Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6 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):
3
Dose descriptor starting point:
NOAEL
DNEL value:
16 mg/m³
Modified dose descriptor starting point:
NOAEC
DNEL value:
17 mg/m³
Explanation for the modification of the dose descriptor starting point:

See table DNELchronicfor systemic effects by inhalation exposure explanation in the field aditional information workers

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:
No correction for exposure duration is required, as the data are obtained from a 2-generation study
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling is required
AF for other interspecies differences:
1
Justification:
No further differences
AF for intraspecies differences:
3
Justification:
The default assessment factor for workers, as proposed in the ECETOC Guidance
AF for the quality of the whole database:
1
Justification:
The database is complete and of high quality
AF for remaining uncertainties:
1
Justification:
All endpoints covered, no uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
800 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Dose descriptor starting point:
NOAEL
DNEL value:
16 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
9 600 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

See table DNELchronicfor systemic effects by dermal exposure in Additional information - workers

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:
 No correction for exposure duration is required, as the data are obtained from a 2-generation study
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling factor for rat
AF for other interspecies differences:
1
Justification:
no other differences
AF for intraspecies differences:
3
Justification:
The default assessment factor for workers, as proposed by ECETOC
AF for the quality of the whole database:
1
Justification:
Database is complete and of good 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:
high hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

This information will be updated based on the studies requested in ECHA decision number CCH-D-2114375518-38-01.

According to the REACH guidance on information requirements and chemical safety assessment a leading DN(M) EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible. In the present case, DNELs have been derived according to the ECETOC guidance, using the assessment factors as proposed by ECETOC (ECETOC, Technical Report No. 86, 2003). In case no substance specific data were available, read-across from an appropriate read-across candidate was used. In this situation, a correction for molecular weight was used since it was assumed that the toxicity is exerted by the number of molecules rather than by the amount of substance expressed in weight. No assessment factor was used to correct for uncertainties that may occur when read-across is used. The reason is that the read-across substances used appear to have higher toxic potential than zinc bis(dibutyldithiocarbamate) (ZDBC). This becomes clear in the read-across justification available in the current dossier.

Kinetics

No toxicokinetic data on ZDBC are available. The approach used for the different routes of exposure for DNEL derivation is described below.

Oral absorption

Information on long-term toxicity of ZDBC is derived from the results of the repeated dose oral toxicity studies with the substance itself, as well as by read-across from its two structural analogues, zinc bis(diethyldithiocarbamate) (ZDEC) and zinc bis(dimethyldithiocarbamate) (ZDMC). A default value of 50% for oral absorption, recommended by Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment was used in case of route-to-route extrapolation if DNELs were calculated based on the data on ZDBC or ZDEC, as no substance-specific data on oral absorption of these substances are available. For ZDMC, 60% oral absorption was determined in the GLP-compliant study with rats. Therefore, in case the DNEL was based on an oral study with ZDMC, the oral absorption value of 60% was used to determine the internal dose. In case of route-to-route extrapolation by using oral data from ZDBC, the default value of 50% oral absorption was used since this represents a lower internal dose (meaning worse-case).  

Inhalation absorption

As no data are available on inhalation absorption, the default value of 100%, as set in Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, will be used for DNEL derivation in case of oral-to-respiratory route extrapolation.

Dermal absorption

Regarding dermal absorption, an available in vitro study on structural analogue ZDMC indicated 0.1% dermal absorption. As ZDBC is a larger molecule than ZDMC, it is expected that dermal absorption will not exceed this value. Based on this, the dermal absorption percentage used fore the DNEL derivation is set to 0.1% for ZDBC.

Acute toxicity

ZDBC is not classified for acute toxicity and therefore derivation of a DNELacuteis not necessary.

ZDBC is classified as irritating to the skin, eyes and respiratory tract and as sensitizing to skin. As no qualitative data are available on these endpoints, a DNEL can not be derived. A qualitative risk assessment will be performed.

Long-term toxicity

A 17-week diet study with rats is available for ZDBC. A NOAEL of 41 mg/kg bw/day (males) and 47 mg/kg bw/day (females) was established in this study based on increased relative liver and kidney weight and reduced body weight gain and food intake at the highest dose.

 

Data on reproductive and developmental toxicity are not available for ZDBC. Regarding reproductive toxicity, a reliable 2-generation diet study with rats is available for its structural analogue ZDMC. In this study, no adverse effects on fertility were noted at the highest tested dose, resulting in a NOAEL of 25 mg/kg bw/day. Signs of parental toxicity, manifested as reduced body weight and food consumption, were observed in the high-dose group, resulting in a NOAELparental of 10 mg/kg bw/day. Using a correction for molecular weight, this results in NOAELreproductive= 25 x(478/306) = 39 mg/kg bw/day and NOAELparental= 10 x(478/306) = 16 mg/kg bw/day.

 

Regarding developmental toxicity, data are available on a structural analogue of ZDBC, ZDEC. In the study with rats administered ZDEC in olive oil by gavage at dose levels up to 250 mg/kg bw/day during gestation days 7-15, no adverse effects on development were found up to the highest dose. Signs of severe maternal toxicity were noted at the same dose level while at 125 mg/kg bw/day only slight diarrhea was noted in some animals. Therefore a dose level of 125 mg/kg bw/day was chosen as a NOAEL for parental toxicity, while the NOAEL for developmental toxicity was set at 250 mg/kg bw/day. Applying the correction for molecular weight, this results in NOAELdevelopment of 250 x (478/366) = 327 mg/kg bw/day and NOAELmaternal = 125 x (478/366) = 163 mg/kg bw/day.

 

Based on these data, no DNELs need to be derived for reproductive and developmental toxicity for ZDBC, as the substance is not toxic to fertility and development and established NOAELs for these effects are higher than the NOAELs for systemic toxicity.

 

DNELs for systemic toxicity for ZDBC shall be derived in two ways, using the two lowest NOAELs of 41 mg/kg bw/day, obtained in a 17-week oral toxicity study with ZDBC, and 16 mg/kg bw/day obtained in a two-generation study with ZDMC,using the scientifically based assessment factors as reported by ECETOC (2003).The lowest of these DNELs shall be considered critical and will be taken forward for risk assessment. As NOAEL for parental toxicity observed in a developmental study with ZDEC is significantly higher, and the same assessment factors shall be applied for reproductive and developmental toxicity studies, they will not lead to a critical DNEL. Therefore no DNEL calculation using this NOAEL as a point of departure has been performed.

 

DNEL calculation using as a starting point a NOAEL of 41 mg/kg bw/day, established in a 17-week diet study with rats with ZDBC

 

For workers:

 

DNELchronicfor systemic effects by inhalation exposure:

 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 41 mg/kg bw/day

Based on 17-weeks study with ZDBC (increased liver and kidney weight; decreased body weight and food uptake)

Step 2) Modification of starting point

0.5

 

  1

 

 

 

0.38 m3/kg bw

 

 

 

6.7 m3/10 m3

Proportion oral absorption (default value, as proposed in the REACH guidance (R.8.4.2)

 

Proportion inhalation absorption (default value, as proposed in the REACH guidance (R.8.4.2)

 

Standard respiratory volume of a rat, corrected for 8 h exposure, as proposed in the REACH Guidance (R.8.4.2)

 

Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m3/10 m3).

Step 3) Assessment factors

 

 

Interspecies

1

No allometric scaling is required

Intraspecies

3

The default assessment factor for workers, as proposed in the ECETOC Guidance

Exposure duration

2

Correction from subchronic to chronic exposure duration

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

41 x (0.5 / 1) x (6.7/10) / (0.38 x 1 x 3 x 2 x 1 x 1) = 6 mg/m3

 

DNELchronic for systemic effects by dermal exposure:

 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 41 mg/kg bw/day

Based on 17-weeks study with ZDBC (increased liver and kidney weight; decreased body weight and food uptake)

Step 2) Modification of starting point

0.5

 

 

 0.001

 

 

Proportion oral absorption (default value, as proposed in the REACH guidance (R.8.4.2)

 

Value obtained in in vitro skin penetration study with ZDMC

Step 3) Assessment factors

 

 

Interspecies

4

Allometric scaling factor for rat

Intraspecies

3

The default assessment factor for workers, as proposed by ECETOC

Exposure duration

2

 Correction from subchronic to chronic exposure duration

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

= 41 x (0.5 / 0.001) / (4 x 3 x 2 x 1 x 1) = 825 mg/kg bw/day

DNEL derivation using as a starting point a NOAEL of 16 mg/kg bw/day (corrected for molecular weight), established in a 2-generation diet study with rats with a structural analogue ZDMC

 

For workers:

 

DNELchronicfor systemic effects by inhalation exposure:

 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 16 mg/kg bw/day

Based on 2-generation reproductive study with ZDMC (reduced body weight and food consumption in parental animals), corrected for molecular weight

Step 2) Modification of starting point

0.6

 

 

 1

 

 

 0.38 m3/kg bw

 

 

 

6.7 m3/10 m3

Percentage oral absorption, based on the toxicokinetics study with ZDMC

 

Proportion inhalation absorption (default value, as proposed in the REACH guidance (R.8.4.2)

 

Standard respiratory volume of a rat, corrected for 8 h exposure, as proposed in the REACH Guidance (R.8.4.2)

 

Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m3/10 m3).

Step 3) Assessment factors

 

 

Interspecies

1

No allometric scaling is required

Intraspecies

3

The default assessment factor for workers, as proposed in the ECETOC Guidance

Exposure duration

1

No correction for exposure duration is required, as the data are obtained from a 2-generation study

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

16 x (0.6 / 1) x (6.7/10) / (0.38 x 1 x 3 x 1 x 1 x 1) =6 mg/m3

  

DNELchronic for systemic effects by dermal exposure:

 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 16 mg/kg bw/day

Based on 2-generation reproductive study with ZDMC (reduced body weight and food consumption in parental animals), corrected for molecular weight

Step 2) Modification of starting point

0.6

 

 

 

0.001

 

 

Percentage oral absorption, based on the toxicokinetics study with ZDMC

 

 

Value obtained inin vitroskin penetration study with ZDMC

Step 3) Assessment factors

 

 

Interspecies

4

Allometric scaling factor for rat

Intraspecies

3

The default assessment factor for workers, as proposed by ECETOC

Exposure duration

1

 No correction for exposure duration is required, as the data are obtained from a 2-generation study

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

= 16 x (0.6 / 0.001) / (4 x 3 x 1 x 1 x 1) =800 mg/kg bw/day

Choice of the critical DNELs

 

As can be seen from the results above, the DNEL values calculated based on the results of the studies with ZDBC itself and its structural analogue ZDMC are essentially in the same order of magnitude and in general very close, if not identical. However, the use of a NOAEL of 16 mg/kg bw/day (corrected for molecular weight) established in a two-generation oral toxicity study with ZDMC as a point of departure for DNEL derivation leads to slightly lower DNELs in comparison with the ones obtained based on a NOAEL of 41mg/kg bw/day established in a 17-week oral toxicity study with ZDBC. Consequently, using a precautionary principle, the former DNELs shall be considered critical and will be taken forward to risk characterization.


References

 

ECETOC, Technical Report No. 86. Derviation of Assessment Factors for Human Health Risk Assessment, February 2003. ISSN-0773-6347-86.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2 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
DNEL value:
16 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
8.34 mg/m³
Explanation for the modification of the dose descriptor starting point:

See table DNEL chronic for systemic effects by inhalation expsoure in the field Additional information - General Population

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:
No correction for exposure duration is required, as the data are obtained from a 2-generation study
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling is required
AF for other interspecies differences:
1
Justification:
No other differences
AF for intraspecies differences:
5
Justification:
The default assessment factor for general population, as proposed in the ECETOC Guidance
AF for the quality of the whole database:
1
Justification:
Database is complete and of good 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:
medium hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
480 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):
20
Dose descriptor starting point:
NOAEL
DNEL value:
16 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
8 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

See table DNELchronic for systemic effects by dermal exposure in the field Additional information - General Population

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:
No correction for exposure duration is required, as the data are obtained from a 2-generation study
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling factor for rat
AF for other interspecies differences:
1
Justification:
No other differences
AF for intraspecies differences:
5
Justification:
The default assessment factor for general population, as proposed by ECETOC
AF for the quality of the whole database:
1
Justification:
Databse is complete and of good 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:
high hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
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):
20
Dose descriptor starting point:
NOAEL
DNEL value:
16 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:
No correction for exposure duration is required, as the data are obtained from a 2-generation study
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling factor for rat
AF for other interspecies differences:
1
Justification:
No other differences
AF for intraspecies differences:
5
Justification:
The default assessment factor for general population, as proposed by ECETOC
AF for the quality of the whole database:
1
Justification:
Database is complete and of good 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:
medium hazard (no threshold derived)

Additional information - General Population

This information will be updated based on the studies requested in ECHA decision number CCH-D-2114375518-38-01.

According to the REACH guidance on information requirements and chemical safety assessment a leading DN(M) EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible. In the present case, DNELs have been derived according to the ECETOC guidance, using the assessment factors as proposed by ECETOC (ECETOC, Technical Report No. 86, 2003). In case no substance specific data were available, read-across from an appropriate read-across candidate was used. In this situation, a correction for molecular weight was used since it was assumed that the toxicity is exerted by the number of molecules rather than by the amount of substance expressed in weight. No assessment factor was used to correct for uncertainties that may occur when read-across is used. The reason is that the read-across substances used appear to have higher toxic potential than zinc bis(dibutyldithiocarbamate) (ZDBC). This becomes clear in the read-across justification available in the current dossier.

Kinetics

No toxicokinetic data on ZDBC are available. The approach used for the different routes of exposure for DNEL derivation is described below.

Oral absorption

Information on long-term toxicity of ZDBC is derived from the results of the repeated dose oral toxicity studies with the substance itself, as well as by read-across from its two structural analogues, zinc bis(diethyldithiocarbamate) (ZDEC) and zinc bis(dimethyldithiocarbamate) (ZDMC). A default value of 50% for oral absorption, recommended by Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment was used in case of route-to-route extrapolation if DNELs were calculated based on the data on ZDBC or ZDEC, as no substance-specific data on oral absorption of these substances are available. For ZDMC, 60% oral absorption was determined in the GLP-compliant study with rats. Therefore, in case the DNEL was based on an oral study with ZDMC, the oral absorption value of 60% was used to determine the internal dose. In case of route-to-route extrapolation by using oral data from ZDBC, the default value of 50% oral absorption was used since this represents a lower internal dose (meaning worse-case).  

Inhalation absorption

As no data are available on inhalation absorption, the default value of 100%, as set in Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, will be used for DNEL derivation in case of oral-to-respiratory route extrapolation.

Dermal absorption

Regarding dermal absorption, an available in vitro study on structural analogue ZDMC indicated 0.1% dermal absorption. As ZDBC is a larger molecule than ZDMC, it is expected that dermal absorption will not exceed this value. Based on this, the dermal absorption percentage used fore the DNEL derivation is set to 0.1% for ZDBC.

 Acute toxicity

ZDBC is not classified for acute toxicity and therefore derivation of a DNELacute is not necessary.

ZDBC is classified as irritating to the skin, eyes and respiratory tract and as sensitizing to skin. As no qualitative data are available on these endpoints, a DNEL can not be derived. A qualitative risk assessment will be performed.

Long-term toxicity

A 17-week diet study with rats is available for ZDBC. A NOAEL of 41 mg/kg bw/day (males) and 47 mg/kg bw/day (females) was established in this study based on increased relative liver and kidney weight and reduced body weight gain and food intake at the highest dose.

 

Data on reproductive and developmental toxicity are not available for ZDBC. Regarding reproductive toxicity, a reliable 2-generation diet study with rats is available for its structural analogue ZDMC. In this study, no adverse effects on fertility were noted at the highest tested dose, resulting in a NOAEL of 25 mg/kg bw/day. Signs of parental toxicity, manifested as reduced body weight and food consumption, were observed in the high-dose group, resulting in a NOAELparental of 10 mg/kg bw/day. Using a correction for molecular weight, this results in NOAELreproductive = 25 x(478/306) = 39 mg/kg bw/day and NOAELparental = 10 x(478/306) = 16 mg/kg bw/day.

 

Regarding developmental toxicity, data are available on a structural analogue of ZDBC, ZDEC. In the study with rats administered ZDEC in olive oil by gavage at dose levels up to 250 mg/kg bw/day during gestation days 7-15, no adverse effects on development were found up to the highest dose. Signs of severe maternal toxicity were noted at the same dose level while at 125 mg/kg bw/day only slight diarrhea was noted in some animals. Therefore a dose level of 125 mg/kg bw/day was chosen as a NOAEL for parental toxicity, while the NOAEL for developmental toxicity was set at 250 mg/kg bw/day. Applying the correction for molecular weight, this results in NOAELdevelopment of 250 x (478/366) = 327 mg/kg bw/day and NOAELmaternal = 125 x (478/366) = 163 mg/kg bw/day.

 

Based on these data, no DNELs need to be derived for reproductive and developmental toxicity for ZDBC, as the substance is not toxic to fertility and development and established NOAELs for these effects are higher than the NOAELs for systemic toxicity.

 

DNELs for systemic toxicity for ZDBC shall be derived in two ways, using the two lowest NOAELs of 41 mg/kg bw/day, obtained in a 17-week oral toxicity study with ZDBC, and 16 mg/kg bw/day obtained in a two-generation study with ZDMC,using the scientifically based assessment factors as reported by ECETOC (2003).The lowest of these DNELs shall be considered critical and will be taken forward for risk assessment. As NOAEL for parental toxicity observed in a developmental study with ZDEC is significantly higher, and the same assessment factors shall be applied for reproductive and developmental toxicity studies, they will not lead to a critical DNEL. Therefore no DNEL calculation using this NOAEL as a point of departure has been performed.

 

DNEL calculation using as a starting point a NOAEL of 41 mg/kg bw/day, established in a 17-week diet study with rats with ZDBC.

For general population:

 

DNELchronic for systemic effects by inhalation exposure:

 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 41 mg/kg bw/day

Based on 17-weeks study with ZDBC (increased liver and kidney weight; decreased body weight and food uptake)

Step 2) Modification of starting point

0.5

 

  1

 

 

 

 1.15 m3/kg bw

 

 

Proportion oral absorption (default value, as proposed in the REACH guidance (R.8.4.2)

 

Proportion inhalation absorption (default value, as proposed in the REACH guidance (R.8.4.2)

 

Standard respiratory volume of a rat, corrected for 24 h exposure, as proposed in the REACH Guidance (R.8.4.2)

Step 3) Assessment factors

 

 

Interspecies

1

No allometric scaling is required

Intraspecies

5

The default assessment factor for general population, as proposed in the ECETOC Guidance

Exposure duration

2

Correction from subchronic to chronic exposure duration

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

41 x (0.5 / 1) / (1.15 x 1 x 5 x 2 x 1 x 1) = 2 mg/m3

 

DNELchronic for systemic effects by dermal exposure:

 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 41 mg/kg bw/day

Based on 17-weeks study with ZDBC (increased liver and kidney weight; decreased body weight and food uptake)

Step 2) Modification of starting point

0.5

 

  0.001

 

Proportion oral absorption (default value, as proposed in the REACH guidance (R.8.4.2)

 

Value obtained in in vitro skin penetration study with ZDMC

Step 3) Assessment factors

 

 

Interspecies

4

Allometric scaling factor for rat

Intraspecies

5

The default assessment factor for general population, as proposed by ECETOC

Exposure duration

2

Correction from subchronic to chronic exposure duration

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

= 41 x (0.5 / 0.001) / (4 x 5 x 2 x 1 x 1) = 491 mg/kg bw/day

 

DNELchronic for systemic effects by oral exposure:

 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 41 mg/kg bw/day

Based on 17-weeks study with ZDBC (increased liver and kidney weight; decreased body weight and food uptake)

Step 2) Modification of starting point

1

 

No modification of the starting point is required

Step 3) Assessment factors

 

 

Interspecies

4

Allometric scaling factor for rat

Intraspecies

5

The default assessment factor for general population, as proposed by ECETOC

Exposure duration

2

Correction from subchronic to chronic exposure duration

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

41 / (4 x 5 x 2 x 1 x 1) = 1 mg/kg bw/day

 

DNEL derivation using as a starting point a NOAEL of 16 mg/kg bw/day (corrected for molecular weight), established in a 2-generation diet study with rats with a structural analogue ZDMC

For general population:

  

DNELchronic for systemic effects by inhalation exposure:

 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 16 mg/kg bw/day

Based on 2-generation reproductive study with ZDMC (reduced body weight and food consumption in parental animals), corrected for molecular weight

Step 2) Modification of starting point

0.6

 

 

 

1

 

 

 

 1.15 m3/kg bw

 

 

Percentage oral absorption, based on the toxicokinetics study with ZDMC

 

 

Proportion inhalation absorption (default value, as proposed in the REACH guidance (R.8.4.2)

 

Standard respiratory volume of a rat, corrected for 24 h exposure, as proposed in the REACH Guidance (R.8.4.2)

Step 3) Assessment factors

 

 

Interspecies

1

No allometric scaling is required

Intraspecies

5

The default assessment factor for general population, as proposed in the ECETOC Guidance

Exposure duration

1

No correction for exposure duration is required, as the data are obtained from a 2-generation study

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

16 x (0.6 / 1) / (1.15 x 1 x 5 x 1 x 1 x 1) =2 mg/m3

 

 

DNELchronicfor systemic effects by dermal exposure:

 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 16 mg/kg bw/day

Based on 2-generation reproductive study with ZDMC (reduced body weight and food consumption in parental animals), corrected for molecular weight

Step 2) Modification of starting point

0.6

 

 

 

0.001

 

 

Percentage oral absorption, based on the toxicokinetics study with ZDMC

 

 

Value obtained inin vitroskin penetration study with ZDMC

Step 3) Assessment factors

 

 

Interspecies

4

Allometric scaling factor for rat

Intraspecies

5

The default assessment factor for general population, as proposed by ECETOC

Exposure duration

1

No correction for exposure duration is required, as the data are obtained from a 2-generation study

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

= 16 x (0.5 / 0.001) / (4 x 5 x 1 x 1 x 1) x =480 mg/kg bw/day

 

DNELchronic for systemic effects by oral exposure:

 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 16 mg/kg bw/day

Based on 2-generation reproductive study with ZDMC (reduced body weight and food consumption in parental animals), corrected for molecular weight

Step 2) Modification of starting point

1

 

No modification of the starting point is required

Step 3) Assessment factors

 

 

Interspecies

4

Allometric scaling factor for rat

Intraspecies

5

The default assessment factor for general population, as proposed by ECETOC

Exposure duration

1

No correction for exposure duration is required, as the data are obtained from a 2-generation study

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

16 / (4 x 5 x 1 x 1 x 1) =1 mg/kg bw/day

  

Choice of the critical DNELs

 

As can be seen from the results above, the DNEL values calculated based on the results of the studies with ZDBC itself and its structural analogue ZDMC are essentially in the same order of magnitude and in general very close, if not identical. However, the use of a NOAEL of 16 mg/kg bw/day (corrected for molecular weight) established in a two-generation oral toxicity study with ZDMC as a point of departure for DNEL derivation leads to slightly lower DNELs in comparison with the ones obtained based on a NOAEL of 41mg/kg bw/day established in a 17-week oral toxicity study with ZDBC. Consequently, using a precautionary principle, the former DNELs shall be considered critical and will be taken forward to risk characterization.


References

 

ECETOC, Technical Report No. 86. Derviation of Assessment Factors for Human Health Risk Assessment, February 2003. ISSN-0773-6347-86.