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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.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:
2.3 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):
100
Modified dose descriptor starting point:
NOAEC
Value:
234 mg/m³
Explanation for the modification of the dose descriptor starting point:
There is no long term study available using the inhalation route. Thus, as starting point for the calculation, the LOAEL of the subacute oral gavage study has to be taken into account. Furthermore, there are no quantitative data on absorption rates for oral or inhalation route available. Vulkacit I has a molecular weight of 364.5 , the log Pow given in IUCLID is > 4 and it is nearly unsoluble in water. Moderate log P values (between (-1 and 4) are favorable for absorption directly across the respiratory tract epithelium by passive diffusion. Any lipophilic compound may be taken up by micellular solubilisation but this mechanism may be of particular importance for highly lipophilic compound (Log P >4) particular those that are poorly soluble in water (1 mg/l or less) that would otherwise be poorly absorbed. Therefore is can be assumed that inhalation absorption is in the same range as oral absorption and no further default value has to be introduced Furthermore, as required in the ECHA guidance document to extrapolate from LOAEC to NOAEC a factor of 3 has to be introduced. Overall: LOAEL: 100 mg/kg bw; body weight worker: 70 kg; air volume inhaled per shift: 10 m3; LOAEL -> NOAEL: factor of 3
AF for dose response relationship:
1
Justification:
A factor of 3 is already applied in the NOAEC starting point derivation.
AF for differences in duration of exposure:
2
Justification:
Hemolytic anemia with accompanied by histopathological effects in spleen and kidney are observed at all doses tested in the sub-acute toxicity study. Hemolytic anemia that accompany methaemoglobinaemia or haemolysis is considered to be an acute effect (e.g. see The MAK-Collection Part I: MAK Value Documentations, Aniline, Vol. 26. DFG, 2011). Since there are fundamental physiological differences between rats and humans and disorders observed in humans that accompany methaemoglobinaemia or haemolysis, is not expected that these effects occur in human spleens. Based on the effects observed a test proposal is included in the dossier for a 90-day oral study in rats according to OECD TG 408. In the meantime a provisional DNEL is calculated taking into account a time extrapolation factor of 2. This factor will be reconsidered once the data from the 90 day study become available.
AF for interspecies differences (allometric scaling):
4
Justification:
Default rat-> human
AF for other interspecies differences:
2.5
Justification:
default factor REACH Guidance R8
AF for intraspecies differences:
5
Justification:
default factor REACH Guidance R8
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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:
0.33 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):
300
Modified dose descriptor starting point:
LOAEL
Value:
100 mg/kg bw/day
AF for dose response relationship:
3
Justification:
LOAEL -> NOAEL
AF for differences in duration of exposure:
2
Justification:
Hemolytic anemia with accompanied by histopathological effects in spleen and kidney are observed at all doses tested in the sub-acute toxicity study. Hemolytic anemia that accompany methaemoglobinaemia or haemolysis is considered to be an acute effect (e.g. see The MAK-Collection Part I: MAK Value Documentations, Aniline, Vol. 26. DFG, 2011). Since there are fundamental physiological differences between rats and humans and disorders observed in humans that accompany methaemoglobinaemia or haemolysis, is not expected that these effects occur in human spleens. Based on the effects observed a test proposal is included in the dossier for a 90-day oral study in rats according to OECD TG 408. In the meantime a provisional DNEL is calculated taking into account a time extrapolation factor of 2. This factor will be reconsidered once the data from the 90 day study become available.
AF for interspecies differences (allometric scaling):
4
Justification:
default factor REACH Guidance R8
AF for other interspecies differences:
2.5
Justification:
default factor REACH Guidance R8
AF for intraspecies differences:
5
Justification:
default factor REACH Guidance R8
AF for the quality of the whole database:
1
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

Introductory Note

There is no sub chronic study available as required by Regulation (EC)1907/2006 (REACH) ANNEX IX section 8.6.2

There is a reliable short term toxicity study (28 days) which was performed according to OECD TG 407 and GLP available In this available 28-day gavage study with rats (0, 100, 300 and 1000 mg/kg bw/day given as suspension in Solutol 15 HS /Ethanol /water = 4 : 1 : 5, Wirnitzer 2013) N,N’-Dimethyldiphenylthiuram disulphide caused significant hemolytic anemia from 100 mg/kg bw/day (LOAEL) onwards increasing in severity with the dose accompanied by histopathological effects in spleen and kidney but not in the liver, discolored feces at mid and high dose rats (both sexes) and reduced body weight development in high dosed rats. Dose-related increasing significant reticulocytosis can be interpreted as adaptive process. A NOAEL was not established.

Based on the severe effects observed a 90-day oral study in rats according to OECD TG 408 and GLP is proposed.

In the mean time, until the results of the sub-chronic studies are available, it is considered important to provide a practical recommendation to the users of Vulkacit I and therefore to propose provisory DNELs (systemic, long term) for which the available subacute oral rat study will be considered. The procedure will be re-assessed as soon as the results of the planned repeated dose oral toxicity study are available

Furthermore, Vulkacit I is not irritating to the skin or mucous membranes. Therefore, no local DNELs will be derived.

Worker

There is no German or European Occupational Exposure Limit (OEL) available which could be used as starting point for derivation of systemic Worker- DNELs for Vulkacit I following dermal and inhalation route of exposure. DNEL for oral exposure has no relevance for the situation of workers.

DNEL (systemic, long term, dermal route)

There is no long term dermal study available. Therefore, the oral LOAEL has to be considered instead. According to ECHA Guidance Document, Chapter R8 Version 2, December 2010, no additional default factors have to be introduced when performing oral-to-dermal extrapolation because it can be assumed that dermal absorption will not be higher than oral absorption.

LOAEL (oral) = LOAEL (dermal) = 100 mg/kg bw/day

Assessment factors:

For LOAEL to NOAEL: 3

For exposure duration : subacute to chronic: 2

Hemolytic anemia with accompanied by histopathological effects in spleen and kidney are observed at all doses tested in the sub-acute toxicity study. Hemolytic anemia that accompany methaemoglobinaemia or haemolysis is considered to be an acute effect (e.g. see The MAK-Collection Part I: MAK Value Documentations, Aniline, Vol. 26. DFG, 2011). Since there are fundamental physiological differences between rats and humans and disorders observed in humans that accompany methaemoglobinaemia or haemolysis, is not expected that these effects occur in human spleens. Based on the effects observed a test proposal is included in the dossier for a 90-day oral study in rats according to OECD TG 408. In the meantime a provisional DNEL is calculated taking into account a time extrapolation factor of 2. This factor will be reconsidered once the data from the 90 day study become available.

For interspecies differences rat vs human: 4

For remaining interspecies differences: 2.5

For intraspecies differences worker 5

For reliablility of dose response: 1

For quality of the whole database: 1

Overall factor: 300

Thus, DNEL (systemic , long term, dermal route): 0.33 mg/kg bw/d

DNEL (systemic, short term, dermal route)

There is no short term study available which could be considered.

Therefore it is proposed for precaution purposes that the DNEL (systemic, long term, dermal route) can be taken as surrogate for the DNEL (systemic, short term, dermal route).

DNEL (systemic, long term inhalation route)

There is no long term study available using the inhalation route. Thus, as starting point for the calculation, the LOAEL of the subacute oral gavage study has to be taken into account. Furthermore, there are no quantitative data on absorption rates for oral or inhalation route available. Vulkacit I has a molecular weight of 364.5 , the log Pow given in IUCLID is > 4 and it is nearly unsoluble in water. Moderate log P values (between (-1 and 4) are favorable for absorption directly across the respiratory tract epithelium by passive diffusion. Any lipophilic compound may be taken up by micellular solubilisation but this mechanism may be of particular importance for highly lipophilic compound (Log P >4) particular those that are poorly soluble in water (1 mg/l or less) that would otherwise be poorly absorbed. Therefore is can be assumed that inhalation absorption is in the same range as oral absorption and no further default value has to be introduced

LOAEL (oral) = 100 mg/kg bw/day

For LOAEL to NOAEL                            3

For extrapolation oral to inhalation              1

Respiratory volume worker       10 m³/ 8h

Body weight worker                     70 kg

NOAEC (subacute, inhalation)       234 mg/m³ starting point

For exposure duration : subacute to chronic:       2

For interspecies differences rat vs human:            4

For remaining interspecies differences:              2.5

For intraspecies differences worker                     5

For reliablility of dose response:                            1

For quality of the whole database:                         1

Overall factor: 100

Thus, the DNEL (long term, systemic, inhalation route) is 2.3 mg/m³

DNEL (systemic, short term, inhalation route)

The LC50 (rat) is > 5000 mg/m³/4h. In general, human is more susceptible for toxicological effects by inhalation exposure than rat. Therefore, and since there are no other data available using the inhalation route, it is proposed for precaution purposes that the DNEL (systemic, lomg term, inhalation route) can be taken as surrogate for the DNEL (systemic, short term, inhalation route).

Summary

The relevant DNELs for worker are:

DNEL (systemic, dermal route, long term and short term exposure): 0.33 mg/kg bw

DNEL (systemic, inhalation route, long term and short term exposure): 2.3 mg/m³

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.59 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):
200
Modified dose descriptor starting point:
NOAEC
Value:
117 mg/m³
Explanation for the modification of the dose descriptor starting point:
There is no long term study available using the inhalation route. Thus, as starting point for the calculation, the LOAEL of the subacute oral gavage study has to be taken into account. Furthermore, there are no quantitative data on absorption rates for oral or inhalation route available. Vulkacit I has a molecular weight of 364.5 , the log Pow given in IUCLID is > 4 and it is nearly unsoluble in water. Moderate log P values (between (-1 and 4) are favorable for absorption directly across the respiratory tract epithelium by passive diffusion. Any lipophilic compound may be taken up by micellular solubilisation but this mechanism may be of particular importance for highly lipophilic compound (Log P >4) particular those that are poorly soluble in water (1 mg/l or less) that would otherwise be poorly absorbed. Therefore is can be assumed that inhalation absorption is in the same range as oral absorption and no further default value has to be introduced Furthermore, as required in the ECHA guidance document to extrapolate from LOAEC to NOAEC a factor of 3 has to be introduced. Overall: LOAEL: 100 mg/kg bw; body weight worker: 70 kg; air volume inhaled per day: 20 m3; LOAEL -> NOAEL: factor of 3
AF for dose response relationship:
1
Justification:
A factor of 3 is already applied in the NOAEC starting point derivation.
AF for differences in duration of exposure:
2
Justification:
Hemolytic anemia with accompanied by histopathological effects in spleen and kidney are observed at all doses tested in the sub-acute toxicity study. Hemolytic anemia that accompany methaemoglobinaemia or haemolysis is considered to be an acute effect (e.g. see The MAK-Collection Part I: MAK Value Documentations, Aniline, Vol. 26. DFG, 2011). Since there are fundamental physiological differences between rats and humans and disorders observed in humans that accompany methaemoglobinaemia or haemolysis, is not expected that these effects occur in human spleens. Based on the effects observed a test proposal is included in the dossier for a 90-day oral study in rats according to OECD TG 408. In the meantime a provisional DNEL is calculated taking into account a time extrapolation factor of 2. This factor will be reconsidered once the data from the 90 day study become available.
AF for interspecies differences (allometric scaling):
4
Justification:
default factor REACH Guidance R8
AF for other interspecies differences:
2.5
Justification:
default factor REACH Guidance R8
AF for intraspecies differences:
10
Justification:
default factor REACH Guidance R8
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Route of original study:
Oral
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:
0.17 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):
600
Modified dose descriptor starting point:
LOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
There is no long term dermal study available. Therefore, the oral LOAEL has to be considered for derivation of the DNEL (oral) as well as for The DNEL (dermal route). According to ECHA Guidance Document, Chapter R8 Version 2, December 2010, no additional default factors have to be introduced when performing oral-to-dermal extrapolation because it can be assumed that dermal absorption will not be higher than oral absorption. Furthermore, as required in the ECHA guidance document to extrapolate from LOAEL to NOAEL a factor of 3 has to be introduced
AF for dose response relationship:
3
Justification:
LOAEL -> NOAEL
AF for differences in duration of exposure:
2
Justification:
Hemolytic anemia with accompanied by histopathological effects in spleen and kidney are observed at all doses tested in the sub-acute toxicity study. Hemolytic anemia that accompany methaemoglobinaemia or haemolysis is considered to be an acute effect (e.g. see The MAK-Collection Part I: MAK Value Documentations, Aniline, Vol. 26. DFG, 2011). Since there are fundamental physiological differences between rats and humans and disorders observed in humans that accompany methaemoglobinaemia or haemolysis, is not expected that these effects occur in human spleens. Based on the effects observed a test proposal is included in the dossier for a 90-day oral study in rats according to OECD TG 408. In the meantime a provisional DNEL is calculated taking into account a time extrapolation factor of 2. This factor will be reconsidered once the data from the 90 day study become available.
AF for interspecies differences (allometric scaling):
4
Justification:
default factor REACH Guidance R8
AF for other interspecies differences:
2.5
Justification:
default factor REACH Guidance R8
AF for intraspecies differences:
10
Justification:
default factor REACH Guidance R8
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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:
0.17 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):
600
Modified dose descriptor starting point:
LOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No route to route extrapolation has to be performed.
AF for dose response relationship:
3
Justification:
LOAEL -> NOAEL
AF for differences in duration of exposure:
2
Justification:
Hemolytic anemia with accompanied by histopathological effects in spleen and kidney are observed at all doses tested in the sub-acute toxicity study. Hemolytic anemia that accompany methaemoglobinaemia or haemolysis is considered to be an acute effect (e.g. see The MAK-Collection Part I: MAK Value Documentations, Aniline, Vol. 26. DFG, 2011). Since there are fundamental physiological differences between rats and humans and disorders observed in humans that accompany methaemoglobinaemia or haemolysis, is not expected that these effects occur in human spleens. Based on the effects observed a test proposal is included in the dossier for a 90-day oral study in rats according to OECD TG 408. In the meantime a provisional DNEL is calculated taking into account a time extrapolation factor of 2. This factor will be reconsidered once the data from the 90 day study become available.
AF for interspecies differences (allometric scaling):
4
Justification:
default factor REACH Guidance R8
AF for other interspecies differences:
2.5
Justification:
default factor REACH Guidance R8
AF for intraspecies differences:
10
Justification:
default factor REACH Guidance R8
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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

There is no sub chronic study available. as required by Regulation (EC)1907/2006 (REACH) ANNEX IX section 8.6.2

There is a reliable short term toxicity study (28 days) which was performed according to OECD TG 407 and GLP available In this available 28-day gavage study with rats (0, 100, 300 and 1000 mg/kg bw/day given as suspension in Solutol 15 HS /Ethanol /water = 4 : 1 : 5, Wirnitzer 2013) N,N’-Dimethyldiphenylthiuram disulphide caused significant hemolytic anemia from 100 mg/kg bw/day (LOAEL) onwards increasing in severity with the dose accompanied by histopathological effects in spleen and kidney but not in the liver, discolored feces at mid and high dose rats (both sexes) and reduced body weight development in high dosed rats. Dose-related increasing significant reticulocytosis can be interpreted as adaptive process. A NOAEL was not established.

Based on the severe effects observed a 90-day oral study in rats according to OECD TG 408 and GLP is proposed.

In the mean time, until the results of the sub-chronic studies are available, it is considered important to provide a practical recommendation to the users of Vulkacit I and therefore to propose provisory DNELs (systemic, long term) for which the available subacute oral rat study will be considered. The procedure will be re-assessed as soon as the results of the planned repeated dose oral toxicity study are available

Furthermore, Vulkacit I is not irritating to the skin or mucous membranes. Therefore, no local DNELs will be derived.

General public

DNEL (systemic, long term, oral route and dermal route)

There is no long term dermal study available. Therefore, the oral LOAEL has to be considered for derivation of the DNEL (oral) as well as for the DNEL (dermal route). According to ECHA Guidance Document, Chapter R8 Version 2, December 2010, no additional default factors have to be introduced when performing oral-to-dermal extrapolation because it can be assumed that dermal absorption will not be higher than oral absorption.

LOAEL (oral) = LOAEL (dermal) = 100 mg/kg bw/day

For LOAEL to NOAEL        3

NOAEL( subacute, oral route and dermal route): 33 mg/kg bw/day starting point

For exposure duration : subacute to chronic: 2

Hemolytic anemia with accompanied by histopathological effects in spleen and kidney are observed at all doses tested in the sub-acute toxicity study. Hemolytic anemia that accompany methaemoglobinaemia or haemolysis is considered to be an acute effect (e.g. see The MAK-Collection Part I: MAK Value Documentations, Aniline, Vol. 26. DFG, 2011). Since there are fundamental physiological differences between rats and humans and disorders observed in humans that accompany methaemoglobinaemia or haemolysis, is not expected that these effects occur in human spleens. Based on the effects observed a test proposal is included in the dossier for a 90-day oral study in rats according to OECD TG 408. In the meantime a provisional DNEL is calculated taking into account a time extrapolation factor of 2. This factor will be reconsidered once the data from the 90 day study become available.

For interspecies differences rat vs human: 4

For remaining interspecies differences: 2.5

For intraspecies differences (general public) 10

For reliablility of dose response: 1

For quality of the whole database: 1

Overall factor: 200

Thus, DNEL (systemic , long term, oral route): 0.17 mg/kg bw/d

Thus, DNEL (systemic, long term, dermal route): 0.17 mg/kg bw/d

DNEL (systemic, short term, oral route and dermal route)

The LD50 (oral is > 5000 mg/kg bw and no mortality and no clinical signs of intoxication were observed. Therefore is is proposed for precaution purposes that the DNEL(systemic , long term, oral route can be taken as surrogate for the DNEL (systemic, short term, oral route). as the considerations for the long term dermal DNEL apply also for the respective short term DNEL is is proposed that also the DNEL (systemic, long term, dermal route) can be taken as surrogate for the DNEL (systemic, short term, dermal route)

DNEL (systemic, long term inhalation route)

There is no long term study available using the inhalation route. Thus, as starting point for the calculation, the LOAEL of the subacute oral gavage study has to be taken into account. Furthermore, there are no quantitative data on absorption rates for oral or inhalation route available. Vulkacit I has a molecular weight of 364.5 , the log Pow given in IUCLID, is > 4 and it is nearly unsoluble in water. Moderate log P values (between (-1 and 4) are favorable for absorption directly across the respiratory tract epithelium by passive diffusion. Any lipophilic compound may be taken up by micellular solubilisation but this mechanism may be of particular importance for highly lipophilic compound (Log P >4) particular those that are poorly soluble in water (1 mg/l or less) that would otherwise be poorly absorbed. Therefore is can be assumed that inhalation absorption is in the same range as oral absorption and no further default value has to be introduced

LOAEL (oral) = 100 mg/kg bw/day

Corrected inhalatory LOAC= oraler LOAEL x 70 : 20

For LOAEC to NOAEC        3

NOAEC (subacute): 117 mg/m³ startring point

For exposure duration : subacute to chronic: 2

Hemolytic anemia with accompanied by histopathological effects in spleen and kidney are observed at all doses tested in the sub-acute toxicity study. Hemolytic anemia that accompany methaemoglobinaemia or haemolysis is considered to be an acute effect (e.g. see The MAK-Collection Part I: MAK Value Documentations, Aniline, Vol. 26. DFG, 2011). Since there are fundamental physiological differences between rats and humans and disorders observed in humans that accompany methaemoglobinaemia or haemolysis, is not expected that these effects occur in human spleens. Based on the effects observed a test proposal is included in the dossier for a 90-day oral study in rats according to OECD TG 408. In the meantime a provisional DNEL is calculated taking into account a time extrapolation factor of 2. This factor will be reconsidered once the data from the 90 day study become available.

For interspecies differences rat vs human: 4

For remaining interspecies differences: 2.5

For intraspecies differences genral public 10

For reliablility of dose response: 1

For quality of the whole database: 1

Overall factor: 200

Thus the DNEL (systemic, long term, inhalation route) is 0.59 mg/m³

DNEL (systemic, short term, inhalation route)

The LC50 (rat) is > 5000 mg/m³/4h. It is proposed for precaution purposes that the DNEL (systemic, long term, inhalation route) can be taken as surrogate for the DNEL (systemic, short term, inhalation route).

Summary

The relevant DNELs for general public are:

DNEL (systemic, oral route, long term and short term exposure): 0.17 mg/kg bw

DNEL (systemic, dermal route, long term and short term exposure): 0.17 mg/kg bw

DNEL (systemic, inhalation route, long term and short term exposure): 0.59 mg/m³