Benzamide, N-[[4-[(cyclopropylamino)carbonyl]phenyl]sulfonyl]-2-methoxy-

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

13.8 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):

5

Dose descriptor starting point:

NOAEL

Value:

39 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

68.8 mg/m³

Explanation for the modification of the dose descriptor starting point:

The calculation of the DNEL is based on an oral NOAEL observed in an oral combined repeated dose toxicity / carcinogenicity study (OECD 453; 2006).

To correct the interspecies difference between rat and human the NOAEL has to be corrected as follows:

Corrected starting point for the inhalative route for workers:

= NOAEL(oral) * (1/0.38 m³/kg bw/day) * (ABSoral-rat/ABSinh-human) * (6.7 m³ (8h) /10 m³ (8h))

As described in the ECHA Guidance R.8 (2012), it is assumed that inhalation absorption is 100%. In the toxicokinetic studies with the test substance it was shown that the oral absorption is close to 100%. (ABSoral-rat = oral absorption in rats, ABSinh-human = inhalation absorption rate in humans).

= 39 mg/kg bw/day * (1/0.38 m³/kg bw/day) * (1/1) * 0.67 m³ = 68.8 mg/m³

Thus, the corrected starting point for workers was 68.8 mg/m³ for inhalation.

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL

AF for differences in duration of exposure:

1

Justification:

The DNEL is based on a chronic study

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling not used for inhalation route

AF for other interspecies differences:

1

Justification:

The toxicokinetic data indicate that the test substance will not be metabolised

AF for intraspecies differences:

5

Justification:

Default value for workers according to ECHA REACH Guidance

AF for the quality of the whole database:

1

Justification:

The DNEL is based on a high-quallity study

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

52 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):

50

Dose descriptor starting point:

NOAEL

Value:

39 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

2 600 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The calculation of the dermal DNEL is based on the oral NOAEL of 39 mg/kg bw/day observed in an oral combined repeated dose toxicity / carcinogenicity study (OECD 453, 2006). The NOAEL is corrected to account for dermal penetration rates through human skin. For the test substance, an in vitro dermal penetration study using human skin is available (M-279026-01-2, 2006). The study was performed by the use of the test substance in an agrochemical formulation (SC450) at two concentrations: the neat product (nominal value = 225 mg/mL) and a representative spray dilution (nominal value = 0.27 mg/mL) were tested. For the neat product, the mean percentage of the test substance considered to be potentially absorbable over a period of 24 h was 0.85%. For the spray dilution, the mean percentage of the test substance potentially absorbable over a period of 24 h was 1.5%. As the workers will only be exposed to the formulation and not to the active substance, the % absorbed through the human skin assessed by the in vitro dermal penetration study is taken into account in the DNEL derivation. The oral absorption rate is assumed to be 100%, based on almost complete oral absorption seen in the toxicokinetic studies.

Corrected dermal NOAEL = 39 * (100/1.5) = 2600 mg/kg bw/day

AF for dose response relationship:

1

Justification:

The dose descriptor starting poiont is based on a NOAEL

AF for differences in duration of exposure:

1

Justification:

The DNEL is based on a chronic study

AF for interspecies differences (allometric scaling):

4

Justification:

The experimental animal was rat

AF for other interspecies differences:

2.5

Justification:

Default value according to ECHA REACH Guidance

AF for intraspecies differences:

5

Justification:

Default value for workers according to ECHA REACH Guidance

AF for the quality of the whole database:

1

Justification:

The DNEL is based on a high-quality study

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Dermal

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

No DNELs have been derived for the short-term dermal and inhalation exposure of the test substance for workers, as it is assumed that the assessment of hazard is sufficiently covered by deriving the respective DNELs for long-term exposure. No quantitative dose-response data are available for local short-term effects on skin and respiratory tract of the test substance.

The long-term worker DNEL for dermal systemic effects is based on a combined chronic toxicity/carcinogenicity study performed according to OECD 453 (M-281767-01-1, 2006). In this study, the test substance was administered to groups of 60 male and 60 female rats by continuous dietary treatment at 1000, 4000 and 8000 ppm, corresponding to 39, 159 and 321 mg/kg bw/day in males and 56, 220 and 447 mg/kg bw/day in females, respectively, over a 24-month period. Additionally, groups of 10 male and 10 female rats were treated at 200, 1000, 4000 and 8000 ppm cyprosulfamide, corresponding to 9, 45, 181 and 364 mg/kg bw/day in males and 13, 62, 249 and 491 mg/kg bw/day in females, over a 12-month period to investigate chronic toxicity only. The mortality rate was higher in females at 8000 ppm after 24 months of treatment and was largely due to secondary treatment-related nephropathy following administration. Mean cumulative body weight gain was reduced during the first week of treatment by 7 and 12% in males and females treated at 8000 ppm, respectively, compared to the controls. Urinalysis revealed the presence of sulfonamide-like crystals throughout the study in both sexes, the effect being more pronounced in females than in males. At the 12-month interim sacrifice, treatment-related non-neoplastic findings were seen microscopically in the kidney and the urinary bladder. At the 24-month sacrifice, treatment-related effects were found in the urinary tract, i.e. kidney, urinary bladder, and ureters. These changes were due to treatment-induced nephropathy, characterized in the kidney by a combination of hyperplastic and inflammatory changes associated with the presence of stones. Urothelial hyperplasia was noted in the urinary bladder in both sexes at the 12-month interim sacrifice, whereas intraluminal stones and multifocal/diffuse urothelial hyperplasia were also observed in the urinary bladder and in a number of ureters in both sexes at the carcinogenicity phase. A slightly higher incidence of the commonly occurring lesion diffuse bilateral tubular degeneration of the testis and bilateral oligospermia of the epididymis was observed at the carcinogenicity phase. Neoplastic changes comprised of a high dose-related transitional cell carcinoma in the kidney of one male and a transitional cell carcinoma in the urinary bladder of one female. These findings, seen only at 8000 ppm, were considered to be secondary to the combination of hyperplastic and inflammatory changes associated with the presence of stones. Thus, the test substance was considered not to be directly carcinogenic in the rat. The NOAEL over a 24 month period of dietary administration with the test substance was 1000 ppm in both sexes (equivalent to 39 mg/kg bw/day in males and 56 mg/kg bw/day in females).

The oral NOAEL of 39 mg/kg bw/day was chosen as starting point for deriving the dermal DNEL as there is no dermal repeated dose toxicity study. To convert the oral NOAEL [mg/kg bw/day] into a dermal NAEL [mg/kg bw/day], the differences in absorption between routes as well as differences in dermal absorption between rats and humans have to be accounted for (Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health, European Chemicals Agency, Version 2.1, November 2012).

For the test substance, an in vitro dermal penetration study using human skin is available (M-279026-01-2, 2006). The study was performed by the use of the test substance in an agrochemical formulation (SC450) at two concentrations: the neat product (nominal value = 225 mg/mL) and a representative spray dilution (nominal value =0.27 mg/mL) were tested. For the neat product, the mean percentage of the test substance considered to be potentially absorbable over a period of 24 h was 0.85%. For the spray dilution, the mean percentage of the test substance potentially absorbable over a period of 24 h was1.5%. As the workers will only be exposed to the formulation and not to the active substance, the % absorbed through the human skin assessed by the study is taken into account in the DNEL derivation.

The long-term worker DNEL for inhalation systemic effects is again based on the combined chronic toxicity/carcinogenicity performed according to OECD 453 (M-281767-01-1, 2006). This study was chosen as the starting point for deriving the inhalation DNEL as there is no inhalation repeated dose study. According to the “Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health” (European Chemicals Agency, Version 2.1, November 2012), the oral NOAEL should be converted into an inhalatory NAEC: the oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (0.38 m³/kg for 8 h exposure). Additionally, it should be taken into account that during 8 h light activity at work the respiratory rate becomes higher (10 m³/person) than standard (6.7 m³/person). Considering these differences, the corrected starting point is a NAEC of 68.8 mg/m³. No allometric scaling factor for the rat was included since differences have already been considered for correcting the starting point. The absorption via the inhalation route is considered to be in the same order as via the oral route. No treatment-related effects were observed for acute toxicity via the oral or inhalation exposure route using the limit test.

In general, assessment factors (AF) recommended by ECHA (Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. European Chemicals Agency, Version 2.1, November 2012) were used when applicable to derive the DNELs. Several AFs for which there is additional information were refined. The difference in metabolic rate between humans and the test species has been taken into account, where relevant. The AF for remaining interspecies differences has been set at 2.5, as the test concentrations (ppm in diet) have been converted into a dose. However, this was only appropriate for the oral and dermal DNEL calculation. The toxicokinetic data indicate that the test substance will not be metabolised (see toxicokinetics). An AF for exposure duration is not applied.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.4 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):

10

Dose descriptor starting point:

NOAEL

Value:

39 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

33.9 mg/m³

Explanation for the modification of the dose descriptor starting point:

The calculation of the DNEL is based on an oral NOAEL observed in an oral combined repeated dose toxicity / carcinogenicity study (OECD 453; 2006).

To correct the interspecies difference between rat and human the NOAEL has to be corrected as follows:

Corrected starting point for the inhalative route for general population:

= NOAEL(oral) * (1/1.15 m³/kg bw/day) * (ABSoral-rat/ABSinh-human)

As described in the ECHA Guidance R.8 (2012), it is assumed that inhalation absorption is 100%. In the toxicokinetic studies with the test substance it was shown that the oral absorption is close to 100%. (ABSoral-rat = oral absorption in rats, ABSinh-human = inhalation absorption rate in humans).

= 39 mg/kg bw/day * (1/1.15 m³/kg bw/day) * (1/1) = 33.9 mg/m³

Thus, the corrected starting point for workers was 33.9 mg/m³ for inhalation.

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL

AF for differences in duration of exposure:

1

Justification:

The DNEL is based on a chronic study

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling not used for inhalation route

AF for other interspecies differences:

1

Justification:

The toxicokinetic data indicate that the test substance will not be metabolised

AF for intraspecies differences:

10

Justification:

Default value for the general population according to ECHA REACH Guidance

AF for the quality of the whole database:

1

Justification:

The DNEL is based on a high-quallity study

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

26 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):

100

Dose descriptor starting point:

NOAEL

Value:

39 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

2 600 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The calculation of the dermal DNEL is based on the oral NOAEL of 39 mg/kg bw/day observed in an oral combined repeated dose toxicity / carcinogenicity study (OECD 453; 2006). The NOAEL is corrected to account for dermal penetration rates through human skin. For the test substance, an in vitro dermal penetration study using human skin is available (M-279026-01-2, 2006). The study was performed by the use of the test substance in an agrochemical formulation (SC450) at two concentrations: the neat product (nominal value = 225 mg/mL) and a representative spray dilution (nominal value = 0.27 mg/mL) were tested. For the neat product, the mean percentage of the test substance considered to be potentially absorbable over a period of 24 h was 0.85%. For the spray dilution, the mean percentage of the test substance potentially absorbable over a period of 24 h was 1.5%. As the workers will only be exposed to the formulation and not to the active substance, the % absorbed through the human skin assessed by the study is taken into account in the DNEL derivation. The oral absorption rate is assumed to be 100%, based on almost complete oral absorption seen in the toxicokinetic studies.

Corrected dermal NOAEL = 39 * (100/1.5) = 2600 mg/kg bw/day

AF for dose response relationship:

1

Justification:

The dose descriptor starting poiont is based on a NOAEL

AF for differences in duration of exposure:

1

Justification:

The DNEL is based on a chronic study

AF for interspecies differences (allometric scaling):

4

Justification:

The experimental animal was rat

AF for other interspecies differences:

2.5

Justification:

Default value according to ECHA REACH Guidance

AF for intraspecies differences:

10

Justification:

Default value for the general population according to ECHA REACH Guidance

AF for the quality of the whole database:

1

Justification:

The DNEL is based on a high-quality study

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Dermal

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.39 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):

100

Dose descriptor starting point:

NOAEL

Value:

39 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No modification of the dose descriptor starting point is necessary.

AF for dose response relationship:

1

Justification:

The dose descriptor starting poiont is based on a NOAEL

AF for differences in duration of exposure:

1

Justification:

The DNEL is based on a chronic study

AF for interspecies differences (allometric scaling):

4

Justification:

The experimental animal was rat

AF for other interspecies differences:

2.5

Justification:

Default value according to ECHA REACH Guidance

AF for intraspecies differences:

10

Justification:

Default value for general population according to ECHA REACH Guidance

AF for the quality of the whole database:

1

Justification:

The DNEL is based on a high-quality study

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

The general population is not exposed to the test substance. However, the long-term consumer DNELs for oral, dermal and inhalation systemic effects have been derived. No DNELs have been derived for the short-term dermal, inhalation and oral exposure for the general population, as it is assumed that the assessment of hazard is sufficiently covered by deriving the respective DNELs for long-term exposure. No quantitative dose-response data are available for local short-term effects on skin and respiratory tract of the test substance.

The long-term DNEL for dermal systemic effects is based on a combined chronic toxicity/carcinogenicity study performed according to OECD 453 (M-281767-01-1, 2006). In this study, the test substance was administered to groups of 60 male and 60 female rats by continuous dietary treatment at 1000, 4000 and 8000 ppm, corresponding to 39, 159 and 321 mg/kg bw/day in males and 56, 220 and 447 mg/kg bw/day in females, respectively, over a 24-month period. Additionally, groups of 10 male and 10 female rats were treated at 200, 1000, 4000 and 8000 ppm cyprosulfamide, corresponding to 9, 45, 181 and 364 mg/kg bw/day in males and 13, 62, 249 and 491 mg/kg bw/day in females, over a 12-month period to investigate chronic toxicity only. The mortality rate was higher in females at 8000 ppm after 24 months of treatment and was largely due to secondary treatment-related nephropathy following administration. Mean cumulative body weight gain was reduced during the first week of treatment by 7 and 12% in males and females treated at 8000 ppm, respectively, compared to the controls. Urinalysis revealed the presence of sulfonamide-like crystals throughout the study in both sexes, the effect being more pronounced in females than in males. At the 12-month interim sacrifice, treatment-related non-neoplastic findings were seen microscopically in the kidney and the urinary bladder. At the 24-month sacrifice, treatment-related effects were found in the urinary tract, i.e. kidney, urinary bladder, and ureters. These changes were due to treatment-induced nephropathy, characterized in the kidney by a combination of hyperplastic and inflammatory changes associated with the presence of stones. Urothelial hyperplasia was noted in the urinary bladder in both sexes at the 12-month interim sacrifice, whereas intraluminal stones and multifocal/diffuse urothelial hyperplasia were also observed in the urinary bladder and in a number of ureters in both sexes at the carcinogenicity phase. A slightly higher incidence of the commonly occurring lesion diffuse bilateral tubular degeneration of the testis and bilateral oligospermia of the epididymis was observed at the carcinogenicity phase. Neoplastic changes comprised of a high dose-related transitional cell carcinoma in the kidney of one male and a transitional cell carcinoma in the urinary bladder of one female. These findings, seen only at 8000 ppm, were considered to be secondary to the combination of hyperplastic and inflammatory changes associated with the presence of stones. Thus, the test substance was considered not to be directly carcinogenic in the rat. The NOAEL over a 24 month period of dietary administration with the test substance was 1000 ppm in both sexes (equivalent to 39 mg/kg bw/day in males and 56 mg/kg bw/day in females).

The oral NOAEL of 39 mg/kg bw/day was chosen as starting point for deriving the dermal DNEL as there is no dermal repeated dose toxicity study. To convert the oral NOAEL [mg/kg bw/day] into a dermal NAEL [mg/kg bw/day], the differences in absorption between routes as well as differences in dermal absorption between rats and humans have to be accounted for (Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health, European Chemicals Agency, Version 2.1, November 2012).

For the test substance, an in vitro dermal penetration study using human skin is available (M-279026-01-2, 2006). The study was performed by the use of the test substance in an agrochemical formulation (SC450) at two concentrations: the neat product (nominal value = 225 mg/mL) and a representative spray dilution (nominal value = 0.27 mg/mL) were tested. For the neat product, the mean percentage of the test substance considered to be potentially absorbable over a period of 24 h was 0.85%. For the spray dilution, the mean percentage of the test substance potentially absorbable over a period of 24 h was 1.5%. The % absorbed through the human skin assessed by the study is taken into account in the DNEL derivation.

The long-term DNEL for inhalation systemic effects is again based on the combined chronic toxicity/carcinogenicity study performed according to OECD 453 (M-281767-01-1, 2006). This study was chosen as the starting point for deriving the inhalation DNEL as there is no inhalation repeated dose study According to the “Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health” (European Chemicals Agency, Version 2.1, November 2012), the oral NOAEL should be converted into an inhalatory NAEC: the oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (1.15 m³/kg for 24 h exposure). Therefore, the corrected starting point is a NAEC of 33.9 mg/m³. No allometric scaling or additional interspecies factors were included since interspecies differences have already been considered for correcting the starting point. The absorption via the inhalation route is considered to be in the same order as via the oral route. No treatment-related effects were observed for acute toxicity via the oral or inhalation exposure route using the limit test.

The long-term DNEL for oral systemic effects is also based on the combined chronic toxicity/carcinogenicity study performed according to OECD 453 (M-281767-01-1, 2006). Since the study was performed via the oral route, the value can be used directly to derive the oral DNEL.

In general, assessment factors (AF) recommended by ECHA (Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. European Chemicals Agency, Version 2.1, November 2012) were used when applicable to derive the DNELs. Several AFs for which there is additional information were refined. The difference in metabolic rate between humans and the test species has been taken into account, where relevant. The AF for remaining interspecies differences has been set at 2.5, as the test concentrations (ppm in diet) have been converted into a dose. However, this was only appropriate for the oral and dermal DNEL calculation. The toxicokinetic data indicates that the test substance will not be metabolised (see toxicokinetics). An AF for exposure duration is not applied.