Formaldehyde, reaction products with diethanolamine and 6(or 7)-methyl-1H-benzotriazole

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.3 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

Dose descriptor starting point:

NOAEL

Value:

45 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

39.7 mg/m³

Explanation for the modification of the dose descriptor starting point:

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 ³/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) = 45 mg/kg / 0.38 m³/kg x 0.5 x (6.7 m³/10m³) = 39.7 mg/m³

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

extrapolation from subacute to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling is part of the route to route extrapolation

AF for other interspecies differences:

1

Justification:

no additional factor required

AF for intraspecies differences:

5

Justification:

standard factor for worker

AF for the quality of the whole database:

1

Justification:

the database is considered sufficient

AF for remaining uncertainties:

1

Justification:

No remaining factor required

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.8 mg/m³

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Dose descriptor starting point:

LOAEL

Value:

500 mg/kg bw/day

Modified dose descriptor starting point:

LOAEC

Value:

441 mg/m³

Explanation for the modification of the dose descriptor starting point:

Based on the acute oral LD50 of 1472 mg/kg bw the test substance is 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 500 mg/kg bw based on clinical signs (no mortalities). 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) = 500 mg/kg / 0.38 m³/kg x 0.5 x (6.7 m³/10 m³) = 441 mg/m³

AF for dose response relationship:

10

Justification:

uncertainties related to using a LOAEL derived in the acute oral toxicity study

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling is part of the route to route extrapolation

AF for other interspecies differences:

1

Justification:

no additional factor required

AF for intraspecies differences:

5

Justification:

standard factor for worker

AF for the quality of the whole database:

1

Justification:

the database is considered sufficient

AF for remaining uncertainties:

1

Justification:

no additional uncertainties

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:

0.4 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

Dose descriptor starting point:

NOAEL

Value:

45 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

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.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

extrapolation from subacute to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

extrapolation from rat to human

AF for other interspecies differences:

1

Justification:

no additiona lfactor required

AF for intraspecies differences:

5

Justification:

standard factor for worker

AF for the quality of the whole database:

1

Justification:

the database is considered sufficient

AF for remaining uncertainties:

1

Justification:

no additiona lfactor required

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)

Acute/short term exposure

Hazard assessment conclusion:

medium 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 performed with the read across candidate (see CSR for read across justification) was qualified as the most relevant study. The dose descriptor chosen was the NOAEL of 45 mg/kg/day.

 

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

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.3 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

Dose descriptor starting point:

NOAEL

Value:

45 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

19.6 mg/m³

Explanation for the modification of the dose descriptor starting point:

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) = 45 mg/kg / 1.15 m³/kg x 0.5 = 19.6 mg/m³

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

extrapolation from subacute to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling is part of the route to route extrapolation

AF for other interspecies differences:

1

Justification:

no further factor required

AF for intraspecies differences:

10

Justification:

standard factor for consumer

AF for the quality of the whole database:

1

Justification:

the database is considered sufficient

AF for remaining uncertainties:

1

Justification:

no further factor required

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.2 mg/m³

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Dose descriptor starting point:

LOAEL

Value:

500 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

217 mg/m³

Explanation for the modification of the dose descriptor starting point:

Based on the acute oral LD50 of 1472 mg/kg bw the test substance is 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 500 mg/kg bw based on clinical signs (no mortalities). 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) = 500 mg/kg / 1.15 m³/kg x 0.5 = 217 mg/m³

AF for dose response relationship:

10

Justification:

uncertainties related to using a LOAEL derived in the acute oral toxicity study

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling is part of the route to route extrapolation

AF for other interspecies differences:

1

Justification:

no further factor required

AF for intraspecies differences:

10

Justification:

standard factor for consumer

AF for the quality of the whole database:

1

Justification:

the database is considered sufficient

AF for remaining uncertainties:

1

Justification:

no further factor required

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:

0.2 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

Dose descriptor starting point:

NOAEL

Value:

45 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

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.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable

AF for differences in duration of exposure:

6

Justification:

default extrapolation factor for exposure duration is used: subacute to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

1

Justification:

no additional factor required

AF for intraspecies differences:

10

Justification:

The default value for the more heterogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

the database is considered sufficient

AF for remaining uncertainties:

1

Justification:

no additional factor required

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

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:

0.2 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

Dose descriptor starting point:

NOAEL

Value:

45 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The NOAEL of 45 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.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable

AF for differences in duration of exposure:

6

Justification:

default extrapolation factor for exposure duration is used: subacute to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

1

Justification:

no additional factor required

AF for intraspecies differences:

10

Justification:

The default value for the more heterogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

the database is considered sufficient

AF for remaining uncertainties:

1

Justification:

no additional factor required

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

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

For the derivation of the DNELs, the combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test in rats performed with the read across candidate (see CSR for read across justification) was qualified as the most relevant study. The dose descriptor chosen was the NOAEL of 45 mg/kg/day.

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