Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.14 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
12.5
Modified dose descriptor starting point:
NOAEC
Value:
1.76 mg/m³
Explanation for the modification of the dose descriptor starting point:
Corrected dose descriptor 1x1/0.38x6.7/10=1.76 mg/m3
AF for dose response relationship:
1
Justification:
This factor is applied because the dose-descriptor starting point is a NOAEC.
AF for differences in duration of exposure:
1
Justification:
No uncertainty factor because the study is a rat prenatal developmental study
AF for interspecies differences (allometric scaling):
1
Justification:
AF not used for inhalation because it is an oral to inhalation route.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 is applied for uncertainties
AF for intraspecies differences:
5
Justification:
A factor of 5 is applied for workers
AF for the quality of the whole database:
1
Justification:
The studies performed with AZDN are reliable studies
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
199 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
12.5
Modified dose descriptor starting point:
LOAEC
Value:
1 570 mg/m³
Explanation for the modification of the dose descriptor starting point:
Time extrapolation to the reference period of 15 minutes for acute effects, using the modified Haber's law (Cnx t = k) with ancoefficient of 3 for extrapolation from a longer to a shorter exposure duration : LOAEC (15 minutes) = 2489 mg/m3
AF for dose response relationship:
1
AF for interspecies differences (allometric scaling):
2.5
AF for other interspecies differences:
1
AF for intraspecies differences:
5
Justification:
A factor of 5 is applied for workers
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
194.17 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEL
Value:
1 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
A dermal penetration study is available. the mean penetrated amount is 0.0103% of human skin.
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
Justification:
No uncertainty factor because the study is a rat prenatal developmental study
AF for interspecies differences (allometric scaling):
2.5
AF for other interspecies differences:
4
AF for intraspecies differences:
5
Justification:
A factor 5 is used for workers
AF for the quality of the whole database:
1
Justification:
Quality of the studies performed with AZDN are reliable.
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:
hazard unknown (no further information necessary)
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

Worker Acute DNEL (inhalation, systemic)

The acute inhalation rat toxicity study using AZDN (Dupont., 1984, report unavailable (awaiting for Dupont), questionable validity(quoted K3), described in the SIDS 2002) was used for DNEL derivation. In this study, three concentrations were tested: 1.57, 3.40, and 7.78 mg/L during one hour exposure. Only one death was recorded 1 day after exposure to 1.57 mg/L. No other death was observed at any dose-level. Most rats exhibited moderate to severe weight losses 1 or 2 days after exposure, followed by a return to a normal weight gain rate. Most females exhibited sporadic weight losses during the 2-week observation period.

 

Step 1: Selection of the relevant dose descriptor:

LOAEC (1 hour) = 1.57 mg/L=1570 mg/m3

 

Step 2: Modification of the starting point:

Time extrapolation to the reference period of 15 minutes for acute effects, using the modified Haber's law (Cnx t = k) with ancoefficient of 3 for extrapolation from a longer to a shorter exposure duration :

LOAEC (15 minutes) = 2489 mg/m3

 

Step 3: Assessment factors:

- Interspecies differences: as massive exposure by inhalation is considered, no toxicokinetic assessment factor is applied. However, a factor of 2.5 to correct for differences other than differences in metabolic rate is applied.

- Intraspecies differences: the default assessment factor of 5 is applied.

- Severity: no additional safety factor taking into account the very low severity of effects

- Quality of whole database: a factor of 1 is applied based on the good quality of the whole database.

- Global assessment factor: 2.5 x 5 x 1 = 12.5

 

Step 4: DNEL derivation:

Worker DNEL (acute, systemic effects, inhalation) = 2489x1/12.5= 199 mg/m3

 

Worker Long term DNEL (inhalation, systemic)

  • Step 1: Selection of the relevant dose descriptor:

-NOAEL (Maternal systemic toxicity) =1 mg/kg/day,

-The lowest NOAEL was recorded in the prenatal developmental study in rats (according to OECD 414) performed with the compound AZDN. In this study, the LOAEL was equal to 5 mg/kg/day based on transient effects of reduced body weight gain and reduced mean food intake while no effects were observed on foetal development.

 

·        Step 2: Modification of the starting point:

-Conversion into an inhalatory rat NOAEC by dividing by 0.38 m3/kg (8-hour respiratory volume in the rat).

-No correction for inhalatory and oral absorption rates (considered to be 100 %)

-Correction for activity driven differences in respiratory volume in workers compared to individuals at rest (6.7 m3/10 m3) .

-Corrected dose descriptor:NOAEC (worker, 8 h)= 1 x 1/0.38 x 6.7/10 =1.76 mg/m3

  • Step 3: Assessment factors:

-Interspecies : no allometric scaling factor is applied because an oral-to-inhalation route extrapolation is performed. However, a factor of2.5to correct for differences other than differences in metabolic rate is applied.

-Intraspecies : the default assessment factor of5is applied.

-Differences in exposure duration: none (as it is a prenatal developmental study)

-Dose-response relationship: a factor of1is applied due to the use of a NOAEL as dose descriptor and the low toxicity of the test substance.

-Quality of whole database: a factor of1is applied based on the good quality of the whole database.

-Global assessment factor: 2.5 x 5 x 1 x 1 x 1 =12.5

  • Step 4: DNEL derivation:

 Worker DNEL (long term, systemic effects, inhalation)= 1.76 x 1/12.5 =0.14 mg/m3

 

2. Worker Long term DNEL (Dermal, systemic)

Occupational exposure to AZDN may also occur by dermal exposure. Although no dermal repeated dose toxicity studies are available, a dermal abosption study on human skin is available. We derived a dermal DNEL based on the Oral NOAEL selected for the derivation of the inhalation DNEL.

 

Step 1) Relevant dose-descriptor

The NOAEL was selected based on the rat prenatal developmental study in rats (OECD 414).

-NOAEL, rats =(maternal toxicity) =1 mg/kg/day

Step 2) Modification of starting point:

Correction for oral to dermal absorption:

A dermal penetration study is available: The mean penetrated amount is 0.0103%of applied dose on human skin.No difference in dermal absorption is expected between rats and humans, no correction factor will be applied.

      • Corrected dermal NOAEL, route    = oral NOAEL x (ABSoral-rat/ABSderm-rat) x (ABSderm-rat/ ABSderm-human)
      • = oral NOAEL x (ABSoral-rat/ABSderm-human)

NOAEL corrected = 1 x (100 / 0.0103) = 9708.73 mg/kg bw

Step 3) Assessment factors

- Interspecies: 2.5 x 4

- Intraspecies : 5

- Exposure duration:none

- Dose response:1

- Quality of database:1

Global assessment factor = 50

DNEL Value (long term, systemic effects, dermal)= 9708.73 / 50 =194.17 mg/kg bw.

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.07 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
Modified dose descriptor starting point:
NOAEC
Value:
1.76 mg/m³
Explanation for the modification of the dose descriptor starting point:
Corrected dose descriptor 1x1/0.38x6.7/10=1.76 mg/m3
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
Justification:
A factor of 1 is used as the key study is a rat developmental study
AF for interspecies differences (allometric scaling):
1
Justification:
AF not used for inhalation because it is an oral to inhalation route.
AF for other interspecies differences:
2.5
Justification:
as recommanded by ECHA guidance
AF for intraspecies differences:
10
Justification:
A factor of 10 is used ofr 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:
99.56 mg/m³
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
LOAEC
Value:
1 570 mg/m³
Explanation for the modification of the dose descriptor starting point:
Time extrapolation to the reference period of 15 minutes for acute effects, using the modified Haber's law (Cnx t = k) with ancoefficient of 3 for extrapolation from a longer to a shorter exposure duration : LOAEL (15 minutes) = 2489 mg/m3
AF for dose response relationship:
1
AF for interspecies differences (allometric scaling):
2.5
AF for other interspecies differences:
1
AF for intraspecies differences:
10
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
97.08 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Value:
1 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
A dermal penetration study is available. The mean penetrated amount is 0.0103% of human skin.
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
Justification:
based on a rat developmental study.
AF for interspecies differences (allometric scaling):
4
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
Justification:
10 is used 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:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
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:
0.01 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Value:
1 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
The rat developmental suty was performed by oral route, no extrapolation is needed.
AF for dose response relationship:
1
Justification:
This factor is applied because the dose-descriptor starting point is a NOAEC.
AF for differences in duration of exposure:
1
Justification:
No uncertainty factor because the study is a rat prenatal developmental study
AF for interspecies differences (allometric scaling):
4
Justification:
A factor of 4 is applied for the rat species
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 is applied for uncertainties
AF for intraspecies differences:
10
Justification:
A factor of 10 is applied for the general population
AF for the quality of the whole database:
1
Justification:
The studies performed with AZDN are reliable studies
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

General population Acute DNEL (inhalation, systemic)

The acute inhalation rat toxicity study using AZDN (Dupont., 1984, report unavailable (awaiting for Dupont), questionable validity(quoted K3), described in the SIDS 2002) was used for DNEL derivation. In this study, three concentrations were tested: 1.57, 3.40, and 7.78 mg/L during one hour exposure. Only one death was recorded 1 day after exposure to 1.57 mg/L. No other death was observed at any dose-level. Most rats exhibited moderate to severe weight losses 1 or 2 days after exposure, followed by a return to a normal weight gain rate. Most females exhibited sporadic weight losses during the 2-week observation period.

 

Step 1: Selection of the relevant dose descriptor:

LOAEC (1 hour) = 1.57 mg/L=1570 mg/m3

 

Step 2: Modification of the starting point:

Time extrapolation to the reference period of 15 minutes for acute effects, using the modified Haber's law (Cnx t = k) with ancoefficient of 3 for extrapolation from a longer to a shorter exposure duration :

LOAEL (15 minutes) = 2489 mg/m3

 

Step 3: Assessment factors:

- Interspecies differences: as massive exposure by inhalation is considered, no toxicokinetic assessment factor is applied. However, a factor of 2.5 to correct for differences other than differences in metabolic rate is applied.

- Intraspecies differences: the default assessment factor of 10 is applied.

- Severity: no additional safety factor taking into account the very low severity of effects

- Quality of whole database: a factor of 1 is applied based on the good quality of the whole database.

- Global assessment factor: 2.5 x 10 x 1 = 25

 

Step 4: DNEL derivation:

Worker DNEL (acute, systemic effects, inhalation) = 2489x1/25= 99.56 mg/m3

General population Long term DNEL (Dermal, systemic)

Occupational exposure to AZDN may also occur by dermal exposure. Although no dermal repeated dose toxicity studies are available, a dermal absorption study on human skin is available. We derived a dermal DNEL based on the Oral NOAEL selected for the derivation of the inhalation DNEL.

 

Step 1) Relevant dose-descriptor

The lowest NOAEL was selected based on the rat prenatal developmental study in rats (OECD 414).

-NOAEL, rats =(maternal toxicity) =1 mg/kg/day

Step 2) Modification of starting point:

Correction for oral to dermal absorption:

A dermal penetration study is available: The mean penetrated amount is 0.0103%of applied dose on human skin.

      • Corrected dermal NOAEL, route    = oral NOAEL x (ABSoral-rat/ABSderm-rat) x (ABSderm-rat/ ABSderm-human)
      • = oral NOAEL x (ABSoral-rat/ABSderm-human)

NOAEL corrected = 1 x (100 / 0.0103) = 9708.73 mg/kg bw

Step 3) Assessment factors

- Interspecies: 2.5 x 4

- Intraspecies : 10

- Exposure duration:none

- Dose response:1

- Quality of database:1

Global assessment factor = 100

DNEL Value (long term, systemic effects, dermal)= 9708.73 / 100 =97.08 mg/kg bw.