Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.69 mg/m³
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
12.5
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
Justification:
As the endpoint is reproductive toxicity, there is no adjustment for duration of exposure, as gestation is a finite measure.
AF for interspecies differences (allometric scaling):
1
AF for other interspecies differences:
2.5
Justification:
Default factor for worker
AF for intraspecies differences:
5
Justification:
Default factor for worker
AF for the quality of the whole database:
1
Justification:
Comprehensive data are available: acute, sub-acute, sub-chronic and chronic toxicity studies.
AF for remaining uncertainties:
1
Justification:
Comprehensive data are available: acute, sub-acute, sub-chronic and chronic toxicity studies.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.45 mg/m³
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL
Explanation for the modification of the dose descriptor starting point:

The standard extrapolation factor of 5x was used for the short-term DNEL from the long-term DNEL

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:
0.19 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
Justification:
As the endpoint is reproductive toxicity, there is no adjustment for duration of exposure, as gestation is a finite measure.
AF for interspecies differences (allometric scaling):
4
Justification:
Default rat -> human
AF for other interspecies differences:
2.5
AF for intraspecies differences:
5
Justification:
Default factor for worker
AF for the quality of the whole database:
1
Justification:
Comprehensive data are available: acute, sub-acute, sub-chronic and chronic toxicity studies.
AF for remaining uncertainties:
1
Justification:
Comprehensive data are available: acute, sub-acute, sub-chronic and chronic toxicity studies.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.95 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL
Explanation for the modification of the dose descriptor starting point:

The standard extrapolation factor of 5x was use for a short-term DNEL from a long-term

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

Long Term DNEL Derivation for 6PPD

The starting NOAEL was 7 mg/kg/day from an extended 1-generation reproductive toxicity study. In that study, females (and males, but moot to the derivation) were treated with 6PPD daily for 10 weeks of pre-breeding, 2 weeks of breeding followed by 21 days of gestation until parturition.  The NOAEL was based on dystocia (difficult delivery) which was observed in both the range-finder, which had a 2-week pre-treatment period and the main study with a 10 week pre-treatment period.  As the primary effect observed was part of gestation (parturition) no correction factors for duration of study are applied, as gestation is a fixed time period, and thus there is no adjustment for duration.

 

Modification of the dose descriptor:

General population long-term inhalation:

               NOAEL of 7 mg/kg/day * ECHA default bioavailability of animal oral of 50% to human inhalationof 100%, = 3.5 mg/kg/day. Divided by the standard respiratory volume of 1.35 m3kg bw/24 hr =     Adjusted NOAEC of 2.59 mg/m3

               Adjustment factors:   2.5 for remaining interspecies, 10 for intraspecies,Total Adjustment         factors = 25.   As the primary effect observed was part of gestation (parturition) correction      factors for duration of study are not applied, as gestation is a fixed time period, and thus      there is no adjustment for duration.

               General population long term inhalation DNEL =2.59 mg/m3/ 25 =0.10 mg/m3

 

General population long term oral/dermal:

               NOAEL of 7 mg/kg/day. There is no bioavailability difference between animal to human oral      exposures, sothe adjusted NOAEL = 7 mg/kg/day

               Adjustment factors:   4 for allometric scaling,2.5 for remaining interspecies, 10 for intraspecies,              Total Adjustment factors = 100.   As the primary effect           observed was part of gestation(parturition) correction               factors for duration of study are not applied, as gestation is a fixed timeperiod, and thus there is no adjustment for duration.

               General population long term inhalation DNEL = 7 mg/kg/day /100=0.07 mg/kg/day

 

 

 

Worker long term dermal:

               NOAEL of 7 mg/kg/day. There is no bioavailability difference between animal to human oral      exposures. A factor of 1.4 is applied for exposure conditions for anadjusted NOAEL = 9.8      mg/kg/day

               Adjustment factors:   4 for allometric scaling,2.5 for remaining interspecies, 5 for intraspecies,Total Adjustment factors = 50.   As the primary effect observed was part of gestation               (parturition) correction               factors for duration of study are not applied, as gestation is a fixed timeperiod, and thus there is no adjustment for duration.

               Worker long term oral/dermal DNEL = 9.8 mg/kg/day/50=0.19 mg/kg/day

 

               Worker long term inhalation:

               NOAEL of 7 mg/kg/day. ECHA default bioavailability of animal oral of 50% to human inhalation of 100%, = 3.5 mg/kg/day, / 0.38 m3 bw/8hr = 9.21, * 0.67 (respiratory volumes) * 1.4 (exposure   conditions) for anadjusted NOAEL = 8.6 mg/m3

               Adjustment factors:   2.5 for remaining interspecies, 5 for intraspecies,Total Adjustment           factors = 12.5.   As the primary effect observed was part of gestation (parturition) correction       factors for duration of study are not applied, as gestation is a fixed time         period, and thus there is no adjustment for duration.

               Worker long term oral/dermal DNEL = 8.6 mg/m3/12.5=0.69 mg/m3

 

Short Term DNEL Derivation for 6PPD

Short-Term DNEL values are derived based ECHA guidance suggesting that a five-fold difference in the short and long term DNEL is protective in the absence of other data suggesting a more restrictive need.

 

Type

Worker

General Population

Long Term Inhalation

0.69 mg/m3

0.10 mg/m3

Short Term Inhalation

3.45 mg/m3

0.50 mg/m3

Long Term Oral/Dermal*

0.19 mg/kg/day

0.07 mg/kg/day

Short Term Oral/Dermal

0.95 mg/kg/day

0.35 mg/kg/day

*Oral worker values are not derived

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.1 mg/m³
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
Justification:
As the endpoint is reproductive toxicity, there is no adjustment for duration of exposure, as gestation is a finite measure.
AF for interspecies differences (allometric scaling):
1
AF for other interspecies differences:
2.5
Justification:
Default factor for the general population
AF for intraspecies differences:
10
Justification:
Default factor for the general population
AF for the quality of the whole database:
1
Justification:
Comprehensive data are available: acute, sub-acute, sub-chronic and chronic toxicity studies.
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.5 mg/m³
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL
Explanation for the modification of the dose descriptor starting point:

The standard extrapolation factor of 5x was used for the short-term DNEL from the long-term DNEL

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:
0.07 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
Justification:
As the endpoint is reproductive toxicity, there is no adjustment for duration of exposure, as gestation is a finite measure.
AF for interspecies differences (allometric scaling):
4
Justification:
Default factor for the general population
AF for other interspecies differences:
2.5
Justification:
Default factor for the general population
AF for intraspecies differences:
10
Justification:
Default factor for the general population
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.35 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL
Explanation for the modification of the dose descriptor starting point:

The standard extrapolation factor of 5x was used for the short-term DNEL from the long-term DNEL

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:
0.07 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
Justification:
As the endpoint is reproductive toxicity, there is no adjustment for duration of exposure, as gestation is a finite measure.
AF for interspecies differences (allometric scaling):
4
Justification:
default rat -> humanDefault factor for the general population
AF for other interspecies differences:
2.5
Justification:
Default factor for the general population
AF for intraspecies differences:
10
Justification:
Default factor for the general population
AF for the quality of the whole database:
1
Justification:
Comprehensive data are available: acute, sub-acute, sub-chronic and chronic toxicity studies.
AF for remaining uncertainties:
1
Justification:
Comprehensive data are available: acute, sub-acute, sub-chronic and chronic toxicity studies.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.35 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL
Explanation for the modification of the dose descriptor starting point:

The standard extrapolation factor of 5x was used for the short-term DNEL from the long-term DNEL

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Long Term DNEL Derivation for 6PPD

The starting NOAEL was 7 mg/kg/day from an extended 1-generation reproductive toxicity study. In that study, females (and males, but moot to the derivation) were treated with 6PPD daily for 10 weeks of pre-breeding, 2 weeks of breeding followed by 21 days of gestation until parturition.  The NOAEL was based on dystocia (difficult delivery) which was observed in both the range-finder, which had a 2-week pre-treatment period and the main study with a 10 week pre-treatment period.  As the primary effect observed was part of gestation (parturition) no correction factors for duration of study are applied, as gestation is a fixed time period, and thus there is no adjustment for duration.

 

Modification of the dose descriptor:

General population long-term inhalation:

               NOAEL of 7 mg/kg/day * ECHA default bioavailability of animal oral of 50% to human inhalationof 100%, = 3.5 mg/kg/day. Divided by the standard respiratory volume of 1.35 m3kg bw/24 hr =     Adjusted NOAEC of 2.59 mg/m3

               Adjustment factors:   2.5 for remaining interspecies, 10 for intraspecies,Total Adjustment         factors = 25.   As the primary effect observed was part of gestation (parturition) correction      factors for duration of study are not applied, as gestation is a fixed time period, and thus      there is no adjustment for duration.

               General population long term inhalation DNEL =2.59 mg/m3/ 25 =0.10 mg/m3

 

General population long term oral/dermal:

               NOAEL of 7 mg/kg/day. There is no bioavailability difference between animal to human oral      exposures, sothe adjusted NOAEL = 7 mg/kg/day

               Adjustment factors:   4 for allometric scaling,2.5 for remaining interspecies, 10 for intraspecies,              Total Adjustment factors = 100.   As the primary effect           observed was part of gestation(parturition) correction               factors for duration of study are not applied, as gestation is a fixed timeperiod, and thus there is no adjustment for duration.

               General population long term inhalation DNEL = 7 mg/kg/day /100=0.07 mg/kg/day

 

 

 

Worker long term dermal:

               NOAEL of 7 mg/kg/day. There is no bioavailability difference between animal to human oral      exposures. A factor of 1.4 is applied for exposure conditions for anadjusted NOAEL = 9.8      mg/kg/day

               Adjustment factors:   4 for allometric scaling,2.5 for remaining interspecies, 5 for intraspecies,Total Adjustment factors = 50.   As the primary effect observed was part of gestation               (parturition) correction               factors for duration of study are not applied, as gestation is a fixed timeperiod, and thus there is no adjustment for duration.

               Worker long term oral/dermal DNEL = 9.8 mg/kg/day/50=0.19 mg/kg/day

 

               Worker long term inhalation:

               NOAEL of 7 mg/kg/day. ECHA default bioavailability of animal oral of 50% to human inhalation of 100%, = 3.5 mg/kg/day, / 0.38 m3 bw/8hr = 9.21, * 0.67 (respiratory volumes) * 1.4 (exposure   conditions) for anadjusted NOAEL = 8.6 mg/m3

               Adjustment factors:   2.5 for remaining interspecies, 5 for intraspecies,Total Adjustment           factors = 12.5.   As the primary effect observed was part of gestation (parturition) correction       factors for duration of study are not applied, as gestation is a fixed time         period, and thus there is no adjustment for duration.

               Worker long term oral/dermal DNEL = 8.6 mg/m3/12.5=0.69 mg/m3

 

Short Term DNEL Derivation for 6PPD

Short-Term DNEL values are derived based ECHA guidance suggesting that a five-fold difference in the short and long term DNEL is protective in the absence of other data suggesting a more restrictive need.

 

Type

Worker

General Population

Long Term Inhalation

0.69 mg/m3

0.10 mg/m3

Short Term Inhalation

3.45 mg/m3

0.50 mg/m3

Long Term Oral/Dermal*

0.19 mg/kg/day

0.07 mg/kg/day

Short Term Oral/Dermal

0.95 mg/kg/day

0.35 mg/kg/day

*Oral worker values are not derived