Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.76 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):
30
Modified dose descriptor starting point:
NOAEC
DNEL value:
52.9 mg/m³
Explanation for the modification of the dose descriptor starting point:
No data for the inhalation route were available; a route to route extrapolation was performed according to ECHA guidance.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
17.6 mg/m³
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.5 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):
120
Modified dose descriptor starting point:
NOAEL
DNEL value:
60 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No data for the dermal route were available; a route to route extrapolation was performed according to ECHA guidance.
Acute/short term exposure
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

Identification of relevant dose descriptor

For the derivation of the DNELs, the combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test in rats was qualified as the most relevant study. The dose descriptor chosen was the NOAEL of 60 mg/kg/day.

 

Calculation of DNELs

Systemic, long-term, inhalative

Because no inhalation study is available, a route to route extrapolation was performed. The NOAEL (oral) is converted into a NOAEC (corrected) in accordance to guidance on information requirements and chemical safety assessment, Chapter R.8, ECHA, May 2008. The NOAEL (oral) has to be divided by a factor of 0.38 m3/kg body weight and corrected for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m3/10 m3). In addition, a default factor of 2 is applied to account for differences in oral and inhalative absorption properties. The corrected starting point is therefore:

NOAEC (corrected) = 60 mg/kg / 0.38 m3/kg x 0.5 x (6.7 m3/10m3) = 52.9 mg/m3

The DNEL is calculated as follows: NOAEL (corrected) / Sum of assessment factors applicable.

The following assessment factors according to "ECHA guidance on information requirements and chemical safety assessment, Chapter R8" were chosen:

Intraspecies differences (worker): 5

Interspecies variations: 1

Exposure duration: 6

Dose-response factor: 1

Quality of whole database factor: 1

The overall assessment factor employed for the inhalation route is therefore 30.

DNEL = 52.9 mg/m3/ 30 = 1.76 mg/m3

 

Systemic, long-term, dermal:

DNEL = NOAEL (oral) / Sum of assessment factors applicable

The dermal route is typically covered by oral route information in the absence of data for this administration route. Since no data on skin penetration is available a worst case approach was chosen and an absorption of 100% is assumed. The following assessment factors according to "ECHA guidance on information requirements and chemical safety assessment, Chapter R8" were chosen:

Intraspecies differences (worker): 5

Interspecies variations: 1

Allometric scaling (rat to human): 4

Exposure duration: 6

Dose-response factor: 1

Quality of whole database factor: 1

Overall, an assessment factor of 120 was employed for the dermal route.

DNEL= 60 mg/kg body weight / 120 = 0.5 mg/kg body weight.

Systemic, short-term, inhalative

Based on the acute oral LD50 of 1674 mg/kg bw the test substance is considered to be harmful if swallowed and subject to classification. In view of this acute toxicity hazard, a worker DNEL (acute/short-term exposure by inhalation) is derived to account for potential peak exposures.Because no inhalation study is available, a route to route extrapolation was performed.In the acute oral toxicity study, the LOAEL was 1000 mg/kg bw based on one female mortality.The LOAEL (oral) is converted into a LOAEC (corrected) in accordance to guidance on information requirements and chemical safety assessment, Chapter R.8, ECHA, May 2008. The LOAEL (oral) has to be divided by a factor of 0.38 m3/kg body weight and corrected for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m3/10 m3). In addition, a default factor of 2 is applied to account for differences in oral and inhalative absorption properties.

The corrected starting point is therefore:LOAEC (corrected) = 1000 mg/kg / 0.38 m3/kg x 0.5 x (6.7 m3/10m3) = 882 mg/m3

The following assessment factors were chosen:

Intraspecies differences (worker): 5

Interspecies variations: 1

Exposure duration: 1

Dose-response factor: 10 (for using a LOAEL)

Quality of whole database factor: 1

The overall assessment factor employed for the inhalation route is therefore 50. DNEL = 875 mg/m3/ 50 = 17.6 mg/m3

Rationale for omitting "Factor 2.5"

According to ECETOC’s “guidance on Assessment Factors to derive a DNEL, Technical Report No. 110”, the application of a factor of 2.5 for ‘remaining uncertainties’ is unjustified. There is evidence that multiplicative association between inter- and intraspecies assessment factors is overly conservative and that the inclusion of a factor for remaining differences is unnecessary. ECETOC further recommends using allometric scaling and the 5th percentile of the human distribution of intraspecies variability. Consequently, the ‘remaining uncertainty’ for interspecies variability is already accounted for by the intraspecies AF (Calabrese, 1985; Hattis et al 1987). This is further supported by results of the ongoing ERASM project which examines studies in rats and mice to determine interspecies differences based on a probabilistic approach. In their recent publication (Escher, 2013), the authors confirmed the ECETOC position regarding the factor of 2.5 for remaining uncertainties (i. e. the factor does not apply). Therefore, the factor of 2.5 for remaining uncertainties is omitted for this risk assessment.

Literature:

- Calabrese EJ, Uncertainty factors and interindividual variation, Regul Toxicol Pharmacol. 1985 Jun;5(2):190-6.

- Hattis D et al, Human variability in susceptibility to toxic chemicals-a preliminary analysis of pharmacokinetic data from normal volunteers, Risk Anal. 1987 Dec;7(4):415-26.

- Escher SE et al, Interspecies extrapolation based on the RepDose database—A probabilistic approach, Toxicology Letters 218 (2013) 159– 165

Systemic, short-term, dermal

According to the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose[concentration]-response for human health", a DNEL for acute systemic toxicity should be derived if an acute systemic toxicity hazard leading to classification is identified. This is the case for the test substance. However, it is further stated that high peak exposures are usually assessed for the inhalation route only. Although peak exposures might also occur for the dermal route, these are not normally assessed, so the establishment of acute toxicity DNELs for dermal peak exposures appears superfluous. Therefore, no systemic dermal DNEL for short-term exposures was calculated.

Local, long-term and short-term, dermal

The substance was found to be corrosive and sensitizing to the skin. A reliable DNEL for skin sensitization and for corrosion could not be derived. The qualitative assessment revealed the test substance to be a strong sensitizer according to the Potency categorization suggested in ECHA guidance document R.8. Safety is addressed by a qualitative risk assessment and personal protective equipment is recommended.

Local, long-term and short-term, inhalative

No DNELs for local effects after inhalation were calculated because the substance is corrosive and a sensitizer and no quantitative data suitable to derive a DNEL for that effect were available. However, due to the low vapor pressure exposure by inhalation is expected to be low. Safety is addressed by a qualitative risk assessment and personal protective equipment is recommended.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.43 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):
60
Modified dose descriptor starting point:
NOAEC
DNEL value:
26.1 mg/m³
Explanation for the modification of the dose descriptor starting point:
No data for the inhalation route were available; a route to route extrapolation was performed according to ECHA guidance.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.3 mg/m³
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.25 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):
240
Modified dose descriptor starting point:
NOAEL
DNEL value:
60 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No data for the dermal route were available; a route to route extrapolation was performed according to ECHA guidance.
Acute/short term exposure
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.25 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):
240
Modified dose descriptor starting point:
NOAEL
DNEL value:
60 mg/kg bw/day
Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

Identification of relevant dose descriptor

The dose descriptor chosen is the same as for workers (see above). The NOAEL of 60 mg/kg observed in the combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test in rats was used as starting point to derive the DNELs.

 

Calculation of DNELs

Systemic, long-term, inhalative

Because no inhalation study is available, a route to route extrapolation was performed. The NOAEL (oral) has to be modified into a NOAEC (corrected) in accordance to guidance on information requirements and chemical safety assessment, Chapter R.8, ECHA, May 2008. Here, the NOAEL has to be divided by a factor of 1.15 m3/kg body weight. In addition, a default factor of 2 is applied to account for differences in oral and inhalative absorption properties. The corrected starting point is therefore:

NOAEC (corrected) = 60 mg/kg / 1.15 m3/kg x 0.5 = 26.1 mg/m3

The DNEL is calculated as follows: NOAEC (corrected) / Sum of assessment factors applicable.

The following assessment factors according to "ECHA guidance on information requirements and chemical safety assessment, Chapter R8" were chosen:

Intraspecies differences (general population): 10

Interspecies variations: 1

Exposure duration: 6

Dose-response factor: 1

Quality of whole database factor: 1

The overall assessment factor employed for the inhalation route is therefore 60.

DNEL = 26.1 mg/m3/ 60 = 0.43 mg/m3

 

Systemic, long-term, dermal:

DNEL = NOAEL (oral) / Sum of assessment factors applicable

The dermal route is typically covered by oral route information in the absence of data for this administration route. Since no data on skin penetration is available a worst case approach was chosen and an absorption of 100% is assumed. The following assessment factors according to "ECHA guidance on information requirements and chemical safety assessment, Chapter R8" were chosen:

Intraspecies differences (worker): 10

Interspecies variations: 1

Allometric scaling (rat to human): 4

Exposure duration: 6

Dose-response factor: 1

Quality of whole database factor: 1

Overall, an assessment factor of 240 was employed for the dermal route.

DNEL= 60 mg/kg body weight / 240 = 0.25 mg/kg body weight.

Systemic, long-term, oral:

The NOAEL of 1000 mg/kg body weight observed in the combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test in rats was used as starting point for DNEL derivation. The following assessment factors according to "ECHA guidance on information requirements and chemical safety assessment, Chapter R8" were chosen:

Intraspecies differences (general population): 10

Interspecies variations: 1

Allometric scaling (rat to human): 4

Exposure duration: 6

Dose-response factor: 1

Quality of whole database factor: 1

Overall, an assessment factor of 240 was employed for the dermal route.

DNEL= 60 mg/kg body weight / 240 = 0.25 mg/kg body weight.

Systemic, short-term, inhalative

Based on the acute oral LD50 of 1674 mg/kg bw the test substance is considered to be harmful if swallowed and subject to classification. In view of this acute toxicity hazard, a general population DNEL (acute/short-term exposure by inhalation) is derived to account for potential peak exposures.Because no inhalation study is available, a route to route extrapolation was performed. In the acute oral toxicity study, the LOAEL was 1000 mg/kg bw based on one female mortality. The LOAEL (oral) has to be modified into a LOAEC (corrected) in accordance to guidance on information requirements and chemical safety assessment, Chapter R.8, ECHA, May 2008. Here, the LOAEL has to be divided by a factor of 1.15 m3/kg body weight. In addition, a default factor of 2 is applied to account for differences in oral and inhalative absorption properties. The corrected starting point is therefore: LOAEC (corrected) = 1000 mg/kg / 1.15 m3/kg x 0.5 = 434.8 mg/m3

The following assessment factors were chosen:

Intraspecies differences (general population): 10

Interspecies variations: 1

Exposure duration: 1

Dose-response factor: 10 (for using a LOAEL)

Quality of whole database factor: 1

The overall assessment factor employed for the inhalation route is therefore 100.

DNEL = 434.8 mg/m3/ 100 = 4.3 mg/m3

Rationale for omitting "Factor 2.5"

According to ECETOC’s “guidance on Assessment Factors to derive a DNEL, Technical Report No. 110”, the application of a factor of 2.5 for ‘remaining uncertainties’ is unjustified. There is evidence that multiplicative association between inter- and intraspecies assessment factors is overly conservative and that the inclusion of a factor for remaining differences is unnecessary. ECETOC further recommends using allometric scaling and the 5th percentile of the human distribution of intraspecies variability. Consequently, the ‘remaining uncertainty’ for interspecies variability is already accounted for by the intraspecies AF (Calabrese, 1985; Hattis et al 1987). This is further supported by results of the ongoing ERASM project which examines studies in rats and mice to determine interspecies differences based on a probabilistic approach. In their recent publication (Escher, 2013), the authors confirmed the ECETOC position regarding the factor of 2.5 for remaining uncertainties (i. e. the factor does not apply). Therefore, the factor of 2.5 for remaining uncertainties is omitted for this risk assessment.

Literature:

- Calabrese EJ, Uncertainty factors and interindividual variation, Regul Toxicol Pharmacol. 1985 Jun;5(2):190-6.

- Hattis D et al, Human variability in susceptibility to toxic chemicals-a preliminary analysis of pharmacokinetic data from normal volunteers, Risk Anal. 1987 Dec;7(4):415-26.

- Escher SE et al, Interspecies extrapolation based on the RepDose database—A probabilistic approach, Toxicology Letters 218 (2013) 159– 165

Systemic, short-term, dermal and oral

According to the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose[concentration]-response for human health", a DNEL for acute systemic toxicity should be derived if an acute systemic toxicity hazard leading to classification is identified. This is the case for the test substance. However, it is further stated that high peak exposures are usually assessed for the inhalation route only. Although peak exposures might also occur for the dermal route, these are not normally assessed, so the establishment of acute toxicity DNELs for dermal and oral peak exposures appears superfluous. Therefore, no systemic dermal and oral DNEL for short-term exposures were calculated.

Local, long-term and short-term, dermal

The substance was found to be corrosive and sensitizing to the skin. A reliable DNEL for skin sensitization and for corrosion could not be derived. However, since the product content in end user articles is 2% or less, the hazard for irritating effects is considered to be low.

Local, long-term and short-term, inhalative

No DNELs for local effects after inhalation were calculated because the substance is corrosive and a sensitizer and no quantitative data suitable to derive a DNEL were available. However, due to the low vapor pressure exposure by inhalation is expected to be low. In addition, end user products only contain small amounts of the test article (up to 2%), therefore the risk of local effects is strongly reduced.