Scientific Opinion on the safety of chromium picolinate as a source of chromium added for nutritional purposes to foodstuff for particular nutritional uses and to foods intended for the general population

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Article
Panel on Food Additives and Nutrient Sources Added to Food
EFSA Journal
EFSA Journal 2010;8(12):1883 [49 pp.].
doi
10.2903/j.efsa.2010.1883
Panel members at the time of adoption
F. Aguilar, B. Dusemund, P. Galtier, J. Gilbert, D.M. Gott, S. Grilli, R. Gürtler, J. König, C. Lambré, J-C. Larsen, J-C. Leblanc, A. Mortensen, D. Parent-Massin, I. Pratt, I.M.C.M. Rietjens, I. Stankovic, P. Tobback, T. Verguieva, R.A. Woutersen
Acknowledgements

The Panel wishes to thank the members of the ANS Working Group B on Food Additives and Nutrient Sources: M. Bakker, D. Boskou, B. Dusemund, D. Gott, T. Hallas-Møller, A. Hearty, J. König, D. Marzin, D. Parent-Massin, I.M.C.M. Rietjens, G.J.A. Speijers, P. Tobback, T. Verguieva, R.A. Woutersen for the preparatory work on this scientific opinion.

Contact
Type
Opinion of the Scientific Committee/Scientific Panel
On request from
European Commission
Question Number
EFSA-Q-2009-00763
Adopted
10 November 2010
Published
1 December 2010
Last Updated
13 December 2010. This version replaces the previous one/s.
Affiliation
European Food Safety Authority (EFSA), Parma, Italy
Note
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Abstract

Following a request from the European Commission, the Panel on Food Additives and Nutrient Sources added to Food provides a scientific opinion on the safety of chromium picolinate as a source of chromium added for nutritional purposes to foodstuff for particular nutritional uses (PARNUTS) and to foods intended for the general population, and on the bioavailability of chromium from this source. Chromium picolinate is obtained synthetically. The Panel noted that specifications for chromium(III) picolinate should ensure that levels of chromium(VI) which is a genotoxic carcinogen are as low as possible and at least are such that they result in an adequate margin of exposure. The Panel noted that results of the new genotoxicity studies suggest that in vitro at high concentrations chromium picolinate might cause DNA damage. From long-term carcinogenicity studies, it was concluded that there was equivocal evidence for the carcinogenic activity of chromium picolinate in male rats, and no evidence of carcinogenic activity of chromium picolinate in female rats, and female and male mice. The incidences of preputial gland adenomas were not dose related and did not occur consistently across species, and not across sexes. They are rather common in the rat strain used. Therefore the Panel concluded that a NOAEL could be established. The Panel noted that the margin of safety between the NOAEL of 2400 mg/kg bw/day chromium picolinate, resulting from the long-term study conducted by the NTP, equivalent to 2100 mg/kg bw picolinate/day would amount to at least four orders of magnitude assuming a combined intake of picolinate from all sources. The Panel concluded that the uses of chromium(III) picolinate as a source of chromium added for nutritional purposes to PARNUTS and foods intended for the general population (fortified foods and food supplements)would not be of concern provided that the amount of total chromium does not exceed 250 μg/day, the value established by the WHO for supplemental intake of chromium that should not be exceeded.

Summary

This scientific output published on 13 December 2010, replaces the earlier version published on 1 December 2010.

Following a request from the European Commission, the Panel on Food Additives and Nutrient Sources added to Food (ANS) provides a scientific opinion on the safety of chromium picolinate as a source of chromium added for nutritional purposes to foodstuff for particular nutritional uses (PARNUTS) and to foods intended for the general population, and on the bioavailability of chromium from this source.

Chromium picolinate is obtained synthetically, and specifications are proposed by the petitioner. High Performance Liquid Chromatography (HPLC) analysis has been used to confirm that the salt is manufactured to > 95% purity. The specifications include a restriction on the percentage of chromium(III) within the range of 12.18-12.68%. The absence of chromium(VI) is confirmed for potassium chromium sulphate which is the starting material used for the manufacture of chromium picolinate. The petitioner indicated that chromium(VI) should therefore, not be present in the final product as manufactured, and that it is not routinely tested for.

The Panel noted that specifications for chromium(III) picolinate should ensure that levels of chromium(VI) which is a genotoxic carcinogen are as low as possible and at least are such that they result in an adequate margin of exposure (EFSA, 2005).

The Panel noted that the bioavailability of inorganic chromium(III) from food sources and food supplements is generally very low (0.1-2%). The Panel concluded that chromium bioavailability from chromium picolinate is low and that chromium from chromium picolinate is equally or slightly more bioavailable than chromium from other chromium compounds.

In a previous opinion the Panel noted that recent reviews and evaluations of chromium(III) point at conflicting outcomes of genotoxicity assays and report diverging views and conclusions on the consequences of this genotoxicity issue for the ultimate safety assessment of chromium(III). In this previous opinion, the Panel indicated that given this situation, the safety of chromium(III) might need to be re-evaluated in light of these recent reviews and evaluations.

The present opinion provides an overview of the genotoxicity studies on chromium picolinate. While the results of in vitro assays using bacterial mutagenicity assays have been consistently negative, the results of in vitro chromosomal aberration studies using Chinese hamster ovary (CHO) cells are conflicting.

Due to the conflicting results of the in vitro studies, the Expert Group on Vitamins and Minerals (EVM) of the UK Food Standards Agency (FSA) noted in 2003 that unlike other trivalent chromium compounds, chromium picolinate may cause deoxyribonucleic acid damage. The FSA requested that the Committee on Mutagenicity of Chemicals in Food, Consumer Products and the Environment (COM), an advisory body to the FSA, reviews all of the available data pertaining to the mutagenicity of trivalent chromium, particularly chromium picolinate. The COM commissioned chromosomal aberration studies to examine the results reported by Stearns et al. due to irregularities in study designs and/or lack of information regarding the nature of the test material and impurities. The results from the new studies refuted the results. The COM concluded that the balance of data suggest that chromium picolinate should be regarded as not being mutagenic in vitro, that the available in vivo tests in mammals with chromium picolinate were negative and that in view of the negative in vitro results with commercial grade chromium picolinate, there is no further requirement for in vivo testing.

The evaluation of the Committee on Mutagenicity of Chemicals in Food, Consumer Products and the Environment of the UK (COM), who evaluated the genotoxicity of chromium picolinate in 2004, led to the overall conclusion that the balance of the data in the in vitro genotoxicity assays suggest that chromium picolinate, containing chromium(III), is negative with respect to genotoxicity.

These conclusions have been supported by the work conducted by the US National Toxicology Programme (NTP), in which further in vitro and in vivo assessment resulted in a confirmation of a lack of mutagenic potential for chromium picolinate monohydrate in the presence and absence of metabolic activation. The FSA subsequently revised its opinion on the consumption of chromium picolinate, and released a statement indicating “there is no need to avoid chromium picolinate”.

The Panel evaluated additional studies on the genotoxicity of chromium(III) compounds, which were not covered by the COM evaluation.

These studies covered new in vitro and in vivo genotoxicity studies. The Panel noted that although these new studies gave some equivocal results, two studies may be considered to be most essential. First of all this includes the study performed with chromium picolinate in bone marrow of Sprague-Dawley rats performed according to OECD guideline 475 at single oral doses up to 2000 mg/kg bw chromium(III) picolinate in which chromium(III) picolinate did not induce chromosomal aberrations in cells derived from male or female rats at any of the concentrations tested in comparison to the control. In addition these studies include the study reported by NTP reporting an in vivo micronucleus assay, in which male rats were given orally chromium(III) picolinate (anhydrous) at doses up to 2500 mg/kg bw, and mice were given orally chromium(III) picolinate monohydrate at doses up to about 50 000 mg/kg bw/day for 13 weeks. Chromium(III) picolinate (anhydrous) did not produce chromosomal damage as determined by the absence of micronuclei in the in vivo rat micronucleus assay. Chromium(III) picolinate monohydrate was negative in the male mice. The weak increases in the presence of micronuclei in female mice were considered equivocal findings as the anhydrous form did not show this effect at all.

The Panel concluded that in very large amounts, certain trivalent chromium compounds are cytotoxic and have been shown to cause chromosomal damage. The authors of the studies reporting these effects and others have suggested that the chromosomal toxicity of high-concentration trivalent chromium compounds may be due to pro-oxidant action that can be suppressed with antioxidants.

The Panel noted that results of the new genotoxicity studies suggest that in vitro at high concentrations chromium picolinate might cause DNA damage.

As all but one (Bailey et al., 2006) of these developmental/reproductive toxicity studies did not reveal any significant adverse effects, the Panel concluded that at present there are no indications that chromium picolinate (at dose levels up to 200 mg/kg bw/day chromium picolinate) causes developmental toxicity in mice.

Chromium picolinate monohydrate did not produce significant indications of toxicity in a 13-week study conducted by the NTP in rats and mice at dose levels up to 50 000 mg/kg diet (equal to 4240 mg/kg bw/day for male rats, 4250 mg/kg bw/day for female rats, 11 900 mg/kg bw/day for male mice and 9140 mg/kg bw/day for female mice). This indicates a No-Observed-Adverse-Effect Level (NOAEL), in male rats, of 4240 mg/kg bw/day chromium picolinate monohydrate. The carcinogenicity study conducted by the NTP in mice demonstrated that there were no adverse effects associated with the dietary administration of chromium picolinate monohydrate at levels as high as 50 000 mg/kg diet for a period of 2 years, which is equivalent to a NOAEL of 6565 mg chromium picolinate monohydrate/kg bw/day for male mice and 6100 mg/kg bw/day chromium picolinate monohydrate for female mice. The administration of 10 000 mg/kg diet chromium picolinate monohydrate in the diet of rats for 2 years induced a statistically significant increase in the incidence of preputial neoplasms as compared to control and historical data. Although this effect did not rise above historical levels in the high dose group for rats (50 000 mg/kg diet), the NTP considered this result equivocal evidence of carcinogenicity in male rats.

From these long-term carcinogenicity studies performed by the NTP, it was concluded that there was equivocal evidence of carcinogenic activity of chromium picolinate in male rats, and that there was no evidence of carcinogenic activity of chromium picolinate in female rats and female and male mice. The increase in preputial gland adenomas was only observed in male rats, and these tumors are rather common in the rat strain used. The incidences of these adenomas were not dose related and did not occur consistently across species, and not across sexes. Therefore the Panel concluded that this benign lesion is not related to treatment and that the NOAEL in the rat study was 2400 mg/kg bw/day chromium picolinate.

The petitioner proposes to use chromium picolinate as an alternative to existing forms of trivalent chromium in fortified foods intended for general consumption and in PARNUTS foods. The intake of chromium from chromium picolinate can be considered separately, from its proposed use in fortified foods, supplements and PARNUTs, and also through its potential intake from the combined uses including background intake from the diet.

The petitioner intends to use chromium picolinate in fortified foods for the general population at levels of up to 30% of the Recommended Daily Allowance (RDA) for chromium of 40 µg per serving (equivalent to 12 µg of chromium or approximately 97 µg of chromium picolinate per serving).

The Panel noted that chromium picolinate is typically consumed from food supplement products at levels of up to 600 µg/day chromium. The Panel noted that the intake of chromium picolinate from its use in food supplements at levels up to 600 μg/day chromium would amount to intakes of up to 5 mg chromium picolinate. This amount of chromium picolinate would amount to 83 μg/kg bw/day for a 60 kg person and be about 29 000-fold below the NOAEL of 2400 mg/kg bw/day chromium picolinate resulting from the long-term study conducted by the NTP. However, the Panel also noted that the amount of chromium of 600 μg/day exceeds the value of 250 μg/day, the value that the WHO considered that supplementation of chromium should not exceed.

Two scenarios of combined exposure to chromium were examined. The first scenario related to chromium exposure from its supplemental intake only (i.e. from food supplements, fortified foods and PARNUTS) and for this typical exposure was found to be 0.912 mg/day (0.015 mg/kg bw/day), with an upper intake of 1.54 mg/day (0.026 mg/kg bw/day). The second scenario related to scenario 1 plus the additional exposure from the intake from foods, and for this the typical intake ranged from 0.97-1.07 mg/day (0.016-0.018 mg/kg bw/day), with an upper intake of 2.12 mg /day (0.035 mg/kg bw/day).

The Panel noted that an intake of 1.54 mg/day from food supplements, fortified foods and PARNUTS would be 2.7 to 25 times higher than what could be present in the diet.

In the opinion judging the safety of chromium(III) as a nutrient added for nutritional purposes to foodstuffs for particular nutritional uses and foods intended for the general population (including food supplements)the Panel noted that a Tolerable Upper limit for chromium is not available. The Panel also noted that both the limit of 1 mg chromium/day proposed by the SCF and of 250 μg chromium/day for supplementation proposed by WHO are based on studies that were not designed to test the safety of chromium. The Panel also noted that an intake of 250 μg chromium/day from supplementation would be in the range of intake of chromium from the regular diet. Therefore, the Panel concluded that until more is known about chromium, the value set by WHO seems most adequate to limit the intake of chromium from foods for particular nutritional uses and foods intended for the general population (including food supplements).

Two separate scenarios of exposure to picolinate were examined. The first scenario related to picolinate exposure from both its use in fortified foods and in supplements, and for this the average intake was 5.3 mg/day (0.09 mg/kg bw/day), while intake at the high level was 7.1 mg/day (0.01 mg/kg bw/day). The second scenario related to scenario 1 plus the additional exposure from the proposed use of chromium in PARNUTS, and for this the average intake was 7.5 mg/day (0.1 mg/kg bw/day), with a high intake of 13.7 mg/day (0.2 mg/kg bw/day).

The Panel noted that the margin of safety between the NOAEL of 2400 mg/kg bw/day chromium picolinate, resulting from the long-term study conducted by the NTP, equivalent to 2100 mg/kg bw picolinate/day would amount to at least 4 orders of magnitude assuming a combined intake of picolinate from all sources amounting to about 7.5 (0.1 mg picolinate/kg bw/day) with a high intake of 13.7 mg/day (0.2 mg picolinate/day). Based on this large margin of safety the Panel concluded that the uses of chromium(III) picolinate as a source of chromium in PARNUTS and foods intended for the general population (fortified foods and food supplements)would not be of concern provided that the amount of total chromium does not exceed 250 μg/day, the value the value established by the WHO for supplemental intake of chromium that should not be exceeded.

Keywords
Food supplements, chromium picolinate, CAS Registry Number 14639-25-9
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Number of Pages
49