification:
in accordance with ECHA R8 and ECETOC technical report 110,
AF for the quality of the whole database:
1
Justification:
according to ECETOC technical report 110
AF for remaining uncertainties:
1
Justification:
according to ECETOC technical report 110
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
DNEL extrapolated from long term DNEL

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
DNEL extrapolated from long term DNEL

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.42 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH TGD and ECETOC technical report
Overall assessment factor (AF):
240
Dose descriptor starting point:
NOAEL
DNEL value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

in accordance with ECHA Reach R8 and ECETOC technical report 110.

General population: Dermal long-term systemic DNEL based on NOAEL (OECD 407, oral) in rats:
- NOAEL(dermal) derived according to “Guidance on information requirements and chemical safety assessment Appendix R. 8-2, Example B.5.
corrected NOAEL(dermal)
  

= NOAEL(oral, rat) x Absorption(oral-rat) / Absorption(dermal-human)
= 100 mg/kg bw x 100% / 100%
= 100 mg/kg bw

AF for dose response relationship:
1
Justification:
according to ECHA REACH TGD R8 and ECETOC technical report 110:
AF for differences in duration of exposure:
6
Justification:
according to ECHA R8 and ECETOC technical report 110. Increasing exposure duration does not result in an increase in incidence and severity of adverse effects, based on comparable results from animal studies after repeated oral treatment lasting 14 days, 28 days and up to about 54 days.
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling from rat to human => factor of 2.5 for remaining interspecies differences not taken but included into intraspecies variability consideration
AF for other interspecies differences:
1
Justification:
according to ECHA REACH TGD R8 and ECETOC technical report 110; factor of 2.5 for remaining interspecies differences not taken but included into intraspecies variability consideration
AF for intraspecies differences:
10
Justification:
according to ECHA Reach R8 and ECETOC technical report 110;
AF for the quality of the whole database:
1
Justification:
according to ECHA REACH TGD R8 and ECETOC technical report 110: Good /standard quality of database
AF for remaining uncertainties:
1
Justification:
according to ECHA REACH TGD R8
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
DNEL extrapolated from long term DNEL

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:
0.42 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH TGD and ECETOC technical report
Overall assessment factor (AF):
240
Dose descriptor starting point:
NOAEL
DNEL value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No modification. Relevant study was performed using the oral route.

AF for dose response relationship:
1
Justification:
in accordance with ECHA Reach R8 and ECETOC technical report 110
AF for differences in duration of exposure:
6
Justification:
according to ECHA R8 and ECETOC technical report 110. Increasing exposure duration does not result in an increase in incidence and severity of adverse effects, based on comparable results from animal studies after repeated oral treatment lasting 14 days, 28 days and up to about 54 days.
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling from rat to human => factor of 2.5 for remaining interspecies differences not taken but included into intraspecies variability consideration
AF for other interspecies differences:
1
Justification:
according to ECHA REACH TGD R8 and ECETOC technical report 110; factor of 2.5 for remaining interspecies differences not taken but included into intraspecies variability consideration
AF for intraspecies differences:
10
Justification:
according to ECHA Reach R8 and ECETOC technical report 110;
AF for the quality of the whole database:
1
Justification:
according to ECHA REACH TGD R8 and ECETOC technical report 110: Good /standard quality of database
AF for remaining uncertainties:
1
Justification:
in accordance with ECHA Reach R8
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
DNEL extrapolated from long term DNEL

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

The general population will only come into contact with the diluted substance as part of a formulation and will handle diluted use concentrations.