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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.66 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):
75
Dose descriptor starting point:
NOAEL
Value:
20 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
49.3 mg/m³
Explanation for the modification of the dose descriptor starting point:

For workers inhalation NOAEC is corrected as follows:

NOAECcorr=NOAELoral*(1/0.38 m3 /kg/d)*(ABSoral-rat/ABSinhhuman)*(6.7 m3 (8h)/10 m3 (8h)) *(7 days/5 days) = 20*2.63*1*0.67*1.4 = 49.3 mg/m3

The NOAEL for the OECD 422 (Dunster et al, 2012) used in the DNEL calculation is 20 mg/kg bw/d.

Correction factor for differences in bioavailability (ABS), inhalation vs. oral absorption:

Correction factor for differences in respiratory volume (SRV): 2.63 (1/0.38 m3/kg)

Correction factor for light activity at work (WORKER): 0.67 (6.7 m3/10 m3) for 8h exposure time

Correction for differences between human and experimental exposure conditions (EXPCOND): 1.4 (7 days/5 days)

 

Only 2.6% of the inhalable particles are less than 100 µm and therefore possible uptake of this substance is by oral route following transport of deposited inhaled particles to pharynx and ingestion afterwards. Consequently, the default factor two for the extrapolation of an oral NOAEL to inhalation NOAEC could therefore be omitted in this case.

AF for dose response relationship:
1
Justification:
not required, starting point is NOAEL
AF for differences in duration of exposure:
6
Justification:
extrapolation from sub-acute to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
not for concentrations
AF for other interspecies differences:
2.5
Justification:
default factor for remaining differences
AF for intraspecies differences:
5
Justification:
for worker
AF for the quality of the whole database:
1
Justification:
not required
AF for remaining uncertainties:
1
Justification:
not required
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:
0.07 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
Dose descriptor starting point:
NOAEL
Value:
20 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
20 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

8 h exposure time, no dermal study available.

The NOAEL for the OECD 422 (Dunster et al, 2012) used in the DNEL calculation is 20 mg/kg bw/d.

AF for dose response relationship:
1
Justification:
not required, starting point is NOAEL
AF for differences in duration of exposure:
6
Justification:
extrapolation from sub-acute to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
rat to human
AF for other interspecies differences:
2.5
Justification:
default factor for remaining differences
AF for intraspecies differences:
5
Justification:
for worker
AF for the quality of the whole database:
1
Justification:
not required
AF for remaining uncertainties:
1
Justification:
not required
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

The key study for DNEL derivation was identified as the recent OECD 422 study (Dunster, 2012) where an NOAEL of 20 mg/kg/day was derived based on effects observed at 100 mg/kg/day. The critical effects retained at 100 mg/kg/day were a decreased in red blood cell parameters associated with an extramedullary hematopoiesis of the spleen.

The reason for selecting this study is that the design includes both the OECD 407 and OECD 421 guidelines requirements and the exposure duration included an additional 2 weeks exposure duration when compared to a standard 4 weeks toxicity study. The target organs reported in that study were comparable to the available 28 days study performed by Hatano in 2001. The reliability assessment of this latter study was quite difficult as no full report was available.

No DNELs for acute and local effects were derived because 2 -ethylanthraquinone is not classified for acute dermal toxicity, acute oral toxicity or local irritation. Indeed, no local effects could be observed in repeated dose toxicity studies and therefore no respective DNELs have been derived. The DNELs for chronic systemic toxicity for the inhalation and dermal route were derived via route-to-route extrapolation based on a repeated dose oral toxicity study (Dunster/Watson, 2012).

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.12 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):
150
Dose descriptor starting point:
NOAEL
Value:
20 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
17.4 mg/m³
Explanation for the modification of the dose descriptor starting point:

For general population inhalation NOAEC (24 h exposure/d):

NOAECcorr=NOAELoral*( (1/1.15 m3 /kg/d)*(ABSoral-rat/ABSinhhuman) mg/m3= 20*0.87 = 17.4 mg/m3

The NOAEL for the OECD 422 (Dunster et al, 2012) used in the DNEL calculation is 20 mg/kg bw/d.

Correction factor for differences in bioavailability (ABS), inhalation vs. oral absorption:

Correction factor for differences in respiratory volume (SRV): 0.87 (1/1.15 m3/kg)

Correction for differences between human and experimental exposure conditions (EXPCOND): 1 (7 days/7 days)

 

Only 2.6% of the inhalable particles are less than 100 µm and therefore possible uptake of this substance is by oral route following transport of deposited inhaled particles to pharynx and ingestion afterwards. Consequently, the default factor two for the extrapolation of an oral NOAEL to inhalation NOAEC could therefore be omitted in this case.

AF for dose response relationship:
1
Justification:
not required, starting point is NOAEL
AF for differences in duration of exposure:
6
Justification:
extrapolation from sub-acute to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
not required for concentration
AF for other interspecies differences:
2.5
Justification:
default factor for remaining differences
AF for intraspecies differences:
10
Justification:
general population
AF for the quality of the whole database:
1
Justification:
not required
AF for remaining uncertainties:
1
Justification:
not required
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
Most sensitive endpoint:
acute toxicity
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.03 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:
NOAEL
Value:
20 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

24 h exposure time, no dermal study available

AF for dose response relationship:
1
Justification:
not required, starting point is NOAEL
AF for differences in duration of exposure:
6
Justification:
extrapolation from sub-acute to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
extrapolation rat to human
AF for other interspecies differences:
2.5
Justification:
remaining differences
AF for intraspecies differences:
10
Justification:
general population
AF for the quality of the whole database:
1
Justification:
not required
AF for remaining uncertainties:
1
Justification:
not required
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:
0.03 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
Dose descriptor starting point:
NOAEL
Value:
20 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

There is no route to route extrapolation performed. The NOAEL for the OECD 422 (Dunster et al, 2012) used in the DNEL calculation is 20 mg/kg bw/d.

AF for dose response relationship:
1
Justification:
not required, starting point is NOAEL
AF for differences in duration of exposure:
6
Justification:
extrapolation from sub-acute to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
extrapolation rat to human
AF for other interspecies differences:
2.5
Justification:
remaining differences
AF for intraspecies differences:
10
Justification:
general population
AF for the quality of the whole database:
1
Justification:
not required
AF for remaining uncertainties:
1
Justification:
not required
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

Three studies were deemed possibly relevant for the calculation of inhalation, dermal and oral systemic DNELs: a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (Dunster et al, 2012), a 28 days toxicity study (Hatano, 2001) and an embryo-fetal development study (Stannard, 2017). The NOAEL for the OECD 422 was 20 mg/kg bw/d based on based on a decreased in red blood cell parameters associated with an extramedullary hematopoiesis of the spleen observed at 100 mg/kg/day. The NOAEL for the 28 day toxicity study was 10 mg/kg bw /d also based on a decreased in red blood cell parameters at 50mg/kg bw/day. The NOAEL for the OECD 414 was 15 mg/kg bw/d based on lower maternal bodyweight gain at 50 mg/kg bw/d.

It was decided not to include the 28 day study (Hatano, 2001) in the calculation of the DNELs as the design of the OECD 422 includes 2 additional weeks exposure duration when compared to a standard 4 weeks toxicity study and the target organs reported in that study were comparable to the ones in the available 28 days study performed by Hatano in 2001. Moreover the reliability of this latter study was quite difficult to assess as no full report was available.

The lowest DNEL for general population which was derived from the OECD 422 study (Dunster et al, 2012) was calculated as shown below:


 

OECD 422

 

AF for dose response relationship 

1

AF for difference in duration of exposure

6 

AF for interspecies differences (allometric scaling)

1

AF for other interspecies differences

2.5

AF for intraspecies differences

5

AF for the quality of the whole database

1

AF for remaining uncertainties

1

Overall AF

75

DNEL

0.66

No DNELs for acute and local effects were derived because 2 -ethylanthraquinone is not classified for acute dermal toxicity, acute oral toxicity or local irritation. Indeed, no local effects could be observed in repeated dose toxicity studies and therefore no respective DNELs have been derived. The DNELs for chronic systemic toxicity for the inhalation and dermal route were derived via route-to-route extrapolation based on a repeated dose oral toxicity study (Dunster et al, 2012).

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