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Carcinogenicity

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Description of key information

Carcinogenicity: Carcinogenic (based on the presence of safrole in cinnamon leaf oil in a typical concentration of 1.2%)

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records
Reference
Endpoint:
carcinogenicity
Type of information:
other: Opinion of the Scientific Committee on Food (EC)
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The Scientific Committee produces scientific opinions and advice for risk managers, to provide a sound foundation for European policies and legislation and to support risk managers in taking effective and timely decisions
Conclusions:
According to the Scientific Committee of Food, safrole has been demonstrated to be genotoxic and carcinogenic. As the existence of a threshold can not be assumed, the Committee could not establish a safe exposure limit.
Executive summary:

The substance safrole is present in food as a natural constituent of a number of spices such as nutmeg, mace, cinnamon, anise, black pepper and sweet basil. Nutmeg, mace and their essential oils are the most important dietary sources. The consumer intake was estimated to amount to 0.3 mg/day and the 97.5th percentile to 0.5 mg/day. In a previous evaluation by the Council of Europe, 1995, a rough figure for estimating the intake of safrole was assumed to be 1 mg/person/day from food and spices and 1 mg/person/day from essential oils.

 

Safrole was shown to produce liver tumours in mice and rats after oral administration. Furthermore, liver and lung tumours were observed following subcutaneous injection of safrole in male infant mice. Concerning the carcinogenic potency of safrole, the SCF concludes that this appears to be relatively low and dependent on the metabolism. It appears that mice are more susceptible than rats to the carcinogenic effect of safrole. After metabolic activation of safrole, intermediates are formed that are able to directly react with DNA. In various in vitro mammalian cell systems safrole caused induction of gene mutations, chromosomal aberrations, UDS and SCE. Furthermore, several metabolites of safrole were observed to be directly mutagenic in Salmonella. Chromosome aberrations, SCE and DNA adducts were also observed in the liver of rats after in vivo exposure to safrole.

 

Based on the available information, the Scientific Committee on Food concluded that safrole has been demonstrated to be genotoxic and carcinogenic. The committee could not establish a safe exposure limit, as the existence of a threshold cannot be assumed.

Justification for classification or non-classification

Based on the presence of safrole in cinnamon leaf oil in a typical concentration of 1.2%, cinnamon leaf oil is classified as carcinogenic in accordance with the classification criteria in Annex I of the CLP Regulation (1272/2008/EC)

Additional information

Cinnamon leaf oil contains the constituent safrole, which is considered to be a carcinogen category 2B (the agent is possibly carcinogenic to humans; the exposure circumstance entails exposures that are possibly carcinogenic to humans) by the International Agency for the Research on Cancer (IARC) from the World Health Organisation (WHO) (IARC Monograph Volume 10). Under the European Dangerous Substance Directive, safrole is considered to be a carcinogen category 2 (substance which should be regarded as if they are carcinogenic to humans). According to Regulation 1272/2008/EC (CLP), safrole is considered to be a carcinogen category 1B (may cause cancer).

 

As natural constituent of a number of spices, the Scientific Committee on Food prepared an opinion on the safety of the presence of safrole in food constituent (SCF, 2001). An estimated average intake (for consumers only) is calculated to be 0.3 mg/day and the 97.5th percentile to 0.5 mg/day, based on food intake assessments by UK and France, and assuming a concentration of 0.5 mg safrol/kg food in general, and 2 mg safrol/kg for food containing cinnamon. In a previous evaluation (Council of Europe, 1995), in which a rough figure for estimating the intake of safrole was assumed to be 1 mg/person/day from food and spices and 1 mg/person/day from essential oils.

Furthermore, in Council Directive 88/388/EEC, maximum limits are set for safrole (and isosafrole) obtained from flavourings and other food ingredients with flavouring properties present in foodstuffs as consumed in which flavourings have been used. Safrole (and isosafrole) are not allowed to be added as such to foodstuffs or to flavourings. However, when it is present either naturally or following the additions of flavourings prepared from natural raw materials, maximum limits are 1 mg/kg in foodstuffs and beverages (with exceptions for alcoholic beverages: <25% volume of alcohol 2 mg/kg, >25% volume of alcohol 5 mg/kg, and for foodstuffs containing mace and nutmeg 15 mg/kg).

 

As part of cosmetic products, the International Fragrance Association (IFRA) has issued a standard for the restriction of safrole, isosafrole and dihydrosafrole concentrations in consumer products, based on the conclusions of the Scientific Committee on Cosmetology of the EEC on safrole and on the similarity of the biological activity of these substances (Scientific Committee of Cosmetology of the EEC, opinion reached on September 2, 1980; Communication to the EEC Commission ENV/521/79 and IARC Monograph Vol. 10, 1976, 231-244).

The IFRA standard prohibits the use of safrole as such as a fragrance ingredient. Essential oils containing safrole should not be used at a level such that the total concentration of safrole exceeds 0.01% in consumer products. Furthermore, the total concentration of safrole, isosafrole and dihydrosafrole should not exceed 0.01% in consumer products.

 

As it is not practicable to prohibit the use of safrole-containing fragrances/spices, the amounts of safrole should be kept as low as possible. When the above standards are followed, it is believed that the risk of safrole as a natural constituent in cinnamon leaf oil is kept as low as practicably possible.

 

In cinnamon leaf oil the typical concentration of safrole is 1.2 %, while the maximum concentration of cinnamon leaf oil in consumer products is 5%. This allows the conclusion that the IFRA standard can be maintained for the use of cinnamon leaf oil in consumer products.

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