Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: According to EFSA Scientific Committee on Food - Scientific Panel on Dietetic Products, Nutrition and Allergies (2006) Tolerable Upper Intake Levels for Vitamins and Minerals, see section "exposure related to observations in humans" for details.
Overall assessment factor (AF):
3
Modified dose descriptor starting point:
other: The tolerable upper intake level for nicotinic acid of 10 mg/day is based on the available data indicating occasional flushing at 30 mg per day, using an uncertainty factor of 3 for intraspecies differences.
Value:
1.5 mg/m³
Explanation for the modification of the dose descriptor starting point:
Body weight (worker) 70 kg, respiratory volume (8 h, light activity) 10.00 m3/person, absorption oral/inhalation factor 0.5
AF for dose response relationship:
1
Justification:
See section on exposure related to observations in humans for details, EFSA (2006)
AF for differences in duration of exposure:
1
Justification:
See section on exposure related to observations in humans for details, EFSA (2006)
AF for interspecies differences (allometric scaling):
1
Justification:
See section on exposure related to observations in humans for details, EFSA (2006)
AF for other interspecies differences:
1
Justification:
The uncertainty factor of 3 allows for the fact that a slight effect was reported and only a small number of subjects was used, but takes into account the observed dose-response relationship.
AF for intraspecies differences:
3
Justification:
See section on exposure related to observations in humans for details, EFSA (2006)
AF for the quality of the whole database:
1
Justification:
See section on exposure related to observations in humans for details, EFSA (2006)
AF for remaining uncertainties:
1
Justification:
See section on exposure related to observations in humans for details, EFSA (2006)
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:
0.14 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: According to EFSA Scientific Committee on Food - Scientific Panel on Dietetic Products, Nutrition and Allergies (2006) Tolerable Upper Intake Levels for Vitamins and Minerals, see section "exposure related to observations in humans" for details.
Overall assessment factor (AF):
3
Modified dose descriptor starting point:
other: The tolerable upper intake level for nicotinic acid of 10 mg/day is based on the available data indicating occasional flushing at 30 mg per day, using an uncertainty factor of 3 for intraspecies differences.
Value:
0.43 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Body weight (worker) 70 kg, 100 % dermal absorption
AF for dose response relationship:
1
Justification:
See section on exposure related to observations in humans for details, EFSA (2006)
AF for differences in duration of exposure:
1
Justification:
See section on exposure related to observations in humans for details, EFSA (2006)
AF for interspecies differences (allometric scaling):
1
Justification:
See section on exposure related to observations in humans for details, EFSA (2006)
AF for other interspecies differences:
1
Justification:
The uncertainty factor of 3 allows for the fact that a slight effect was reported and only a small number of subjects was used, but takes into account the observed dose-response relationship.
AF for intraspecies differences:
3
Justification:
See section on exposure related to observations in humans for details, EFSA (2006)
AF for the quality of the whole database:
1
Justification:
See section on exposure related to observations in humans for details, EFSA (2006)
AF for remaining uncertainties:
1
Justification:
See section on exposure related to observations in humans for details, EFSA (2006)
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:
medium hazard (no threshold derived)

Additional information - workers

Derived DNELs are based on results obtained in human studies (see IUCLID section "exposure related to observations in humans" for details). The limiting adverse effect at lower doses is flushing, and this has been reported at much lower intakes than other possible adverse effects. The most severe and potentially life-threatening adverse effects, such as hepatotoxicity, occur at doses one order of magnitude higher than have been reported for flushing. The dose of free nicotinic acid reported to produce flushing consistently in clinical studies is 50 mg/day (Sebrell and Butler, 1938; Spies et al., 1938). The available data indicate that flushing would be unlikely to occur repeatedly in subjects given less than 50 mg/day, but occasional flushing was reported by Sebrell and Butler (1938) at a dose of 30 mg of nicotinic acid daily. A tolerable upper intake level for nicotinic acid of 10 mg/day is based on the available data indicating occasional flushing at 30 mg per day, using an uncertainty factor of 3 to allow for the fact that a slight effect was reported, and that the study was performed in a small number of subjects, but taking into account the steep dose-response relationship. This upper level is 300-fold below the dose frequently used clinically for the treatment of hypercholesterolaemia (3000 mg/day) and which is associated with a high incidence of serious adverse reactions.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.25 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: According to EFSA Scientific Committee on Food - Scientific Panel on Dietetic Products, Nutrition and Allergies (2006) Tolerable Upper Intake Levels for Vitamins and Minerals, see section "exposure related to observations in humans" for details.
Overall assessment factor (AF):
3
Modified dose descriptor starting point:
other: The tolerable upper intake level for nicotinic acid of 10 mg/day is based on the available data indicating occasional flushing at 30 mg per day, using an uncertainty factor of 3 for intraspecies differences.
Value:
0.75 mg/m³
Explanation for the modification of the dose descriptor starting point:
Body weight (general public) 70 kg, respiratory volume (24 h, basal activity) 20.00 m3/person, absorption oral/inhalation factor 0.5
AF for dose response relationship:
1
Justification:
See section on exposure related to observations in humans for details, EFSA (2006)
AF for differences in duration of exposure:
1
Justification:
See section on exposure related to observations in humans for details, EFSA (2006)
AF for interspecies differences (allometric scaling):
1
Justification:
See section on exposure related to observations in humans for details, EFSA (2006)
AF for other interspecies differences:
1
Justification:
The uncertainty factor of 3 allows for the fact that a slight effect was reported and only a small number of subjects was used, but takes into account the observed dose-response relationship.
AF for intraspecies differences:
3
Justification:
See section on exposure related to observations in humans for details, EFSA (2006)
AF for the quality of the whole database:
1
Justification:
See section on exposure related to observations in humans for details, EFSA (2006)
AF for remaining uncertainties:
1
Justification:
See section on exposure related to observations in humans for details, EFSA (2006)
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

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.14 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: According to EFSA Scientific Committee on Food - Scientific Panel on Dietetic Products, Nutrition and Allergies (2006) Tolerable Upper Intake Levels for Vitamins and Minerals, see section "exposure related to observations in humans" for details.
Overall assessment factor (AF):
3
Modified dose descriptor starting point:
other: The tolerable upper intake level for nicotinic acid of 10 mg/day is based on the available data indicating occasional flushing at 30 mg per day, using an uncertainty factor of 3 for intraspecies differences.
Value:
0.43 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Body weight (general public) 70 kg, 100 % dermal absorption
AF for dose response relationship:
1
Justification:
See section on exposure related to observations in humans for details, EFSA (2006)
AF for differences in duration of exposure:
1
Justification:
See section on exposure related to observations in humans for details, EFSA (2006)
AF for interspecies differences (allometric scaling):
1
Justification:
See section on exposure related to observations in humans for details, EFSA (2006)
AF for other interspecies differences:
1
Justification:
The uncertainty factor of 3 allows for the fact that a slight effect was reported and only a small number of subjects was used, but takes into account the observed dose-response relationship.
AF for intraspecies differences:
3
Justification:
See section on exposure related to observations in humans for details, EFSA (2006)
AF for the quality of the whole database:
1
Justification:
See section on exposure related to observations in humans for details, EFSA (2006)
AF for remaining uncertainties:
1
Justification:
See section on exposure related to observations in humans for details, EFSA (2006)
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:
0.14 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: According to EFSA Scientific Committee on Food - Scientific Panel on Dietetic Products, Nutrition and Allergies (2006) Tolerable Upper Intake Levels for Vitamins and Minerals, see section "exposure related to observations in humans" for details.
Overall assessment factor (AF):
3
Modified dose descriptor starting point:
other: The tolerable upper intake level for nicotinic acid of 10 mg/day is based on the available data indicating occasional flushing at 30 mg per day, using an uncertainty factor of 3 for intraspecies differences.
Value:
0.43 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Body weight (general public) 70 kg
AF for dose response relationship:
1
Justification:
See section on exposure related to observations in humans for details, EFSA (2006)
AF for differences in duration of exposure:
1
Justification:
See section on exposure related to observations in humans for details, EFSA (2006)
AF for interspecies differences (allometric scaling):
1
Justification:
See section on exposure related to observations in humans for details, EFSA (2006)
AF for other interspecies differences:
1
Justification:
See section on exposure related to observations in humans for details, EFSA (2006)
AF for intraspecies differences:
3
Justification:
The uncertainty factor of 3 allows for the fact that a slight effect was reported and only a small number of subjects was used, but takes into account the observed dose-response relationship.
AF for the quality of the whole database:
1
Justification:
See section on exposure related to observations in humans for details, EFSA (2006)
AF for remaining uncertainties:
1
Justification:
See section on exposure related to observations in humans for details, EFSA (2006)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

Derived DNELs are based on results obtained in human studies (see IUCLID section "exposure related to observations in humans" for details). The limiting adverse effect at lower doses is flushing, and this has been reported at much lower intakes than other possible adverse effects. The most severe and potentially life-threatening adverse effects, such as hepatotoxicity, occur at doses one order of magnitude higher than have been reported for flushing. The dose of free nicotinic acid reported to produce flushing consistently in clinical studies is 50 mg/day (Sebrell and Butler, 1938; Spies et al., 1938). The available data indicate that flushing would be unlikely to occur repeatedly in subjects given less than 50 mg/day, but occasional flushing was reported by Sebrell and Butler (1938) at a dose of 30 mg of nicotinic acid daily. A tolerable upper intake level for nicotinic acid of 10 mg/day is based on the available data indicating occasional flushing at 30 mg per day, using an uncertainty factor of 3 to allow for the fact that a slight effect was reported, and that the study was performed in a small number of subjects, but taking into account the steep dose-response relationship. This upper level is 300-fold below the dose frequently used clinically for the treatment of hypercholesterolaemia (3000 mg/day) and which is associated with a high incidence of serious adverse reactions.