Regulatory Toxicology and Pharmacology 73 (2015) 196e200

Contents lists available at ScienceDirect

Regulatory Toxicology and Pharmacology

journal homepage: www.elsevier.com/locate/yrtph

Raspberry ketone in food supplements e High intake, few toxicity

data e A cause for safety concern?
Lea Bredsdorff*, Eva Bay Wedebye, Nikolai Georgiev Nikolov, Torben Hallas-Mller,
Kirsten Pilegaard
Technical University of Denmark, National Food Institute, Mrkhj Bygade 19, DK-2860 Sborg, Denmark

a r t i c l e i n f o

a b s t r a c t

Article history:
Received 7 October 2014
Received in revised form
29 June 2015
Accepted 30 June 2015
Available online 6 July 2015

Raspberry ketone (4-(4-hydroxyphenyl)-2-butanone) is marketed on the Internet as a food supplement.

The recommended intake is between 100 and 1400 mg per day. The substance is naturally occurring in
raspberries (up to 4.3 mg/kg) and is used as a avouring substance. Toxicological studies on raspberry
ketone are limited to acute and subchronic studies in rats. When the lowest recommended daily dose of
raspberry ketone (100 mg) as a food supplement is consumed, it is 56 times the established threshold of
toxicological concern (TTC) of 1800 mg/day for Class 1 substances. The margin of safety (MOS) based on a
NOAEL of 280 mg/kg bw/day for lower weight gain in rats is 165 at 100 mg and 12 at 1400 mg. The
recommended doses are a concern taking into account the TTC and MOS. Investigations of raspberry
ketone in quantitative structure-activity relationship (QSAR) models indicated potential cardiotoxic effects and potential effects on reproduction/development. Taking into account the high intake via supplements, the compound's toxic potential should be claried with further experimental studies. In UK
the pure compound is regarded as novel food requiring authorisation prior to marketing but raspberry
ketone is not withdrawn from Internet sites from this country.
2015 Elsevier Inc. All rights reserved.

Keywords:
Raspberry ketone
4-(4-hydroxyphenyl)-2-butanone
Food supplement
Weight loss
Threshold of toxicological concern
Margin of safety
Toxicity
Flavouring
Novel food
Natural

1. Introduction
Raspberry ketone (4-(4-hydroxyphenyl)-2-butanone) is the key
avour of raspberries and has for a long time been widely used by
the food industry as avouring substance and for other purposes in
perfumery and cosmetics. In the last few years, raspberry ketone
has been sold as an ingredient in food supplements where it has
been claimed to have a slimming effect. Raspberry ketone is not
authorized for fortications in food supplements in Denmark and is
regarded as novel food in UK. However, food supplements containing raspberry ketone are marketed on Internet sites intended
for UK or Danish consumers. Raspberry ketone is marketed as
natural, which is often misinterpreted as inherently safe. Currently
the recommended doses for raspberry ketone sold as food supplement on the Internet range from 100 to 1400 mg/day while the

* Corresponding author.
E-mail addresses: leab@food.dtu.dk (L. Bredsdorff), ebawe@food.dtu.dk
(E.B. Wedebye), nign@food.dtu.dk (N.G. Nikolov), tohal@food.dtu.dk (T. HallasMller), kpil@food.dtu.dk (K. Pilegaard).
http://dx.doi.org/10.1016/j.yrtph.2015.06.022
0273-2300/ 2015 Elsevier Inc. All rights reserved.

exposure from natural sources only account for a few mg per day. In
this article we take a closer look at the safety of such doses of
raspberry ketone by reviewing the available toxicity data and
previous evaluations made by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and the European Food Safety
Authority (EFSA). In addition we present a tentative investigation of
raspberry ketone with QSAR (quantitative structureeactivity relationship) models to identify potential hazards based on its chemical
structure.
2. Chemical identity
Raspberry ketone is an aromatic phenolic compound with the
chemical name 4-(4-hydroxyphenyl)-2-butanone and CAS Registry
Number 5471-51-2. Synonyms include: Frambinone; Oxaphenylon;
4-(p-Hydroxyphenyl)-2-butanone; Rheosmin and p-Hydroxybenzyl acetone (SciFinder, 2014). The molecular formula of raspberry ketone is C10H12O2 and the molecular weight is 164.2 g/mol.
Raspberry ketone is relatively insoluble in water and only moderately soluble in ethanol i.e. the water solubility of raspberry ketone
is estimated to be 13.5 g/l (25
C) and the log octanol-water

L. Bredsdorff et al. / Regulatory Toxicology and Pharmacology 73 (2015) 196e200

partition coefcient (Kow) to be 1.48 using EPIWEB 4.1 WSKOW

software (version 1.42). The chemical structure of raspberry ketone
is shown in Fig. 1.
3. Occurrence and manufacturing
Raspberry ketone is the primary aroma compound of the fruit of
raspberry (Rubus idaeus L.) where it is found in the highest concentration but is also found naturally in other berry fruits such as
cranberry, boysenberry, blackberry, sea buckthorn and loganberry
as well as in buckwheat honey according to the Volatile Compounds in Food (VCF) database (TNO, 2014). The content of raspberry ketone in raspberry ranges from 0.009 to 4.3 mg/kg (TNO,
2014).
Raspberry ketone is used as avouring substance in a variety of
processed foods such as soft drinks, puddings, yogurt, baked goods,
sweets and ice cream (Beekwilder et al., 2007; Crispim et al., 2010;
Gaunt et al., 1970).
Extraction of raspberry ketone from raspberries (or other fruits
naturally containing raspberry ketone) is expensive due to seasonal
limitations in addition to the limited concentrations of naturally
occurring raspberry ketone. Instead raspberry ketone can be synthesised chemically via the condensation of p-hydroxybenzaldehyde with acetone or biosynthesised in genetically
modied microorganisms such as bacteria or yeast (Beekwilder
et al., 2007; Serra et al., 2005).
4. Dietary exposure
The dietary exposure of raspberry ketone from fruits and avourings has been estimated to range between 1.8 and 3.8 mg/day
for an adult (Crispim et al., 2010; EFSA, 2011; JECFA, 2001). This
exposure is primarily due to the use of raspberry ketone as avouring substance (Crispim et al., 2010).
The daily doses of raspberry ketone recommended by food
supplement suppliers range from 100 to 1400 mg/day i.e. between
26 and 368 times higher than the highest estimated exposure from
diet.
Since the intake of raspberry ketone from the diet is so limited
compared to the intake from food supplements containing raspberry ketone, this additional exposure is negligible for food supplement users.
5. Metabolism of raspberry ketone
The metabolism of raspberry ketone has been investigated in
rats (n 13), guinea pigs (n 5) and rabbits (n 2) (Sporstl and
Scheline, 1982). Raspberry ketone was rapidly absorbed from the
gastrointestinal tract after administration of a single dosage of
1 mmol/kg (164 mg/kg bw) by oral gavage. The majority of ingested
raspberry ketone was excreted in urine within the rst 24 h as its
phase II conjugated metabolites (glucuronide and/or sulphate
conjugates). The amounts of phase II conjugates excreted in urine
were 59 3 (rats), 70 8 (guinea pigs) and 38 2% (rabbits) of the
dose. Not considering the phase II conjugates, a total of 14

O
CH3
HO
Fig. 1. Raspberry ketone.

197

metabolites were identied in urine. Except for the reduction

product, 4-(4-hydroxyphenyl)butan-2-ol, excreted in 10 1 (rats),
15 3 (guinea pigs) and 31 1% (rabbits) of the dose, the excretion
of the remaining metabolites were less than 10% of the dose. The
total urinary recovery was close to 90% for all three species. Only
trace amounts were excreted in faeces where raspberry ketone was
the only detectable metabolite (Sporstl and Scheline, 1982). To the
best of our knowledge no toxicological information on 4-(4hydroxyphenyl)butan-2-ol has been published.
6. Toxicological data on raspberry ketone
6.1. Toxicological studies
A review of the literature covering the bibliographic databases
SciFinder (encompassing the databases ChemAbs and PubMed) and
Scopus was performed to search for toxicological data on raspberry
ketone. SciFinder was searched for the CAS registry number for
raspberry ketone (5471-51-2) excluding patents, without any other
restrictions. This yielded a total of 397 references. Scopus was
searched for raspberry ketone without any restrictions and yielded a total of 126 references. In addition, grey literature was
searched for on Google, www.INCHEM.org and the homepage of
EFSA (http://www.efsa.europa.eu/). Only one study on the toxicity
of raspberry ketone in laboratory animals was identied in the
literature search (Gaunt et al., 1970). This study in addition to a few
other unpublished studies have previously been described in
evaluations of raspberry ketone as avouring substance by EFSA
and JECFA. A short description is presented here.
An oral LD50 (lethal dose, 50%) value of 1320 mg/kg bw for
raspberry ketone has been reported in both male and female rats
(Gaunt et al., 1970; unpublished study by Merkel 2003 cited from
JECFA, 2011).
Lower weight gain in male rats has been observed in two
separate 90-day studies (Gaunt et al., 1970; unpublished study by
Hoffman 2004 cited from JECFA, 2011). JECFA (2001) established a
No Observed Effect Level (NOEL) for raspberry ketone of 280 mg/kg
bw/day on the basis of a statistically signicant lower weight gain
in male rats in a 90-day feeding study, while EFSA (2011) allocated a
No Observed Adverse Effect Level (NOAEL) of 100 mg/kg bw/day
based on lower relative weights of liver and kidneys from the same
study (Gaunt et al., 1970). When JECFA used raspberry ketone as a
supporting substance (chemically related substance that is used to
ll in potential data gaps for the substance under evaluation) when
evaluating
1-(4-hydroxy-3-methoxyphenyl)-decan-3-one,
a
NOAEL for raspberry ketone of 70 mg/kg bw/day was established
based on a 90-day dietary toxicity study in rats (unpublished study
by Hoffman 2004 cited from JECFA, 2011). The NOAEL was based on
dose-related statistically signicant higher liver weights in the two
highest dose groups (275 and 700 mg/kg bw/day). Additionally,
higher serum enzyme activity levels (alanine aminotransferase and
aspartate aminotransferase) were observed in these dose groups.
The raspberry ketone stemmed from a commercial dietary supplement preparation and the intake level was calculated based on
12% of raspberry ketone in the dietary supplement. No information
on what constituted the remaining 88% of the test material was
provided, which raise doubt regarding whether the observed effects could have been caused by the remaining unspecied 88% of
the test material. This factor could be the explanation for the higher
liver weights observed in this study compared to the lower relative
liver weights found by Gaunt et al. (1970) after dosing with the pure
compound (purity 96%). No genotoxicity studies with raspberry
ketone were identied in the literature search. Raspberry ketone
does not contain structural alerts for genotoxicity (Benigni and
Bossa, 2006).

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No chronic/carcinogenic, reproductive or developmental studies

with raspberry ketone were identied in the literature search.
A small number of studies with raspberry ketone have been
performed in obese rats or mice concomitantly fed a fatty diet with
the objective to show and explain an anti-obese action of raspberry
ketone (Ikemoto et al., 2008; Lili et al., 2011; Morimoto et al., 2005;
Wang et al., 2012). Due to the study designs these studies cannot be
included in the toxicological data or used as evidence of no adverse
effects. It is, however, not uncommon to nd papers where weight
reduction seen in laboratory animals, after oral administration of a
test substance, is interpreted as a slimming or anti-obesity effect
and the tested compound is therefore considered useful for weight
reduction. Nonetheless, in toxicological studies a signicant weight
reduction is not considered an innocuous effect. Body weight is a
useful indicator of the overall health of an animal and is in addition
to changes in relative organ weight an essential part of the risk
assessment of e.g. drugs, chemicals and food additives. As stated by
the International Programme on Chemical Safety (IPCS); Reductions
in body weight or decrements in body weight gain are sensitive indicators of toxicity (IPCS, 2009). Effects on body weight are nonspecic and can be the result of many unrelated factors.
Decreased body weight or decreased body weight gain observed
after repeated exposure can be a direct consequence of exposure to
the toxicant or simply a secondary effect of a specic toxicological
effect where the ability of the organism's resources to adapt are
depleted or exhausted.
6.2. Toxicity based on structureeactivity relationship
The concept of structureeactivity relationship is that molecules
with common structural features are thought to elicit similar biological activities. A hydroxyl group on a free benzene ring present in
many compounds including raspberry ketone has been associated
with estrogenicity. Raspberry ketone has therefore been investigated for endocrine disrupting activity in a few in vitro and in silico
studies.
6.2.1. In vitro studies
Raspberry ketone showed weak estrogenic activity in a recombinant yeast assay and in MVLN cells (human breast cancer cells)
corresponding to approximately 30,000,000 less estrogenic activity
compared to that of 17-b-estradiol (positive control) (Gallegos
Saliner et al., 2003; Schultz et al., 2002; Ying et al., 2014). Ogawa
et al. (2010) reported that raspberry ketone had androgen receptor (AR) antagonist activity with an IC50 value of 252 mM in a MDAkb2 human breast cancer cell line. The high concentration, at which
the AR antagonist activity was observed, shows that raspberry
ketone is a very weak AR antagonist if at all. In addition, the
physiological relevance of such high concentrations is questionable.

reproductive effects and sperm effects), Human Adverse Hepatobiliary Effects Suite (5 models), and Human Adverse Cardiological Effects Suite (13 models). Raspberry ketone was within the
structural applicability domain of all 54 models. Indications of
possible positive effects were seen in 5 models (positive prediction
probability above 0.6), of which 2 were overlapping models related
to reproductive toxicity, 2 were related to developmental toxicity,
and 1 was related to cardiotoxicity. For all ve models the closest
structural analogues with positive experimental data had Tanimoto
distances above 0.6. Forty-six of the predictions were negative
(positive prediction probability below 0.4) and 3 were indeterminate (positive prediction probability between 0.4 and 0.6). In regard
to genotoxicity negative predictions were found in the following
Toxtree decision tree models: In vitro mutagenicity (Ames test)
), Structure Alerts for the
alerts by ISS (Istituto Superiore di Sanita
in vivo micronucleus assay in rodents, and Carcinogenicity (genotox
and non-genotox) and mutagenicity rulebase by ISS (Toxtree,
Estimation of Toxic Hazard e A Decision Tree Approach, Version
2.6.6, http://toxtree.sourceforge.net). Furthermore, raspberry ketone was predicted by a number of models for in vitro and in vivo
genotoxicity made in the Leadscope Predictive Data Miner software, a component of Leadscope Enterprise version 3.1.1-10 with
the following results: Negative predictions in models for in vitro
genotoxicity endpoints: Bacterial Reverse Mutation Test (Ames
test) in Salmonella typhimurium, mutations in the hypoxanthineguanine phosphoribosol transferase locus in Chinese Hamster
Ovary cells, Unscheduled DNA Synthesis in Rat hepatocytes and
Syrian Hamster Embryo Cell Transformation. Furthermore, negative predictions in models for in vivo genotoxicity endpoints;
Dominant lethal mutations in rodents, Sex-linked recessive lethal
test in Drosophila melanogaster, Sister chromatid exchange in
mouse bone marrow, Mouse erythrocyte micronucleus test, and
Comet assay in mouse. Although all models for genotoxicity of
raspberry ketone gave negative predictions, it is the opinion of the
authors that raspberry ketone cannot be considered non-genotoxic
before this has been investigated in vitro (e.g. in the bacterial
mutagenicity (Ames) test and the mammalian chromosome aberration test) taking into account the high exposure levels concerned.
In conclusion results from QSAR models are mostly negative and
only points towards potential hazards, however, considering the
available data it cannot be excluded that raspberry ketone has
potential adverse effects on reproduction or development or is
cardiotoxic. Considering the limited in vivo toxicity studies performed with raspberry ketone and the high amounts of raspberry
ketone recommended by food supplement vendors further testing
of these endpoints should be performed to clarify if a risk is present.
7. Toxicological evaluation of raspberry ketone
7.1. Existing evaluations

6.2.2. In silico studies

In a study by Roncaglioni et al. (2008) no endocrine disrupting
effects of raspberry ketone mediated through the estrogen receptor
were identied by use of QSAR models.
In light of the limited toxicological information on raspberry
ketone we performed an in silico proling of raspberry ketone by
QSAR models. A QSAR screening was performed in the Leadscope
Model Applier Version 1.7.4 software (http://www.leadscope.com/
(accessed 29.09.14.)). A total of 54 commercial models from 4
suites developed in a collaboration with the U.S. Food and Drug
Administration were run: Developmental Toxicity Suite (27 models
for Rats, Mice, Rabbits and overall Rodents related to foetal growth
retardation, foetal weight decrease, foetal death, post-implantation
loss and pre-implantation loss), Reproductive Toxicity Suite (9
models for Rats, Mice and overall Rodents related to overall

No ADI (Acceptable Daily Intake) has been established for

raspberry ketone. Raspberry ketone has been evaluated as a avouring substance on its own and as a supporting substance by
both EFSA (2008, 2011) and JECFA (2001, 2011). The evaluation of
avouring substances by both JECFA and EFSA is based on a stepwise approach that integrates information on intake from current
uses, structure-activity relationships, metabolism and, when
needed, toxicity. One of the key elements in this approach is the
subdivision of avourings into three structural classes (I, II or III)
using the decision tree presented by Cramer et al. (1978). A
threshold of toxicological concern (TTC) (human exposure thresholds) has been specied for each structural class and estimated
exposure levels lower than the TTC are considered to be of no safety
concern. Based on its chemical structure raspberry ketone was

L. Bredsdorff et al. / Regulatory Toxicology and Pharmacology 73 (2015) 196e200

classied into structural class I. The TTC for avourings classied in

structural class I is 1.8 mg/day for an individual weighing 60 kg
(Munro et al., 1996). As the estimated intake of raspberry ketone
from the diet was higher than 1.8 mg/day (estimated by EFSA to be
2.4 mg/day) the Margin of Safety (MOS) was calculated. The MOS is
the reference dose (e.g. NOAEL) divided by the actual exposure of a
chemical substance. The MOS was 2500 for raspberry ketone used
as a avouring substance based on a NOAEL of 100 mg/kg bw/day
for a person weighing 60 kg. EFSA concluded that raspberry ketone
would present no safety concern at the estimated level of intakes.
JECFA reached the same conclusion based on a NOAEL of 280 mg/kg
bw/day and an estimated intake of 3.8 mg/day.
7.2. Margin of safety for recommended doses of raspberry ketone as
food supplements
A MOS of at least 100, accounting for uncertainty factors for
extrapolating between individuals and species, is normally
considered to be sufcient to conclude that there would be no
safety concern at the estimated level of exposure (EFSA, 2012a).
However, this is only applicable when a full set of toxicological
studies are available but the only available toxicological studies on
raspberry ketone are acute and subchronic studies. To extrapolate
from subchronic to chronic study duration in rodents, an assessment factor of minimum 2 is applied and the MOS for raspberry
ketone will consequently be at least 200 (EFSA, 2012b; Nielsen
et al., 2008). The MOS for three exposure levels of raspberry ketone i.e. the highest estimated exposure from the diet (3.8 mg/day);
a low dose (100 mg/day) and a high dose (1400 mg/day) of food
supplements based on the three different NOAELs established by
JECFA and EFSA is presented in Table 1.
As seen in Table 1, all MOS values for supplement intake are
lower than 200 (ranging from 3 to 165) for the lowest as well as the
highest recommended doses of raspberry ketone in food supplements irrespective of which of the three NOAEL values established
by EFSA and JECFA that are used for these calculations. The limited
toxicological data available on raspberry ketone was sufcient
when it was evaluated for use as avouring substance in large part
because the estimated exposure from the diet was relatively low.
However, it is not enough for providing evidence for the safety of
the high doses recommended by vendors of food supplements.

199

toxicological studies necessary for getting a food or food ingredient

considered as novel food varies according to the specic novel food
and is a case by case decision.
In March 2014 raspberry ketone was classied as a Novel Food
by the Food Standards Agency in UK. It was stated that raspberry
ketones other than raspberry fruit extracts prepared using water or
20% ethanol (1:4 ethanol:water) are novel and should fall within
the scope of the EU legislation on novel foods. Additionally, the
conclusion was copied to UK enforcement bodies so that they could
take appropriate action when unauthorised novel foods are found
on
the
market
(http://www.food.gov.uk/science/novel/
unauthorised).
Whether raspberry ketone is generally regarded as novel food in
all EU member states is not clear. So far the substance is not listed in
the novel food catalogue that serves as a non-exhaustive orientation of whether a substance need authorisation under the Novel
Food Regulation (EC, 2014). Even though raspberry ketone apart
from some specied extracts is considered novel food in UK, a
Google search reveals that raspberry ketone is still marketed on the
Internet from UK suppliers. This illustrates the challenge for the
food authorities to ensure that food supplements containing
unauthorised or unsafe constituents are neither sold in physical
stores nor on the Internet where anyone, with access to the
Internet, can promote these supplements everywhere despite national or international regulations.
Advertising on the Internet uses wordings like 100% natural
and pure leading the consumer to believe that the substance is
derived from the fruit. The raspberry ketone in food supplements
are not extracted directly from raspberries as described in Section 3
and the recommended daily doses of raspberry ketone of 100 up to
1400 mg raspberry ketone for food supplements would be gained
by a daily intake of 23e326 kg fresh raspberries (using the highest
reported content of raspberry ketone in raspberries of 4.3 mg/kg). It
is thought-provoking that if raspberry ketone had been marketed
under its chemical name i.e. 4-(4-hydroxyphenyl)-2-butanone
instead of the innocuous sounding trivial name, raspberry ketone,
while additionally being described as naturally occurring in raspberries, it would hardly have gained much popularity as an ingredient in food supplements. The risk assessment of raspberry ketone
sold as food supplement should of course be the same irrespective
of whether it is extracted from natural sources, manufactured
chemically or biosynthesised by microorganisms.

8. Raspberry ketone as novel food?

9. Conclusion
Within EU a novel food is dened as a food or a food ingredient
that has not been used for human consumption to a signicant
degree in the EU before 15 May 1997. Before an ingredient falling
within the scope of the novel food regulation may be marketed, the
companies must send an application presenting the scientic information in a safety assessment report to the national food authority for authorisation with a copy to the EU Commission
(Regulation EC No. 258/97 of the European Parliament concerning
novel foods and novel food ingredients). The requirement for

The recommended daily doses of raspberry ketone, when sold

as food supplement, are between 100 and 1400 mg. Such high
intake levels have never been evaluated as safe for human consumption. They exceed by far the estimated level of dietary exposure used to evaluate raspberry ketone as a avouring substance
(3.8 mg/day) and both TTC and MOS values show that concern
cannot be excluded when raspberry ketone is consumed in these
high amounts. A hazard for potential cardiotoxicity and potential

Table 1
Margin of Safety (MOS) for raspberry ketone at three exposure levels (the maximum intake when used as a avouring substance, i.e. 3.8 mg/person/day, and the minimum and
maximum recommended levels for use in food supplements (100 or 1400 mg/person/day)) based on the three different NOAELs established by EFSA (100 mg/kg bw/day) and
JECFA (70 or 280 mg/kg bw/day). A MOS of at least 200 is usually considered to be sufcient to conclude that there would be no safety concern at the estimated level of
exposure.
Dose (mg/person/day)

Exposurea (mg/kg bw)

MOS (NOAEL 70 mg/kg bw/day)

MOS (NOAEL 100 mg/kg bw/day)

MOS (NOAEL 280 mg/kg bw/day)

3.8
100
1400

0.06
1.7
23

1167
41
3

1667
59
4

4667
165
12

For an individual weighing 60 kg.

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L. Bredsdorff et al. / Regulatory Toxicology and Pharmacology 73 (2015) 196e200

effects of raspberry ketone on reproduction and development was

identied in silico, however, the risk could not be estimated with
the currently available data. Whether the raspberry ketone used in
food supplements is of synthetic or natural origin does not affect its
risk assessment. The pure substance used in food supplements may
be regarded as novel food in EU and can therefore not be sold legally before authorisation.
Acknowledgements
The authors wish to thank senior academic ofcers Karin Kristiane Nrby and Vibe Beltoft for valuable insight into the evaluation
of avouring substances. The work was funded by the Technical
University of Denmark, National Food Institute, Mrkhj Bygade 19,
DK-2860 Sborg, Denmark.
Transparency document
Transparency document related to this article can be found
online at http://dx.doi.org/10.1016/j.yrtph.2015.06.022.
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