Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.2 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance with substance specific modifications
Overall assessment factor (AF):
60
Modified dose descriptor starting point:
NOAEC
Value:
132.24 mg/m³
Explanation for the modification of the dose descriptor starting point:
No data for the submission substance after long-term inhalation exposure available
AF for dose response relationship:
1
Justification:
ECHA Guidance
AF for differences in duration of exposure:
6
Justification:
ECHA Guidance (conservative assumption as effects are local and considered to be concentration dependent)
AF for interspecies differences (allometric scaling):
1
Justification:
ECHA Guidance (inhalation route)
AF for other interspecies differences:
1
Justification:
substance excert effects most probably directly (corrosive nature), no species differences expected
AF for intraspecies differences:
5
Justification:
overall AF for combined intraspecies and remaining uncertainty (modified from ECETOC and German AGS )
AF for the quality of the whole database:
1
Justification:
ECHA Guidance
AF for remaining uncertainties:
2
Justification:
ECHA Guidance, route-to-route extrapolation (oral to inhalation), conservative assumption as leading effect is local and considered to be concentration dependent
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information
Value:
1 mg/m³

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: DNEL derivation considering local effects according to Geman VCI
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.25 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):
60
Modified dose descriptor starting point:
NOAEL
Value:
75 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No data for the submission substance after long-term dermal exposure available (oral absorption equal dermal absorption 100% by default)
AF for dose response relationship:
1
Justification:
ECHA Guidance
AF for differences in duration of exposure:
3
Justification:
reduced default due to concentration dependent dermal corrosivity of submission substance (leading effect less duration dependency)
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA Guidance
AF for other interspecies differences:
5
Justification:
Modified according to ECETOC and German AGS (combined inter-/intraspecies AF)
AF for intraspecies differences:
1
Justification:
Modified according to ECETOC and German AGS (combined inter-/intraspecies AF)
AF for the quality of the whole database:
1
Justification:
ECHA Guidance
AF for remaining uncertainties:
1
Justification:
ECHA Guidance
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

Workers - Hazard via inhalation route

No route-specific acute and/or repeated inhalation toxicity data is available for the submission substance. As default, route-to-route extrapolation is performed using the NOAEL of 75 mg/kg body weight per day from the 28 -day oral toxicity study with the test item, which was identified as key study for repeated dose toxicity. This NOAEL is used as starting point for the derivation of the worker DNEL "long-term inhalation exposure - systemic effects". Although the leading adverse effects are considered local findings in the gastrointestinal tract due to the corrosive properties and thus no species differences are expected, a conservative approach is taken and the default factor of 2 for remaining uncertainties using route-to-route extrapolation is applied. The corrected inhalatory NOAEC is obtained according REACH Guidance R.8 as 132.24 mg/m3. Based on the overall toxicity profile, a treshold mechanism in form of local effects with implications for secondary systemic inflammatory toxicity is most likely. With regard to interspecies differences, alometric scaling concerning oral-to-inhalation extrapolation is not appropriate and no assessment factor is applied (ECHA Guidance). The adjustment for remaining differences is not considered scientifically justified (ECETOC 2010). Analysis of various data sets have revealed that a separate factor for remaining interspecies differences need not always be established because these are being accounted for by the assessment of intraspecies variability. Based on scientific evidence, ECETOC is proposing overall assessment factors of 3 for workers, which includes the remaining interspecies differences. A factor of 1 for remaining interspecies differences is also supported, because it is unlikely that effects driven by irritation/corrosion differ between species. However, taking into account the overall toxicity profile of the submission substance, 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 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]) . Since the assessment is based on the outcome of a 28 -day repeated dose toxicity study, time extrapolation to chronic exposure conditions generally have to be considered. However, because "local cytotoxicity" as concentration dependent effect seems to be dominating in the overall toxicity profile of the submission substance, the full set of default assessment factors for duration extrapolation is not appropriate. Based hereupon, duration adjustment using an assessment factor of 3 seems to be justified and is used. Since the available data are considered adequate for labelling and classification purposes of the submission substance, the quality of the data base is judged sufficient for evaluation and thus, an assessment factor of 1 is applied. The resulting overall assessment factor is 60 (6 x 5 x 2) resulting in a DNEL "long-term inhalation exposure - systemic effects" of 2.2 mg/m3.

The submission substance is corrosive to skin and thus irritative properties of the respiratory tract have to be taken into account when worker are exposed by the inhalation route. Although inhalation is not an exposure pathway of concern due to the very low vapour pressure and because the submission substance is not a solid which excludes exposure to inhalable/respirable particles, a generic cut-off level as surrogate can be derived. Using the proposed approach of DNEL derivations considering local effects according to the Working Group Toxicology of the Geman Chemical Industry Association (VCI [Zitat der reference noch einfügen]), for corrosive substances a generic cut-off value as DNEL surrogate of 1 mg/m3 has been established and will be used for risk characterization.

Wokers - Hazard via dermal route

No route-specific acute and/or repeated dermal toxicity data is available for the submission substance. As default, route-to-route extrapolation is performed using the NOAEL of 75 mg/kg body weight per day from the 28 -day oral toxicity study with the test item, which was identified as key study for repeated dose toxicity. In the absence of dermal penetration data, 100 % absorption via the skin is assumed as default for the route-to-route extrapolation. Hence, 75 mg/kg body weight per day is used as point of departure for the derivation of the worker DNEL "long-term dermal exposure - systemic effects". An allometric scaling factor of 4 as default for interspecies extrapolation (rat to human) is used (ECHA Guidance). Duration adjustment is performed using an reduced assessment factor of 3 which is lower because local irritation / corrosion as concentration dependent effect is less dependent on duration of exposure. To account for intraspecies variability and remaining uncertainties a combined inter-/intraspecies assessment factor of 5 is included (based on the approaches from ECETOC and AGS from Germany). Based hereupon, an overall assessment factor of 60 is calculated. Based hereupon, a worker DNEL "long-term dermal exposure - systemic effects" of 1.25 mg/kg body weight per day is derived.

No DNEL is derived for acute systemic toxicity and for local effects following acute and/or prolonged dermal exposure. The submission substance is corrosive to skin and thus, proper technical and personal risk reduction measures are in place to ensure safe use conditions. According to ECHA Guidance R.14, the emphasis for properly labelled corrosives should be on the presentation of adequate risk management measures rather than on the assessment of the risks from dermal exposure,

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:
893 µg/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):
84
Modified dose descriptor starting point:
NOAEL
Value:
75 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
no route-to-route extrapolation applied
AF for dose response relationship:
1
Justification:
ECHA Guidance
AF for differences in duration of exposure:
3
Justification:
reduced from 6 because effects mainly concentration but not dose / duration driven
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA Guidance
AF for other interspecies differences:
1
Justification:
included in variability assessment
AF for intraspecies differences:
7
Justification:
5 from ECETOC analysis plus 2 for additional variability
AF for the quality of the whole database:
1
Justification:
ECHA Guidance
AF for remaining uncertainties:
1
Justification:
ECHA Guidance, no conspicious behaviour
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

The submitted substance is not used in the consumer sector and respective uses are not supported. DNEL derivations for the general population are therefore not necessary and not required. However, although no consumer uses were identified, an oral DNEL long-term (systemic) was derived to consider indirect exposures via the environment. For the derivation the following assessment factors were applied: Route-to-Route: AF = 1; Interspecies extrapolation: AF = 4 (allometric scaling rat to humans); Remaining differences = 1 (included in variability assessment); Intraspecies variability: AF = 7 (5 following ECETOC analysis plus 2 for additional variability); Exposure duration: AF = 3 (reduced from 6 (subacute to chronic) because effects mainly concentration but not dose driven); Dose-Response: AF = 1 (no conspicious behaviour); Quality of database: AF = 1 (judged sufficient for evaluation). Based on an overall assessment factor of 84, a DNEL oral, long-term (systemic) of 0.89 mg/kg body weight per day was derived.