Registration Dossier

Administrative data

Description of key information

The weight of evidence analysis considered all relevant, adequate and reliable animal and human studies (EFSA, 2006). The human tolerable upper intake level for nicotinic acid was determined to be 10 mg/day or 0.14 mg/kg bw/day at 70 kg per person.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: oral
Remarks:
other: Weight of evidence approach
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Justification for data waiving:
other:
Qualifier:
no guideline followed
Principles of method if other than guideline:
Assessment of all available, relevant, adequate and reliable animal and human data.
GLP compliance:
no
Dose descriptor:
NOAEL
Effect level:
0.14 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: The human tolerable upper intake level for nicotinic acid was determined to be 10 mg/day or 0.14 mg/kg bw/day at 70 kg per person (EFSA, 2006).
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
0.14 mg/kg bw/day
Study duration:
chronic
Species:
other: human
Quality of whole database:
High - Compiled by the European Scientific Committee on Food, Scientific Panel on Dietetic Products, Nutrition and Allergies.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The key subacute animal study was carried out according to EU Method B.7 and OECD 407 (Repeated dose toxicity – oral). The objectives of the study were to determine the palatability and oral toxicity of test item in the rat following administration for 28 days. There was no effect of oral administration of test item in the diet at a dose level of 50 mg/kg/day for 28 days. At 250 and 1000 mg/kg/day there was a slight reduction in body weight gain and a slight increase in relative kidney weight. There was, however, no histopathologic evidence of systemic toxicity. The results obtained in the key study were confirmed in a supporting study.

According to REACH Annex VIII column 1 and 2 experimental studies with dosing via the inhalation and dermal route were waived. Further, the sub-chronic toxicity study requirement according to REACH Annex IX section 8.6.2 was waived based on a weight of evidence approach. Repeated dose toxicity was previously reviewed by the European Commission Scientific Committee on Food, the EFSA Panel on Additives and Products or Substances used in Animal Feed, the US FDA and the UK Food Standards Agency Expert Group on Vitamins and Minerals. An OECD SIDS review concluded that Nicotinic acid is essential for human and animal health. Based on all available information repeated exposure to nicotinic acid does not present a hazard to human health.

In addition to the animal studies presented repeated dose toxicity was assessed in a weight of evidence approach. All relevant, adequate and reliable data was reviewed by the European Commission Scientific Committee on Food, the EFSA Panel on Additives and Products or Substances used in Animal Feed, the US FDA and the UK Food Standards Agency Expert Group on Vitamins and Minerals. An OECD SIDS review concluded that Nicotinamide is essential for human and animal health and that based on the available information, the substance does not present a hazard to human health.

The European Food Safety Authority set a tolerable upper intake level for nicotinic acid. 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 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 hypercholesterolemia (3 g/day) and which is associated with a high incidence of serious adverse reactions.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The weight of evidence analysis considered all relevant, adequate and reliable animal and human studies (EFSA, 2006). The human tolerable upper intake level for nicotinic acid was determined to be 10 mg/day or 0.14 mg/kg bw/day at 70 kg per person.

Justification for classification or non-classification

Based on the data available the substance is not classified and labeled according to Regulation 1272/2008/EEC (CLP) and Directive 67/548/EEC (DSD).