Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
43.75 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other:
Overall assessment factor (AF):
2
Modified dose descriptor starting point:
NOAEC
DNEL value:
87.5 mg/m³
Explanation for the modification of the dose descriptor starting point:
Body weight (worker) 70 kg; respiratory volume 10.00 m3/person (8 h, light activity), 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:
See section on exposure related to observations in humans for details, EFSA (2006)
AF for intraspecies differences:
2
Justification:
An uncertainty factor of 2 was used to account for vulunerable sub-groups, incl. children (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:
12.5 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):
2
Modified dose descriptor starting point:
NOAEL
DNEL value:
25 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
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:
See section on exposure related to observations in humans for details, EFSA (2006)
AF for intraspecies differences:
2
Justification:
An uncertainty factor of 2 was used to account for vulunerable sub-groups, incl. children (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:
high hazard (no threshold derived)

Additional information - workers

Derived DNELs are based on results obtained in human studies (see IUCLID section on exposure related to observations in humans for details). Nicotinamide does not produce the flushing response that has been used as the basis for the upper level for nicotinic acid. There has been only one reported case of hepatotoxicity in a patient receiving high-dose nicotinamide (however, nicotinamide has not been subject to extensive clinical trials [at 3 g per day or more] for use as a hypolipidaemic agent). No significant adverse effects have been reported in trials on the possible benefits of nicotinamide in patients with or at risk of diabetes, which have used doses up to the equivalent of 3 g per day, for periods up to 3 years. The NOAEL from these studies is approximately 25 mg/kg bw/day. This value represents the lowest reported dose in a number of recent trials of high quality, many of which used sensitive markers of hepatic function and glucose homeostasis, and included a range of age groups, with some subjects treated with up to 50 mg/kg bw/day. An uncertainty factor of 2 has been used to allow for the fact that adults may eliminate nicotinamide more slowly than the study groups, many of which were children, and that data for children would not reflect the full extent of intersubject variability that could occur in an older population. The upper level for nicotinamide is established at 12.5 mg/kg bw/day or approximately 900 mg/day for adults.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
21.88 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):
2
Modified dose descriptor starting point:
NOAEC
DNEL value:
43.75 mg/m³
Explanation for the modification of the dose descriptor starting point:
Body weight (general public) 70 kg, respiratory volume (24 h, basal activity), factor absportion oral/inhalation 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:
See section on exposure related to observations in humans for details, EFSA (2006)
AF for intraspecies differences:
2
Justification:
An uncertainty factor of 2 was used to account for vulunerable sub-groups, incl. children (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:
12.5 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):
2
Modified dose descriptor starting point:
NOAEL
DNEL value:
25 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
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:
See section on exposure related to observations in humans for details, EFSA (2006)
AF for intraspecies differences:
2
Justification:
An uncertainty factor of 2 was used to account for vulunerable sub-groups, incl. children (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:
12.5 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):
2
Modified dose descriptor starting point:
NOAEL
DNEL value:
25 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Not applicable
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:
2
Justification:
An uncertainty factor of 2 was used to account for vulunerable sub-groups, incl. children (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

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - General Population

Derived DNELs are based on results obtained in human studies (see IUCLID section on exposure related to observations in humans for details). Nicotinamide does not produce the flushing response that has been used as the basis for the upper level for nicotinic acid. There has been only one reported case of hepatotoxicity in a patient receiving high-dose nicotinamide (however, nicotinamide has not been subject to extensive clinical trials [at 3 g per day or more] for use as a hypolipidaemic agent). No significant adverse effects have been reported in trials on the possible benefits of nicotinamide in patients with or at risk of diabetes, which have used doses up to the equivalent of 3 g per day, for periods up to 3 years. The NOAEL from these studies is approximately 25 mg/kg bw/day. This value represents the lowest reported dose in a number of recent trials of high quality, many of which used sensitive markers of hepatic function and glucose homeostasis, and included a range of age groups, with some subjects treated with up to 50 mg/kg bw/day. An uncertainty factor of 2 has been used to allow for the fact that adults may eliminate nicotinamide more slowly than the study groups, many of which were children, and that data for children would not reflect the full extent of intersubject variability that could occur in an older population. The upper level for nicotinamide is established at 12.5 mg/kg bw/day or approximately 900 mg/day for adults.