Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
20 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: ECETOC
Overall assessment factor (AF):
6
Dose descriptor starting point:
NOAEC
DNEL value:
235 mg/m³
Modified dose descriptor starting point:
NOAEC
DNEL value:
118.1 mg/m³
Explanation for the modification of the dose descriptor starting point:

The NOEC of 94 ppm (235 mg/m3) was taken from a sub-chronic inhalation study. Time Adjustment for 6 hr/day exposure = (6 h/d)/(8 h/d) Adjustment for respiration rate (8 hr) = (6.7 m3)/(10 m3). 

The modified dose descriptor starting point = (235 mg/m3)(6/8)(6.7/10) = 118.1 mg/m3.

AF for dose response relationship:
1
AF for differences in duration of exposure:
2
AF for interspecies differences (allometric scaling):
1
AF for other interspecies differences:
1
AF for intraspecies differences:
3
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:
39 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: ECETOC
Overall assessment factor (AF):
3
Dose descriptor starting point:
NOAEC
DNEL value:
235 mg/m³
Modified dose descriptor starting point:
NOAEC
DNEL value:
118.1 mg/m³
Explanation for the modification of the dose descriptor starting point:

The NOEC of 94 ppm (235 mg/m3) was taken from a sub-chronic inhalation study. Time Adjustment for 6 hr/day exposure = (6 h/d)/(8 h/d) Adjustment for respiration rate (8 hr) = (6.7 m3)/(10 m3). 

The modified dose descriptor starting point = (235 mg/m3)(6/8)(6.7/10) = 118.1 mg/m3.

AF for dose response relationship:
1
AF for interspecies differences (allometric scaling):
1
AF for other interspecies differences:
1
AF for intraspecies differences:
3
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
39 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
other:
Overall assessment factor (AF):
6
Dose descriptor:
NOAEC
DNEL value:
235.7 mg/m³
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
AF for interspecies differences (allometric scaling):
1
AF for other interspecies differences:
1
AF for intraspecies differences:
3
AF for remaining uncertainties:
11
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
79 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
3
Dose descriptor starting point:
NOAEC
DNEL value:
235.7 mg/m³
AF for dose response relationship:
1
AF for interspecies differences (allometric scaling):
1
AF for intraspecies differences:
3
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
417 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
72
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2 500 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
12
Modified dose descriptor starting point:
NOAEL

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

Worker DNELs for Nitromethane

The major use of 1-nitromethane is as a chemical intermediate for the manufacture of other chemicals. The sales of nitromethane is as a fuel additive, a solvent for polymers in coatings and as an extraction solvent has been terminated in early 2015.  

 

Inhalation DNELs

The predominant route of occupational exposure for nitromethane is inhalation. The DNELs were derived using ECETOC guidance document entitled, “Guidance on Assessment Factors to Derive DNELs” Final draft, March 17th, 2010.

1.      Inhalation DNEL: Long-term exposure, systemic effects.

 

The NOEC of 94 ppm (235 mg/m3) was taken from a sub-chronic inhalation study in rats to derive an inhalation DNEL/worker, long-term, systemic.

 

Time Adjustment for 6 hr/day exposure = (6 h/d)/(8 h/d)

Adjustment for respiration rate (8 hr) = (6.7 m3)/(10 m3)  

Allometric Scaling factor (rat) = 1 (not applicable when setting an inhalation DNEL from an inhalation animal study)

Remaining Differences = 1

Sub-chronic to chronic = 2

Intraspecies variation for the worker population = 3

 

Inhalation DNEL worker, long-term, systemic = (235 mg/m3)(6/8)(6.7/10)(1/2)(1/3) =20 mg/m3

2.      Inhalation DNEL: Acute/short-term worker exposure, systemic effects

 

The NOEC of 94 ppm (235 mg/m3) was taken from a sub-chronic inhalation study in rats to derive an inhalation DNEL/worker, short-term, systemic.

 

Time Adjustment for 6 hr/8 hr day exposure = (6 h/d)/(8 h/d)

Adjustment for respiration rate = 6.7 m3/10m3

Allometric Scaling factor (rat) = 1 (not applicable when setting an inhalation DNEL from an inhalation animal study)

Remaining Differences = 1

Sub-chronic to aqcute = N/A

Intraspecies variation for the worker population = 3

 

Inhalation DNEL/worker, short-term, systemic = (235 mg/m3)(6/8)(6.7/10)(1/3) =39 mg/m3

3.      Inhalation DNEL: Long-term exposure, local effects:

 

The NOEC of 188 ppm (469 mg/m3) was taken from a sub-acute inhalation study.

 

Time adjustment for 6 hr/day exposure = (6 hr/day)/(8h/day). Adjustment for respiration rate (8 hr) = (6.7 m3)/(10 m3)

Allometric Scaling factor (rat) = 1 (not appropriate for local effects)

Remaining Differences = 1

Sub-chronic to chronic = 2

Intraspecies variation for the worker population = 3

 

Inhalation DNEL worker = (469 mg/m3)(6/8)(6.7/10)(1/2)(1/3) =39 mg/m3

4.      Inhalation DNEL: Acute/short-term worker exposure, local effects

 

The NOEC of 188 ppm (469 mg/m3) was taken from a sub-chronic inhalation study in rats.

 

Time adjustment for 6 hr/day exposure = (6 hr/day)/(8h/day)

Adjustment for respiration rate (8 hr) = (6.7 m3)/(10 m3) 

Allometric Scaling factor (rat) = 1 (not appropriate for local effects)

Remaining Differences = 1 

Sub-chronic to acute = N/A

Intraspecies variation for the worker population = 3

 

Inhalation DNEL worker = (469 mg/m3)(6/8)(6.7/10)(1/3) =79 mg/m3

  

Dermal DNELs

Dermal DNELs for acute short-term local effects and long-term exposure local effects were not derived for nitromethane. No dermal studies examining the systemic toxicity of nitromethane were found. Instead a route-to-route extrapolation is used from a repeat dose oral study using 1-nitro-propane as a surrogate for read across. No classification or labelling is required for skin and eye irritation or dermal toxicity since it is not irritating to the skin and the dermal LD50 is greater than 2000. Pharmacokinetic studies in monkeys indicate that 1-nitropropane is poorly absorbed from the skin (< 0.1% in 72 hrs). Also, nitromethane is not readily absorbed through the skin and volatilizes quickly from the skin's surface. Therefore, no acute dermal DNELs for local effects are necessary for this compound.

1.      Dermal DNEL: Long-term worker exposure, systemic effects.

 

A NOAEL from an oral 28-day study in rats exposed to 1-nitropropanewas used as a surrogate for read across to nitromethane to derive a dermal DNEL chronic /long-term exposure systemic effects.

 

Dose Modification:

Percutaneous absorption from non-human primate = 0.1%

Therefore: 30 mg/kg/day ÷.001 = 30’000 mg/kg/day

Assessment factors:

Allometric scaling from rat to human = 4

Remaining Difference = 1

Intraspecies adjustment factor for worker population = 3

Exposure Duration (From sub-acute study to chronic) = 6

 

Worker dermal DNEL Long-term exposure, systemic effects = 30’000 mg/kg/day/4*3*6 =417 mg/kg/day

2.      Dermal DNEL: Acute/Short-term worker exposure, systemic effects

 A NOAEL from an oral 28-day study in rats exposed to 1-nitropropane was used as a surrogate for read-across to nitromethane to derive a dermal DNEL acute/short term exposure systemic effects.

 

Dose Modification:

Percutaneous absorption from non-human primate = 0.1%

Therefore: 30 mg/kg/day ÷ 0.001 = 30’000 mg/kg/day

 

Assessment factors:

Allometric scaling from rat to human = 4

Remaining Difference = 1

Intraspecies adjustment factor for worker population = 3

Exposure Duration (Subacute study) = N/A

 

Worker dermal DNEL Acute/Short-term exposure, systemic effects = 30’000 mg/kg/day/4*3 =2’500 mg/kg/day

  

 

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
12 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
5
Modified dose descriptor starting point:
NOAEC

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
10
Dose descriptor:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
23 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
5
Dose descriptor starting point:
NOAEC

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
250 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
120
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 500 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEL

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:
no hazard identified
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 DNELs for Nitromethane

 

The predominant route of occupational exposure for nitromethane is inhalation. Products containing nitromethane are not widely used by consumers.

 

Dermal DNELs:

 

Dermal DNELs for acute short-term local effects and long-term exposure local effects were not derived for nitromethane. No dermal studies examining the systemic toxicity of nitromethane were found. Instead a route-to-route extrapolation is used from a repeat dose oral study using 1-nitropropane as a surrogate for read across. No classification or labeling is required for skin and eye irritation or dermal toxicity since it is not irritating to the skin and the dermal LD50 is greater than

 2000. Pharmacokinetic studies in monkeys indicate that 1-nitropropane is poorly absorbed from the skin (< 0.1% in 72 hrs). Also,nitromethanevolatilizes quickly from the skin's surface. Therefore, no acute dermal DNELs for local effects are necessary for this compound.

Oral DNELs:

Oral DNELs for the acute short/term and long-term systemic effects were not derived for nitromethane. Nitromethane is not sold in any consumer products that would result in exposure vian the oral route.

 

The following DNELs were derived using ECETOX guidance document entitled, “Guidance on Assessment Factors to Derive DNELs” Final draft. March 17th2010.

 

General Population DNELs

 

Dermal DNEL: Acute/Short-Term general population exposure systemic effects

 

A NOAEL from an oral 28 day study in rats exposed to 1-nitropropane was used as a surrogate for read across to nitromethane to derive adermal DNEL acute/short term exposure systemic effects.

 

Dose Modification:

Percutaneous absorption from non-human primate = 0.1%

 

Therefore: 30 mg/kg/day ÷ 0.001 = 30000 mg/kg/day

 

Assessment factors:

Allometric scaling from rat to human = 4

Remaining Difference = 1

Intraspecies adjustment factor for the general population = 5

Exposure Duration (Subacute study) = N/A

 

 General Population dermal DNEL Acute/Short-Term Exposure Systemic Effects = 30000 mg/kg/day/4*5 =1500 mg/kg/day

 

 

Inhalation DNEL: Acute/Short-term general population exposure systemic effects

 

The NOEC of 94 ppm (235 mg/m3) was taken from a sub-chronic inhalation study to derive an inhalation DNEL/general population.

 

Time Adjustment for 6 hr/8 hr day exposure = (6 h/d)/(24 h/d)

 

Allometric Scaling factor (rat) = 1 (Not applicable when setting an inhalation DNEL from an inhalation animal study)

Remaining Differences = 1

Subchronic to Acute = N/A

Intraspecies variation for the general population = 5

Inhalation DNEL/general population = (235 mg/m3)(6/24)(1/5) =12 mg/m3

 

Inhalation DNEL: Acute/short-term general population exposures: local effects

 

The NOEC of 188 ppm (469 mg/m3) was taken from a sub-chronic inhalation study

Time adjustment for 6 hr/day exposure = (6 hr/day)/(24 h/day)

Allometric Scaling factor (rat) = 1 (not appropriate for local effects)

Remaining Differences = 1 

Subchronic to Acute = N/A

Intraspecies variation for the general population = 5

Inhalation DNEL general population= (469 mg/m3)(6/24)(1/5) =23 mg/m3

 

Dermal DNEL: Long Term general population exposures: systemic Effects.

 

A NOAEL from an oral 28 day study in rats exposed to 1-nitropropanewas usedas a surrogate for read across to nitromethane to derive a dermal DNEL chronic /long-term exposure systemic effects.

 

Dose Modification:

Percutaneous absorption from non-human primate = 0.1%

 

Therefore: 30 mg/kg/day ÷.001 = 30000 mg/kg/day

 

Assessment factors:

Allometric scaling from rat to human = 4

Remaining Difference = 1

Intraspecies adjustment factor for general population = 5

Exposure Duration (From Subacute study to Chronic) = 6

 

General population dermal DNEL Acute/Short-Term Exposure Systemic Effects = 30000 mg/kg/day/4*5*6 =250 mg/kg/day

 

Inhalation DNEL: Long-term exposure systemic effects.

 

The NOEC of 94 ppm (235 mg/m3) was taken from a sub-chronic inhalation study.

Time Adjustment for 6 hr/day exposure = (6 h/d)/(24 h/d)

Adjustment from 5 days/week to 7 days/week = (5day/7 days) 

Allometric Scaling factor (rat) = 1 (not applicable when setting an inhalation DNEL from an inhalation animal study)

Remaining Differences = 1

Subchronic to chronic = 2

Intraspecies variation for the general population = 5

inhalation DNEL general population= (235 mg/m3)(6/24)(5/7)(1/2)(1/5) =4 mg/m3

 

Inhalation DNEL: Long-term Exposure local effects:

 

The NOEC of 188 ppm (469 mg/m3) was taken from a sub-chronic inhalation study

Time adjustment for 6 hr/day exposure = (6 hr/day)/(24 h/day)

Adjustment from 5 days/week to 7 days/week = (5 day/7 days)

Allometric Scaling factor (rat) = 1 (not appropriate for local effects)

Remaining Differences = 1

Subchronic to Chronic = 2

Intraspecies variation for the general population = 5

Inhalation DNEL general population = (469 mg/m3)(6/24)(5/7)(1/2)(1/5) =8 mg/m3