1-(N,N-bis(2-ethylhexyl)aminomethyl)-1,2,4-triazole

Toxicological Summary

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

Value:

53 mg/m³

Explanation for the modification of the dose descriptor starting point:

Since no data for the inhalation route were available, a route to route extrapolation was performed following ECHA guidance.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

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

Value:

60 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Since no data for the inhalation route were available, a route to route extrapolation was performed following ECHA guidance.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

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 28-Day oral toxicity study in rats was qualified as the most relevant study. The effects observed were limited to signs of local irritation in the GI tract. In this study, the no-observed-effect-level (NOEL) was 60 mg/kg body weight.

 

Calculation of DNELs

General remarks

In general, systemic DNELs are calculated to give a limit of exposure that is considered as safe regarding systemic toxicity. Based on the toxicity profile of the substance, the systemic DNELs might not be enough to ensure safe handling of the substance. After inhalation and upon dermal exposure, the prominent effects will be corrosivity and sensitization. These local effects might occur even when the exposure is kept below the derived systemic DNEL values. Therefore, the systemic DNELs might not be sufficient for overall risk characterization of this substance. Specific risk management measures need to be followed to avoid any skin contact and to control the local toxicits effects of this article. Nevertheless, the systemic DNELs are derived, even though these DNELs will only ensure safety regarding systemic toxicity effects which might not occur prior to the local effects.

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 m³/10 m³) = 53 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 = 53 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 60 was employed for the dermal route.

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

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 inhalative

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 only be derived if an acute systemic toxicity hazard leading to classification is identified. Therefore, because the substance is not classified for acute toxicity according to Directive 67/548/EEC and Regulation 1272/2008/EC, no systemic DNELs 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. 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.

Overall remark:

The test article is used as a lubricant additive for oil and greases. All end products contain only minimal amounts of this substance, the concentrations range from 50 ppm (0.005%) in transformer oils to 1000 ppm (0.1%) in industrial lubricants. Therefore, the substance does no longer require labeling and safe use can be assumed. In professional settings the substance is usually used at the same low concentration as well. In addition, all workers are required to wear overalls, eye protection and gloves to prevent any contact with skin. Except for application with aerosol formation potential (spraying), exposure by inhalation is low because the substance is a viscous liquid with very low vapor pressure.

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

Value:

26 mg/m³

Explanation for the modification of the dose descriptor starting point:

Since no data for the inhalation route were available, a route to route extrapolation was performed following ECHA guidance.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

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)

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

Value:

60 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Since no data for the inhalation route were available, a route to route extrapolation was performed following ECHA guidance.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

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

Value:

60 mg/kg bw/day

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

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 determined 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 systemic DNELs.

Calculation of DNELs

General remarks

In general, systemic DNELs are calculated to give a limit of exposure that is considered as safe regarding systemic toxicity. Based on the toxicity profile of the substance, the systemic DNELs might not be enough to ensure safe handling of the substance. After inhalation and upon dermal exposure, the prominent effects will be corrosivity and sensitization. These local effects might occur even when the exposure is kept below the derived systemic DNEL values. Therefore, the systemic DNELs might not be sufficient for overall risk characterization of this substance. Specific risk management measures need to be followed to avoid any skin contact and to control the local toxicits effects of this article. Nevertheless, the systemic DNELs are derived, even though these DNELs will only ensure safety regarding systemic toxicity effects which might not occur prior to the local effects.

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 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 (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 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 (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, long-term, oral:

The NOAEL of 200 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.

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, oral and inhalative

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 only be derived if an acute systemic toxicity hazard leading to classification is identified. Therefore, because the substance is not classified for acute toxicity according to Directive 67/548/EEC and Regulation 1272/2008/EC, no systemic DNELs 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, all end products contain only minimal amounts of the substance, the concentrations range from 50 ppm in transformer oils to 1000 ppm in industrial lubricants. Therefore, the substance does no longer require labeling and safe use can be assumed. Nevertheless, 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, all end products contain only minimal amounts of the substance, the concentrations range from 50 ppm in transformer oils to 1000 ppm in industrial lubricants. Therefore, the substance does no longer require labeling and safe use can be assumed. Nevertheless, personal protective equipment is recommended.

Overall remark:

The test article is used as a lubricant additive for oil and greases. All end products contain only minimal amounts of this substance, the concentrations range from 50 ppm (0.005%) in transformer oils to 1000 ppm (0.1%) in industrial lubricants. Therefore, the substance does no longer require labeling and safe use can be assumed. In professional settings the substance is usually used at the same low concentration as well. In addition, all workers are required to wear overalls, eye protection and gloves to prevent any contact with skin. Except for application with aerosol formation potential (spraying), exposure by inhalation is low because the substance is a viscous liquid with very low vapor pressure.