Sodium 3-(2H-benzotriazol-2-yl)-5-sec-butyl-4-hydroxybenzenesulfonate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

34.57 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: see discussion

Overall assessment factor (AF):

10.2

Dose descriptor starting point:

NOAEL

Value:

200 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

352.63 mg/m³

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

490.19 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

40.8

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)

Additional information - workers

Worker:

Based on the available data, Tinogard HS has to be considered as posing the risk of serious eye damage (R41; Cat. 1).

The primary route of anticipated industrial and professional exposure to Tinogard HS is mainly skin contact. Due to the low vapor pressure of the substance, inhalation exposure to vapors is considered to be low. Due to its polar character the substance is not expected to become systemically available to a high extent after inhalation of the dust. In industrial settings, ingestion is not an anticipated route of exposure, but has to be considered for the general population (see below).

Inhalation long-term exposure – systemic effects:

The NOAEL from an oral repeated dose study with rats conducted according to OECD TG 407 (CCR, 1988) and a screening test according to OECD TG 421 (NOTOX, 2011) was identified as the appropriate starting point for DNEL derivation for long-term exposure following inhalation. The NOAEL for general, systemic toxicity of the test substance was 200 mg/kg bw/d for rats based on salivation, higher water consumption, slight effects on the body weight and slight changes in clinical chemistry at the next higher dose level of 800 mg/kg bw/d.

This point of departure was modified to get the corrected starting point for DNEL derivation. As a first step, route-to-route extrapolation was performed as recommended in the "Guidance on information requirements and chemical safety assessment, Chapter R.8, p. 26 f.:

The oral rat NOAEL was converted into the inhalative human NOAEC corrected for differences between the 8-hour standard inhalation volume of rats versus humans, and for differences between the 8-hour inhalation volume of workers in rest versus workers in light activity, by multiplying with the corresponding factors (x 1/0.38 m³/kg/d x 6.7 m³/10 m³). The resulting corrected starting point for inhalation DNEL derivation for workers is equal to 352.63 mg/m³.

For DNEL derivation, the following assessment factors (AF) were applied to the corrected starting point: 

- Interspecies factor: 1

Besides the applied allometric scaling factors no additional interspecies factor for remaining differences has been used based on the fact that concerning inhalation, rodents like the rat are in general more sensitive compared to human as the rat's ventilation frequency is higher. Also anatomical differences as well as air flow patterns between rodents and humans have to be taken into account. Within the ERASM project, studies in rats and mice are being examined to substantiate whether the factors for allometry and 'remaining‘ differences would be appropriate for these species. The results suggest that a factor of 2.5 for 'remaining‘ interspecies differences may be questionable as a standard procedure (Escher and Mangelsdorf, 2009; Batke et al, 2011; Bitsch et al, 2006). 

- Intraspecies factor: 3

Systemic effects in the repeated dose study with rats were minimal and restricted to general systemic toxicity (effects on body weight, water consumption, salivation etc.). Therefore an intraspecies factor of 3 is considered to be sufficient. 

- Exposure duration: 3.4 (Batke et.al., 2011)

Within the ERASM project, time-extrapolation factors were evaluated with the database RepDoseg that currently contains about 670 substances and 2200 studies on repeated-dose toxicity. It has been shown that as long as the material is soluble, the sub-acute to sub-chronic factor was 1.5, rather than 3 , the sub-acute to chronic factor was 3.4 and the sub-chronic to chronic factor was 1.4 (Batke et al, 2011).

- Dose-response: 1

Total AF = 1 x 3 x 3.4 x 1 = 10.2

Based on this calculation the resulting DNEL is 34.57 mg/m³.

Dermal long-term exposure – systemic effects:

The NOAEL from an oral repeated dose study with rats conducted according to OECD TG 407 (CCR, 1988) and a screening test according to OECD TG 421 (NOTOX, 2011) was identified as the appropriate starting point for DNEL derivation for long-term exposure following dermal application. The oral NOAEL for general, systemic toxicity of the test substance was 200 mg/kg bw/d for rats based on salivation, higher water consumption, slight effects on the body weight and slight changes in clinical chemistry at the next higher dose level of 800 mg/kg bw/d.

This point of departure was modified to get the corrected starting point for DNEL derivation.

As available data indicated, that a skin penetration of less than 1 % of the applied dose has to be expected, the NOAEL of 200 mg/kg bw/d can be multiplied with a factor of 100 leading to a corrected dermal NOAEL of 20000 mg/kg bw/d.

For DNEL derivation, the following assessment factors (AF) were applied to the corrected starting point: 

- Interspecies factor: 4 (Reach Guidance Document R. 8)

Besides the applied allometric scaling factors no additional interspecies factor for remaining differences has been used as within the ERASM project, studies in rats and mice are being examined to substantiate whether the factors for allometry and 'remaining‘ differences would be appropriate for these species. The results suggest that a factor of 2.5 for 'remaining‘ interspecies differences may be questionable as a standard procedure (Escher and Mangelsdorf, 2009; Batke et al, 2011; Bitsch et al, 2006). 

- Intraspecies factor: 3

Systemic effects in the repeated dose study with rats were minimal and restricted to general systemic toxicity (effects on body weight, water consumption, salivation etc.). Therefore an intraspecies factor of 3 is considered to be sufficient. 

- Exposure duration: 3.4 (Batke et.al., 2011)

Within the ERASM project, time-extrapolation factors were evaluated with the database RepDoseg that currently contains about 670 substances and 2200 studies on repeated-dose toxicity. It has been shown that as long as the material is soluble, the sub-acute to sub-chronic factor was 1.5, rather than 3 , the sub-acute to chronic factor was 3.4 and the sub-chronic to chronic factor was 1.4 (Batke et al, 2011).

- Dose-response: 1

Total AF = 4 x 3 x 3.4 x 1 = 40.8

Based on this calculation, the resulting DNEL is 490.19 mg/kg bw/d.

- Batke M, Escher S, Hoffmann-Doerr S, Melber C, Messinger H, Mangelsdorf I.(2011).Evaluation of time extrapolation factors based on the database RepDose. Toxicology Letters 205 (2011) 122– 129.

 

- Escher S and Mangelsdorf I. (2009). Evaluation of risk assessment factors for inter-species and time-extrapolation. Toxicol Lett 189:S247-S248. 46th Congress of the European Societies of Toxicology, 13-16 September 2009, Dresden.

 

- Bitsch A, Jacobi S, Melber C, Wahnschaffe U, Simetska N, Mangelsdorf I. (2006).REPDOSE: A database on repeated dose toxicity studies of commercial chemicals – a multifunctional tool. Regul Toxicol Pharmacol 46:202-210.

-ECHA (2008). REACh Guidance document R.8

-ECETOC (2003). Derivation of Assessment factors for Human Health Risk Assessment. Technical Report No. 86, February 2003.

-ECETOC (2010). Guidance on Assessment Factors to Derive DNELs.Technical Report No. 110, October 2010.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

10.23 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

17

Modified dose descriptor starting point:

NOAEC

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

294.11 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

68

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.94 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

68

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)

Additional information - General Population

Consumer

Based on the available data, Tinogard HS has to be considered as posing the risk of serious eye damage (R41; Cat. 1).

For the general population, all three possible routes of exposure (oral, dermal, inhalation) have to be taken into account, however due to the low vapor pressure of the substance, inhalation exposure to vapors is considered to be low. Due to its polar character the substance is not expected to become systemically available to a high extent after inhalation of the dust.

Dermal long-term exposure – systemic effects:

The NOAEL from an oral repeated dose study with rats conducted according to OECD TG 407 (CCR, 1988) and a screening test according to OECD TG 421 (NOTOX, 2011) was identified as the appropriate starting point for DNEL derivation for long-term exposure following dermal exposure. The oral NOAEL for general, systemic toxicity of the test substance was 200 mg/kg bw/d for rats based on salivation, higher water consumption, slight effects on the body weight and slight changes in clinical chemistry at the next higher dose level of 800 mg/kg bw/d.

This point of departure was modified to get the corrected starting point for DNEL derivation.

As available data indicated, that a skin penetration of less than 1 % of the applied dose has to be expected, the NOAEL of 200 mg/kg bw/d can be multiplied with a factor of 100 leading to a corrected dermal NOAEL of 20000 mg/kg bw/d.

For DNEL derivation, the following assessment factors (AF) were applied to the corrected starting point: 

- Interspecies factor: 4 (Reach Guidance Document R. 8)

Besides the applied allometric scaling factors no additional interspecies factor for remaining differences has been used as within the ERASM project, studies in rats and mice are being examined to substantiate whether the factors for allometry and 'remaining‘ differences would be appropriate for these species. The results suggest that a factor of 2.5 for 'remaining‘ interspecies differences may be questionable as a standard procedure (Escher and Mangelsdorf, 2009; Batke et al, 2011; Bitsch et al, 2006). 

- Intraspecies factor: 5

Systemic effects in the repeated dose study with rats were minimal and restricted to general systemic toxicity (effects on body weight, water consumption, salivation etc.). Therefore an intraspecies factor of 5 is considered to be sufficient. 

- Exposure duration: 3.4 (Batke et.al., 2011)

Within the ERASM project, time-extrapolation factors were evaluated with the database RepDoseg that currently contains about 670 substances and 2200 studies on repeated-dose toxicity. It has been shown that as long as the material is soluble, the sub-acute to sub-chronic factor was 1.5, rather than 3 , the sub-acute to chronic factor was 3.4 and the sub-chronic to chronic factor was 1.4 (Batke et al, 2011).

- Dose-response: 1

Total AF = 4 x 5 x 3.4 x 1 = 68

Based on this calculation, the resulting DNEL is 294.11 mg/kg bw/d.

Inhalation long-term exposure – systemic effects:

The NOAEL from an oral repeated dose study with rats conducted according to OECD TG 407 (CCR, 1988) and a screening test according to OECD TG 421 (NOTOX, 2011) was identified as the appropriate starting point for DNEL derivation for long-term exposure following inhalation. The NOAEL for general, systemic toxicity of the test substance was 200 mg/kg bw/d for rats based on salivation, higher water consumption, slight effects on the body weight and slight changes in clinical chemistry at the next higher dose level of 800 mg/kg bw/d.

This point of departure was modified to get the correct starting point for DNEL derivation. As a first step, route-to-route extrapolation was performed as recommended in the "Guidance on information requirements and chemical safety assessment, Chapter R.8, p. 26 f.:

The oral rat NOAEL was converted into the inhalative human NOAEC corrected for differences between the 24-hour standard inhalation volume of rats versus humans by multiplying with the corresponding factor (x 1/1.15 m³/kg/d). The resulting corrected starting point for inhalation DNEL derivation for the general population is equal to 173.91 mg/m³.

For DNEL derivation, the following assessment factors (AF) were applied to the corrected starting point:

- Interspecies factor: 1

Besides the applied allometric scaling factors no additional interspecies factor for remaining differences has been used based on the fact that concerning inhalation, rodents like the rat are in general more sensitive compared to human as the rat's ventilation frequency is higher. Also anatomical differences as well as air flow patterns between rodents and humans have to be taken into account. Within the ERASM project, studies in rats and mice are being examined to substantiate whether the factors for allometry and 'remaining‘ differences would be appropriate for these species. The results suggest that a factor of 2.5 for 'remaining‘ interspecies differences may be questionable as a standard procedure (Escher and Mangelsdorf, 2009; Batke et al, 2011; Bitsch et al, 2006).

 - Intraspecies factor: 5

Systemic effects in the repeated dose study with rats were minimal and restricted to general systemic toxicity (effects on body weight, water consumption, salivation etc.). Therefore an intraspecies factor of 5 is considered to be sufficient. 

 - Exposure duration: 3.4 (Batke et.al., 2011)

Within the ERASM project, time-extrapolation factors were evaluated with the database RepDoseg that currently contains about 670 substances and 2200 studies on repeated-dose toxicity. It has been shown that as long as the material is soluble, the sub-acute to sub-chronic factor was 1.5, rather than 3 , the sub-acute to chronic factor was 3.4 and the sub-chronic to chronic factor was 1.4 (Batke et al, 2011).

- Dose-response: 1

Total AF = 1 x 5 x 3.4 x 1 = 17

Based on this calculation the resulting DNEL is 10.23 mg/m³.

Oral long-term exposure – systemic effects:

The NOAEL from an oral repeated dose study with rats conducted according to OECD TG 407 (CCR, 1988) and a screening test according to OECD TG 421 (NOTOX, 2011) was identified as the appropriate starting point for DNEL derivation for long-term exposure following oral exposure. The oral NOAEL for general, systemic toxicity of the test substance was 200 mg/kg bw/d for rats based on salivation, higher water consumption, slight effects on the body weight and slight changes in clinical chemistry at the next higher dose level of 800 mg/kg bw/d.

The NOAEL of 200 mg/kg bw/day was considered appropriate as point of departure for DNEL derivation. Subsequently, the following assessment factors are taken into account for the final DNEL calculation for the oral route: interspecies differences (4), remaining differences (1), intraspecies differences (5), exposure duration (3.4) (AF = 4 x 5 x 3.4 x 1 = 68).

As a consequence, the resulting DNEL for long-term oral local and systemic effects is 2.94 mg/kg bw/d for the general population.

For DNEL derivation, the following assessment factors (AF) were applied to the corrected starting point: 

- Interspecies factor: 4 (Reach Guidance Document R. 8)

Besides the applied allometric scaling factors no additional interspecies factor for remaining differences has been used as within the ERASM project, studies in rats and mice are being examined to substantiate whether the factors for allometry and 'remaining‘ differences would be appropriate for these species. The results suggest that a factor of 2.5 for 'remaining‘ interspecies differences may be questionable as a standard procedure (Escher and Mangelsdorf, 2009; Batke et al, 2011; Bitsch et al, 2006). 

- Intraspecies factor: 5

Systemic effects in the repeated dose study with rats were minimal and restricted to general systemic toxicity (effects on body weight, water consumption, salivation etc.). Therefore an intraspecies factor of 5 is considered to be sufficient. 

- Exposure duration: 3.4 (Batke et.al., 2011)

Within the ERASM project, time-extrapolation factors were evaluated with the database RepDoseg that currently contains about 670 substances and 2200 studies on repeated-dose toxicity. It has been shown that as long as the material is soluble, the sub-acute to sub-chronic factor was 1.5, rather than 3 , the sub-acute to chronic factor was 3.4 and the sub-chronic to chronic factor was 1.4 (Batke et al, 2011).

- Dose-response: 1

- Batke M, Escher S, Hoffmann-Doerr S, Melber C, Messinger H, Mangelsdorf I.(2011).Evaluation of time extrapolation factors based on the database RepDose. Toxicology Letters 205 (2011) 122– 129.

 

- Escher S and Mangelsdorf I. (2009). Evaluation of risk assessment factors for inter-species and time-extrapolation. Toxicol Lett 189:S247-S248. 46th Congress of the European Societies of Toxicology, 13-16 September 2009, Dresden.

 

- Bitsch A, Jacobi S, Melber C, Wahnschaffe U, Simetska N, Mangelsdorf I. (2006).REPDOSE: A database on repeated dose toxicity studies of commercial chemicals – a multifunctional tool. Regul Toxicol Pharmacol 46:202-210.

-ECHA (2008). REACh Guidance document R.8

-ECETOC (2003). Derivation of Assessment factors for Human Health Risk Assessment. Technical Report No. 86, February 2003.

-ECETOC (2010). Guidance on Assessment Factors to Derive DNELs.Technical Report No. 110, October 2010.