Reaction mass of N-butylphosphorothioic triamide and N-propylphosphorothioic triamide

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.938 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

Overall assessment factor (AF):

10.2

Modified dose descriptor starting point:

NOAEC

Value:

29.97 mg/m³

Explanation for the modification of the dose descriptor starting point:

see discussion

Justification:

see discussion

Justification:

see discussion

Justification:

see discussion

Justification:

see discussion

Justification:

see discussion

Justification:

see discussion

Justification:

see discussion

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

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:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - workers

Worker:

Based on the available data LIMUS-Sambaydestillation, has to be considered as harmful if swallowed (R22 according to Directive 67/548/EEC annex VI; Cat. 4 according to EC/1271/2008), to be irritating to the eyes (R36; Cat. 2), potentially skin sensitizing (R43; Cat. 1B) and toxic to reproduction (fertility, R62/Cat. 2f) respectively.

The primary routes of anticipated industrial and professional exposure to LIMUS-Sambaydestillation, are via inhalation and skin contact. In industrial settings, ingestion is not an anticipated route of exposure.

Dermal short-term and long-term exposure – local and systemic effects:

The substance causes skin sensitization in experimental animals.

For these effects, a qualitative assessment was conducted:

Though sensitization reactions of the skin are generally regarded as threshold effect, deriving a threshold and setting a DNEL is very difficult in practice. As there are only worker uses reported where exposure can be minimized by the appropriate risk management measures and operational conditions, a qualitative assessment was regarded as the most appropriate. Therefore the use of gloves and the use of stringent risk management measures as outlined in ECHA guidance document Part E: Risk Characterization (Table E. 3-1, page 28-32) is required in order to prevent any skin contact with the test substance and thus the occurrence of skin sensitization.

The use of gloves and of stringent risk management measures will also protect the worker from any systemic dermal effects, short-term and long-term.

Professional workers can come in contact with LIMUS via fertilizers. As LIMUS is only a weak skin sensitizer and present in fertilizers at concentrations well below the threshold for classification & labeling of 1 % for Cat. 1B skin sensitizers, the hazard for professional workers is negligible also taking into account that the use of gloves will prevent any occurrence of skin contact.

Inhalation long-term exposure – systemic effects:

The NOAEL from an oral repeated dose study with rats conducted according to OECD TG 407 (BASF, 2009) 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 17 mg/kg bw/d for rats based on salivation and slight effects on the body weight at the next higher dose level of 84 mg/kg bw/d in male rats only. Effects on fertility reported for one component (NBPT) of the reaction mass are only observed at higher dose levels according to the dossier on the ECHA-website and thus not relevant for DNEL-derivation.

The NOAEL of 17 mg/kg bw/day thus was considered appropriate as point of departure for DNEL derivation. 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 29.97 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, food consumption, salivation) and only present in males (LOAEL: 84 mg/kg bw/day) at the next higher dose level. 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 2.938 mg/m³.

 

-        Api AM, Basketter DA, Cadby PA, Cano M-F, Graham E, Gerberick F, Griem P, McNamee P, Ryan CA, Safford B (2006). Dermal Sensitization Quantitative Risk Assessment (QRA) for fragrance ingredients. Technical dossier. March 15, 2006 (revised May 2006).

-       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.

-        Api AM, Basketter, DA, Cadby PA, Cano M-F, Ellis G, Gerberick GF, Griem P, McNamee PM, Ryan CA, Safford R (2008). Dermal sensitization quantitative risk assessment (QRA) for fragrance ingredients. Reg Toxicol Pharmacol 52: 3-23.

-       ECETOC (2003). Contact Sensitization: classification according to potency. Technical Report No. 87, April 2003.

-       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:

0.869 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

Overall assessment factor (AF):

17

Modified dose descriptor starting point:

NOAEC

Value:

14.78 mg/m³

Explanation for the modification of the dose descriptor starting point:

see discussion

Justification:

see discussion

Justification:

see discussion

Justification:

see discussion

Justification:

see discussion

Justification:

see discussion

Justification:

see discussion

Justification:

see discussion

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

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

Overall assessment factor (AF):

68

Modified dose descriptor starting point:

NOAEL

Value:

17 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

see discussion

Justification:

see discussion

Justification:

see discussion

Justification:

see discussion

Justification:

see discussion

Justification:

see discussion

Justification:

see discussion

Justification:

see discussion

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

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

Overall assessment factor (AF):

68

Modified dose descriptor starting point:

NOAEL

Value:

17 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

see discussion

Justification:

see discussion

Justification:

see discussion

Justification:

see discussion

Justification:

see discussion

Justification:

see discussion

Justification:

see discussion

Justification:

see discussion

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

15 mg/kg bw/day

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

Overall assessment factor (AF):

20

Modified dose descriptor starting point:

other: LD0

Value:

300 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

see discussion

Justification:

see discussion

Justification:

see discussion

Justification:

see discussion

Justification:

see discussion

Justification:

see discussion

Justification:

see discussion

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - General Population

Consumer:

Based on the available data LIMUS-Sambaydestillation, has to be considered as harmful if swallowed (R22 according to Directive 67/548/EEC annex VI; Cat. 4 according to EC/1271/2008), to be irritating to the eyes (R36; Cat. 2), potentially skin sensitizing (R43; Cat. 1B) and toxic to reproduction (fertility, R62/Cat. 2f) respectively.

For the general population, all three possible routes of exposure (oral, dermal, inhalation) have to be taken into account.

Dermal short-term and long-term exposure – local effects:

Consumers can come in contact with LIMUS via fertilizers. As LIMUS is only a weak skin sensitizer and present in fertilizers at concentrations well below the threshold for classification & labeling of 1 % for Cat. 1B skin sensitizers, the hazard for consumers is negligible also taking into account that the frequency of fertilizer use per year is very low.

Dermal long-term exposure – systemic effects:

The DNEL for dermal long-term exposure was derived from the no observed adverse effect level obtained in a gavage study conducted with the substance in rats according to OECD TG 07 (BASF, 2009). The NOAEL for general, systemic toxicity of the test substance was 17 mg/kg bw/d for rats based on salivation and slight effects on the body weight at the next higher dose level of 84 mg/kg bw/d in male rats only. Effects on fertility reported for one component (NBPT) of the reaction mass are only observed at higher dose levels according to the dossier on the ECHA-website and thus not relevant for DNEL-derivation.

The NOAEL of 17 mg/kg bw/day thus was considered appropriate as point of departure for DNEL derivation. Although dermal uptake is considered lower than the oral uptake based on differences in the acute oral and dermal LD50 values, no further correction of the starting point was conducted as a worst case. Subsequently, the following assessment factors are taken into account for the final DNEL calculation for the dermal route: interspecies differences (4), remaining differences (1), intraspecies differences (5), exposure duration (3.4) (AF = 4 x 5 x 3.4 x 1 x 1 = 68).

As a consequence, the resulting DNEL for long-term dermal systemic effects is 0.25 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

- Intraspecies factor: 5

Systemic effects in the repeated dose study with rats were minimal and restricted to general systemic toxicity (effects on body weight, food consumption, salivation) and only present in males (LOAEL: 84 mg/kg bw/day) at the next higher dose level. 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

- Remaining differences: 1 (Escher and Mangelsdorf, 2009; Batke et al, 2010; Bitsch et al, 2006).

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).

Inhalation long-term exposure – systemic effects:

The NOAEL from an oral repeated dose study with rats conducted according to OECD TG 407 (BASF, 2009) 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 17 mg/kg bw/d for rats based on salivation and slight effects on the body weight at the next higher dose level of 84 mg/kg bw/d in male rats only. Effects on fertility reported for one component (NBPT) of the reaction mass are only observed at higher dose levels according to the dossier on the ECHA-website and thus not relevant for DNEL-derivation.

The NOAEL of 17 mg/kg bw/day thus was considered appropriate as point of departure for DNEL derivation.

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 14.78 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, food consumption, salivation) and only present in males (LOAEL: 84 mg/kg bw/day) at the next higher dose level. 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 0.869 mg/m³.

Oral short-term –systemic effects:

In addition, a DNEL for oral short-term exposure was derived from the no observed adverse effect level obtained in an acute toxicity study conducted with the substance in rats according to OECD TG 423 (BASF SE, 2008). At the dose of 300 mg/kg bw no mortality was observed. Thus, this dose can be considered to be the NOAEL in rats after a single gavage administration of the substance.

The NOAEL of 300 mg/kg bw/d 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) (AF = 4 x 1 x 5 = 20). These assessment factors are sufficient as outlined in the Technical Report No. 86 of ECETOC in 2003. As a consequence, the resulting DNEL for short-term oral systemic effects is 15 mg/kg bw/d for the general population.

Oral long-term exposure – systemic effects:

In addition, the DNEL for oral long-term exposure was derived from the no observed adverse effect level obtained in a gavage study conducted with the substance in rats according to OECD TG 07 (BASF, 2009). The NOAEL for general, systemic toxicity of the test substance was 17 mg/kg bw/d for rats based on salivation and slight effects on the body weight at the next higher dose level of 84 mg/kg bw/d in male rats only. Effects on fertility reported for one component (NBPT) of the reaction mass are only observed at higher dose levels according to the dossier on the ECHA-website and thus not relevant for DNEL-derivation.

The NOAEL of 17 mg/kg bw/day thus 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 x 1 = 68).

As a consequence, the resulting DNEL for long-term oral local and systemic effects is 0.25 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

- Intraspecies factor: 5

Systemic effects in the repeated dose study with rats were minimal and restricted to general systemic toxicity (effects on body weight, food consumption, salivation) and only present in males (LOAEL: 84 mg/kg bw/day) at the next higher dose level. 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

- Remaining differences: 1 (Escher and Mangelsdorf, 2009; Batke et al, 2010; Bitsch et al, 2006).

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).

-        Api AM, Basketter DA, Cadby PA, Cano M-F, Graham E, Gerberick F, Griem P, McNamee P, Ryan CA, Safford B (2006). Dermal Sensitization Quantitative Risk Assessment (QRA) for fragrance ingredients. Technical dossier. March 15, 2006 (revised May 2006).

- 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.

-        Api AM, Basketter, DA, Cadby PA, Cano M-F, Ellis G, Gerberick GF, Griem P, McNamee PM, Ryan CA, Safford R (2008). Dermal sensitization quantitative risk assessment (QRA) for fragrance ingredients. Reg Toxicol Pharmacol 52: 3-23.

-       ECETOC (2003). Contact Sensitization: classification according to potency. Technical Report No. 87, April 2003.

-       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.