Registration Dossier

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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.93 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):
12.5
Dose descriptor starting point:
NOAEL
Value:
3.6 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
11.62 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 a 52-week feeding study in dogs with the source substance ziram. The established NOAEL value is equivalent to 3.6 mg technical SDDC/kg bw/day.

To take into account the interspecies difference between dog and human the no observed adverse effect level has to be corrected as follows:

The conversion of an oral NOAEL into an inhalatory NAEC is performed using a breathing volume of 0.137 m³/kg bw/8 h for an 11.5-kg dog. Using the calculated standard minute volume for dogs of 3.281 L/min as given in Bide et al. (1997) an assumed breathing volume of 0.137 m³/kg bw/8 h for an 11.5-kg dog can be calculated.

Corrected inhalatory NAEC = oral NOAEL x1/sRVdog x ABSoral-dog/ABSinh-human x sRVhuman/wRV

= 3.6 mg/kg bw/day x 1/0.137 m³/kg bw x 66%/100% x 6.7 m³/10 m³ = 11.62 mg/m³

sRV: standard respiratory volume, ABS: absorption, wRV: worker respiratory volume

Regarding toxicokinetic behaviour, data with the source substance Ziram were taken into account in the dossier of SDDC (for details please refer to the analogue justification). It could be demonstrated, that Ziram is well absorbed from the gastro-intestinal tract in rats, within 48 h after oral administration for 58-61% after a single low dose, for 60-69% after a single high dose and for 71-75% after a repeated low dose (Hardwick & Lappin, 2001), which means an overall oral absorption of 66%.

Applying the read-across approach, an absorption potential of 66% for the oral route is assumed for SDDC, respectively. Thus, the same absorption value (66% for the oral route), which was taken into account for Ziram, were used for the calculation of the DNELs for SDDC.

Thus, the corrected starting point for inhalation route is 11.62 mg/m3

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:
A chronic NOAEL is used as starting point.
AF for interspecies differences (allometric scaling):
1
Justification:
Not necessary for inhalation route
AF for other interspecies differences:
2.5
Justification:
ECHA default
AF for intraspecies differences:
5
Justification:
ECHA default for workers
AF for the quality of the whole database:
1
Justification:
The database is complete and of high quality.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.71 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):
17.5
Dose descriptor starting point:
NOAEL
Value:
3.6 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
47.52 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The calculation of the DNEL is based on an oral NOAEL derived in a 52-week feeding study in dogs with the source substance ziram. This study provides information on the chronic exposure of the source substance, which is considered to be the most reliable for the assessment of hazardous properties during a life span. Moreover, in this study the lowest NOAEL was determined compared with the other repeated dose toxicity studies. The established NOAEL value is equivalent to 3.6 mg technical SDDC/kg bw/day.

Corrected starting point for the dermal route for workers:

Corrected dermal NOAEL = oral NOAEL x ABSoral-rat/ABSdermal-human

= 3.6 mg/kg bw/day x 66% / 5%

= 47.52 mg/kg bw/day

Abs: Absorption

Regarding toxicokinetic behaviour, data with the source substance Ziram were taken into account in the dossier of SDDC. It could be demonstrated, that Ziram is well absorbed from the gastro-intestinal tract in rats, within 48 h after oral administration for 58-61% after a single low dose, for 60-69% after a single high dose and for 71-75% after a repeated low dose (Hardwick & Lappin, 2001), which means an overall oral absorption of 66%. Percutaneous absorption of ziram has been studied in vivo (Cheng, 1991) in the rat and in vitro (Kane, 2006) using human skin samples. Because of the volatile nature of the two metabolites, CS2 and dimethylamine (DMA), the recovery of radioactivity in the in vivo assay in rats was only 70-80%. The non-recovered radioactivity was assumed to be dermally absorbed giving rise to a dermal absorption between 5% (high dose) to almost 30% (low dose). Much better recoveries (91-94%) were obtained with an in vitro human skin model. Both with concentrated (approximately 64% w/v) and diluted aqueous solutions (approximately 0.16% w/v) of Ziram, absorption through human skin was slow (0.004 and 0.05 μg/cm²/h for low and high dose, respectively) and inefficient (2.2% and 0.1% for low and high dose, respectively).

Applying the read-across approach (for details please refer to the analogue justification), an absorption potential of 66% for the oral route and 5% for the dermal route is assumed for SDDC, respectively. Thus, the same absorption values (66% for the oral route and 5% for the dermal route), which were taken into account in the registration dossier with Ziram, were used for the calculation of the DNELs for SDDC.

Thus, the corrected starting point for dermal route is 47.52 mg/kg bw/day.

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:
A chronic NOAEL is used as starting point.
AF for interspecies differences (allometric scaling):
1.4
Justification:
default for dog-to-human
AF for other interspecies differences:
2.5
Justification:
ECHA default
AF for intraspecies differences:
5
Justification:
ECHA default for workers
AF for the quality of the whole database:
1
Justification:
The database is complete and of high quality.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.23 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):
25
Dose descriptor starting point:
NOAEL
Value:
3.6 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
5.78 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 a 52-week feeding study in dogs with the source substance ziram. The established NOAEL value is equivalent to 3.6 mg technical SDDC/kg bw/day.

To take into account the interspecies difference between dog and human the no observed adverse effect level has to be corrected as follows:

The conversion of an oral NOAEL into an inhalatory NAEC is performed using an assumed breathing volume of 0.411 m³/kg bw/24 h for an 11.5-kg dog. Using the calculated standard minute volume for dogs of 3.281 L/min as given in Bide et al. (1997) an assumed breathing volume of 0.411 m³/kg bw/24 h for an 11.5-kg dog can be calculated.

Corrected inhalatory NAEC = oral NOAEL x1/sRVdog x ABSoral-dog/ABSinh-human x sRVhuman/wRV

= 3.6 mg/kg bw/day x 1/0.411 m³/kg bw x 66%/100% x 6.7 m³/10 m³ = 5.78 mg/m³

sRV: standard respiratory volume, ABS: absorption, wRV: worker respiratory volume

Regarding toxicokinetic behaviour, data with the source substance Ziram were taken into account in the dossier of SDDC (for details please refer to the analogue justification). It could be demonstrated, that Ziram is well absorbed from the gastro-intestinal tract in rats, within 48 h after oral administration for 58-61% after a single low dose, for 60-69% after a single high dose and for 71-75% after a repeated low dose (Hardwick & Lappin, 2001), which means an overall oral absorption of 66%.

Applying the read-across approach, an absorption potential of 66% for the oral route is assumed for SDDC, respectively. Thus, the same absorption value (66% for the oral route), which was taken into account for Ziram, were used for the calculation of the DNELs for SDDC.

Thus, the corrected starting point for inhalation route is 5.78 mg/m3

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:
A chronic NOAEL is used as starting point.
AF for interspecies differences (allometric scaling):
1
Justification:
Not necessary for inhalation route
AF for other interspecies differences:
2.5
Justification:
ECHA default
AF for intraspecies differences:
10
Justification:
ECHA default for general population
AF for the quality of the whole database:
1
Justification:
The database is complete and of high quality.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.35 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):
35
Dose descriptor starting point:
NOAEL
Value:
3.6 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
47.52 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The calculation of the DNEL is based on an oral NOAEL derived in a 52-week feeding study in dogs with the source substance ziram.This study provides information on the chronic exposure of the source substance, which is considered to be the most reliable for the assessment of hazardous properties during a life span. Moreover, in this study the lowest NOAEL was determined compared with the other repeated dose toxicity studies.The established NOAEL value is equivalent to 3.6 mg technical SDDC/kg bw/day.

To take into account the interspecies difference between dog and human the no observed adverse effect level has to be corrected as follows:

Corrected dermal NOAEL = oral NOAEL x ABSoral-rat/ABSdermal-human

= 3.6 mg/kg bw/day x 66% / 5%

= 47.52 mg/kg bw/day

Abs: Absorption

Regarding toxicokinetic behaviour, data with the source substance Ziram were taken into account in the dossier of SDDC. It could be demonstrated, that Ziram is well absorbed from the gastro-intestinal tract in rats, within 48 h after oral administration for 58-61% after a single low dose, for 60-69% after a single high dose and for 71-75% after a repeated low dose (Hardwick & Lappin, 2001), which means an overall oral absorption of 66%. Percutaneous absorption of ziram has been studied in vivo (Cheng, 1991) in the rat and in vitro (Kane, 2006) using human skin samples. Because of the volatile nature of the two metabolites, CS2 and dimethylamine (DMA), the recovery of radioactivity in the in vivo assay in rats was only 70-80%. The non-recovered radioactivity was assumed to be dermally absorbed giving rise to a dermal absorption between 5% (high dose) to almost 30% (low dose). Much better recoveries (91-94%) were obtained with an in vitro human skin model. Both with concentrated (approximately 64% w/v) and diluted aqueous solutions (approximately 0.16% w/v) of Ziram, absorption through human skin was slow (0.004 and 0.05 μg/cm²/h for low and high dose, respectively) and inefficient (2.2% and 0.1% for low and high dose, respectively).

Applying the read-across approach (for details please refer to the analogue justification), an absorption potential of 66% for the oral route and 5% for the dermal route is assumed for SDDC, respectively. Thus, the same absorption values (66% for the oral route and 5% for the dermal route), which were taken into account in the registration dossier with Ziram, were used for the calculation of the DNELs for SDDC.

Thus, the corrected starting point for inhalation route is 47.52 mg/kg bw/day.

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:
A chronic NOAEL is used as starting point.
AF for interspecies differences (allometric scaling):
1.4
Justification:
default for dog-to-human
AF for other interspecies differences:
2.5
Justification:
ECHA default
AF for intraspecies differences:
10
Justification:
ECHA default for general population
AF for the quality of the whole database:
1
Justification:
The database is complete and of high quality.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.1 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):
35
Dose descriptor starting point:
NOAEL
Value:
3.6 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Route-to-route extrapolation not necessary

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:
A chronic NOAEL is used as starting point.
AF for interspecies differences (allometric scaling):
1.4
Justification:
default for dog-to-human
AF for other interspecies differences:
2.5
Justification:
ECHA default
AF for intraspecies differences:
10
Justification:
ECHA default for workers
AF for the quality of the whole database:
1
Justification:
The database is complete and of high quality.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population