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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
12.5
Modified dose descriptor starting point:
NOAEC

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
21 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEL

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available

Workers - Hazard for the eyes

Additional information - workers

DNEL – short-term, Worker

The calculations for the long term DNELs for workers are based on a 90-day oral feeding study performed in Fischer 344 rats. The NOAEL in this study was found to be 15 mg/kg bw/d (acid equivalents). This value was used as basis for DNEL calculation.

The molecular weight of sodium 2,4-D is only 10% higher than that of 2,4-D acid. Thus, no MW correction is applied to the point of departure. 

Route-to-route extrapolation (oral to inhalative) was performed according to the ECHA Guidance Document R.8. Test animals were exposed on 7 days a week. For workers, the expected exposure is only 5 days a week. Therefore, a factor of 7/5 was introduced for workers due to the expsure pattern (working time of 5 days a week).

 

Starting point (worker, inhalative) = oral NOAEL × 1/sRVrat× sRVhuman/wRV × 7/5 = 15 mg/kg bw/d ÷ 0.38 m³/kg bw/d × 6.7m³/10m³ × 7/5 = 37 mg/m³

 

Based on human data for 2,4-D acid, 2% dermal absorption is expected (see Section 7.1.2 for details). Therefore a factor of 0.02 for the difference in absorption was introduced for extrapolation from oral to dermal route.

 

Corrected starting point (worker, dermal) = oral NOAEL × 7/5 ÷ 0.02 = 15 mg/kg bw/d ÷ 0.02 × 7/5 =1050 mg/kg bw/d

  

For the calculation of the DNEL, the following safety factors were applied on the corrected starting points:

Dermal DNEL: allometric scaling factor 4; remaining differences 2.5; intraspecies factor 5; exposure duration factor 1; dose-response factor 1; quality of the database 1 =50

Inhalation DNEL: remaining differences 2.5; intraspecies factor 5; exposure duration factor 1; dose-response factor 1; quality of the database 1 =12.5

 

Taken together, the resulting short-term DNELs for workers are

dermal DNEL =1050 mg/kg bw/d ÷ 50 = 21 mg/kg bw/d

inhalation DNEL = 37 mg/m³ ÷ 12.5 =3.0 mg/m³

 

 

DNEL –long-term, Worker

The long-term DNELs for worker are based on the same subchronic NOAEL as the short-term DNELs. Therefore, an additional AF of 2 is applied to account for assessing chronic exposures with subchronic study data. Thus, the long-term DNELs are half as high as the short-term DNELs.

 

The resulting long-term DNELs for workers are

dermal DNEL = 1050 mg/kg bw/d ÷ 100 = 10.5 mg/kg bw/d

inhalation DNEL = 37 mg/m³ ÷ 25 = 1.5 mg/m³

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.26 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
LOAEC
Acute/short term exposure
Hazard assessment conclusion:
DMEL (Derived Minimum Effect Level)
Value:
0.52 mg/m³
DNEL related information
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5.3 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
200
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10.5 mg/kg bw/day
DNEL related information
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.05 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
100
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.15 mg/kg bw/day
DNEL related information
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL

General Population - Hazard for the eyes

Additional information - General Population

DNEL – short-term, General Population

According to the ECHA guidance document R.8 (characterization of dose[concentration]-response for human health), a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified and there is a potential for high peak exposures. This DNEL can be based on repeated dose data if the lethality data is considered to involve too large uncertainties.

The calculations for the short- term DNELs for the general population are therefore also based on a 90-day oral feeding study performed in Fischer 344 rats. The NOAEL in this study was found to be 15 mg/kg bw/d (acid equivalents). This value was used as basis for DNELcalculation.

The molecular weight of sodium 2,4-D is only 10% higher than that of 2,4-D acid. Thus, no MW correction is applied to the point of departure.[VM1] 

Route to route extrapolation (oral to inhalative) was performed according to the ECHA Guidance Document R.8.

The calculation of the corrected starting points for the general population (gen pop) is as follows:

 

Corrected starting point (gen pop[VM2] , inhalative) = oral NOAEL × 1/sRVrat=

15 mg/kg bw/d ÷ 1.15 m3/kg bw/d =13 mg/m3/d

 

Based on human data for 2,4-D acid, 2% dermal absorption is expected (see Section 7.1.2 for details). Therefore a factor of 0.02 for the difference in absorption was introduced for extrapolation from oral to dermal route.[VM3] 

 

Corrected starting point (gen pop, dermal) = oral NOAEL /0.02 =1050 mg/kg bw/d

 

For the calculation of the short-term DNEL, the following safety factors were applied on the corrected starting points:

In deviation to the situation of the workers, the assessment factor for intraspecies variability was set to 10 to account for more variability in the general population.

 

Dermal DNEL: allometric scaling factor 4; remaining differences 2.5; intraspecies factor 10; exposure duration factor 1; dose-response factor 1; quality of the database 1 =100

 

Inhalation DNEL: remaining differences 2.5; intraspecies factor 10; exposure duration factor 1; dose-response factor 1; quality of the database 1 =25

 

Oral DNEL: allometric scaling factor 4; remaining differences 2.5; intraspecies factor 10; exposure duration factor 1; dose-response factor 1; quality of the database 1 =100

 

 Taken together, the resulting short-term DNELs for the general population are

dermal DNEL =1050 mg/kg bw/d ÷ 100 = 10.5 mg/kg bw/d

inhalation DNEL = 13 mg/m³ ÷ 25 = 0.52 mg/m³

oral DNEL = 15 mg/kg bw/day ÷ 100 = 0.15 mg/kg bw/d

 

 

 DNEL – long-term, General Population

For reasons of regulatory consistency, the ADI for the active substance 2,4-D (0.05 mg/kg bw/day) set by the European Commission under Directive 91/414/EEC is also adopted as oral long-term DNEL for the general population. The ADI is based on long-term feeding studies in rats and mice and an AF of 100

The dermal and inhalation long-term DNELs for the general population are based on the same subchronic NOAEL as the short-term DNELs. Therefore, an additional AF of 2 is applied to account for assessing chronic exposures with subchronic study data. Thus, the long-term DNELs are half as high as the short-term DNELs.

 

The resulting long-term DNELs for the general population are

dermal DNEL = 1050 mg/kg bw/d ÷ 200 = 5.3 mg/kg bw/d

inhalation DNEL = 13 mg/m³ ÷ 50 = 0.26 mg/m³

oral DNEL = ADI = 0.05 mg/kg bw/d