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Chromium in food and drinking water Table 13: Developmental and reproductive toxicity studies with Cr(III) compounds. Study (a) Doses in mg Cr(III)/kg b.w. per day NOAEL LOAEL (mg Cr(III)/kg b.w. per day) 1-generation reproductive toxicity Reference 1-generation reproductive oral (diet) Cr 2 O 3 in rats (90 days) F/M: 0; 547/570; 1217/1368 (b) 1217/1368 - Ivankovic and Preussman (1975) Fertility studies 12 weeks oral (drinking water) toxicity study CrCl 3 in rats M: 0, 30 (c) - 30 Bataineh et al. (1997) 12 weeks oral (drinking water) toxicity study CrCl 3 in mice - 49 Elbetieha and Al- M :0, 49, 246 (c) Hamood (1997) 12 weeks oral (drinking water) toxicity study CrCl 3 in mice - 98 Elbetieha and Al- F: 0, 98, 246 (c) Hamood (1997) 4 week oral (diet) toxicity study chromium picolinate in mice M: 0, 25 (b) 25 - McAdory et al. (2011) Developmental toxicity studies GD12– day 20 of lactation oral(drinking water) to CrCl 3 mice - F: 0, 79 (d) (1998) mice exposed to chromium picolinate via diet on GD 6-17 - 25 Bailey et al., 2006 F: 0, 25 (b) mice exposed to CrCl 3 via diet on GD 6-17 F: 0, 39 (b) 39 - Bailey et al. (2006) mice exposed to Cr(III)picolinate or other sources of Cr(III) via diet on GD 6-17 F: 0, 25 (b) (from picolinate) or 3.3 or 26 (b) as Cr(III) cation Cr 3 O(O 2 CCH 2 CH 3 ) 6 (H 2 O) 3 ) + 25 - Bailey et al. (2008a) mice exposed via diet to chromium picolinate from 25 - Bailey et al. F: 0, 25 (b) implantation through weaning (2008b) rats exposed to CrCl3 by gavage on GD 1-3 or 4-6 F: 33.6 (c) - 33.6 (GD 1-3) Toxicity on reproductive organs 13-week oral (diet), B6C3F1 mice M: 1419 Chromium picolinate monohydrate F: 1090 M/F: 0, 2/1.7, 6.2/4.9, 54/44, 273/212, 1419/1090 (b) 14-week oral (diet); F344/N rats M: 506 Chromium picolinate monohydrate F: 507 M: 0, 0.8/0.7, 2.4/2.4, 19.1/19.1, 95.4/93, 506/507 (b) Bataineh et al., 2007 - Rhodes et al. (2005) NTP (2010) - Rhodes et al. (2005) NTP (2010) 24-week oral (diet), Harlan Sprague Dawley rats chromium chloride or chromium picolinate 0, 0.45, 2.25, 4.5 and 9 (b) 9 - Anderson et al. (1997) 35 days oral (diet), mice - 9.2 Zahid et al., 1990 M: 0, 9.2, 19, 46 (c) Chromium sulphate M: male F: female; NOAEL: no-observed-adverse-effect level; LOAEL: lowest-observed-adverse-effect level. (a): In the conversions from concentration to daily doses, the molecular weight (MW) of the anhydrous salts were used when no information on hydration number was available in the original publication. (b): Data reported in the original publication; (c): Conversion using the default correction factor for subacute/subchronic/chronic exposure via drinking water/feed from EFSA SC (2012); (d): Conversion using drinking water/feed consumption data and average body weight reported in the publication. EFSA Journal 2014;12(3):3595 74
7.2.1.4. Genotoxicity Chromium in food and drinking water The mutagenic potential of Cr(III) compounds has been studied extensively and recently reviewed (EFSA ANS Panel, 2010a, b; ATSDR, 2012). Although study results vary depending on the test system, experimental conditions and type of Cr(III) compounds tested, the majority of the assay systems used provide evidence of lack of genotoxicity of Cr(III) compounds both in vitro and in vivo. However, it should be noted that the ultimate mutagen that binds DNA is the trivalent form produced intracellularly from Cr(VI) and therefore the apparent lack of activity of Cr(III) is solely due to its poor cellular uptake (Léonard and Lauwerys, 1980). Here, we will provide a summary of the literature and details only for the most relevant studies. In vitro assays Bacteria and yeast No genotoxic effects have been reported for Cr(III) picolinate in Ames assays using a variety of Salmonella typhimurium strains (BDL, 1995; Esber et al., 1997; NTP, 2010; Juturu and Komorowski, 2002; Whittaker et al., 2005) and concentrations up to 10 000 μg Cr(III) picolinate/plate in the presence or absence of metabolic activation (NTP, 2010). Neither Cr(III) chloride nor picolinic acid were mutagenic in the Ames test (Whittaker et al., 2005). Cr picolinate monohydrate was also negative in assays with Escherichia coli strain WP2uvr/pKM101, when tested with or without exogenous metabolic activation (S9) (NTP, 2010). Although Cr(III) compounds are largely inactive in bacterial mutagenicity assays it appears that some Cr(III) complexes are mutagenic in bacterial strains that are sensitive to oxidative stress. In the study by Sugden et al. (1992) the Cr(III) complexes that were mutagenic in the S. typhimurium strains TA102 and TA2638 (sensitive to oxidative mutagens), i.e. cis-[Cr(phen) 2 Cl 2 ] + and cis-[Cr(bipy) 2 Cl 2 ] + , presented characteristics of reversibility and positive shifts of the Cr(III)/Cr(II) redox couple, as determined by cyclic voltammetry, consistent with the ability of these Cr(III) complexes to serve as electron donors in Fenton-like reactions. In line with their chemical properties the mutagenic complexes displayed a nicking activity on plasmid DNA presumably by the induction of single-strand breaks. The non-mutagenic compounds did not exhibit these properties. It should be noted that Cr(III) picolinate was negative in Salmonella strains 102 and 104 (Juturu and Komorowski, 2002; NTP, 2010) which are sensitive to oxidative mutagens. Kirpnick-Sobol et al. (2006) determined the effects of Cr(III) chloride on the frequencies of DNA deletions measured with the deletion assay in Saccharomyces cerevisiae. A significant increased in the frequency of DNA deletions was observed and a linear correlation with the intracellular Cr concentrations was reported. The authors concluded that Cr(III) is a potent inducer of DNA deletions (even more potent than Cr(VI) tested in the same study) when it is absorbed. Mammalian cells Cr(III) compounds, particularly Cr picolinate, have been tested in numerous bioassays using cultured mammalian cells with mixed, often positive, results. Cr(III) chloride induced chromosomal aberrations in phytohemagglutinin(PHA)-stimulated human lymphocytes (Friedman et al., 1987) that were suppressed by superoxide dismutase (SOD), catalase and mannitol (specific scavenger of hydroxyl radicals). The authors concluded that the production of oxygen free radicals could contribute to the effects observed. Stearns et al. (1995) investigated the potential genotoxicity of chelated Cr(III) picolinate in Chinese hamster ovary (CHO) AA8 cells. Cr(III) picolinate was clastogenic in a concentration-dependent manner from 50 μM to 1 mM. Picolinic acid showed dose-dependent chromosome damage up to 2 mM. The data suggest that the picolinic acid rather than the Cr(III) was responsible for the observed effects, because Cr chloride and Cr nicotinate were not clastogenic at equivalent non toxic Cr concentrations. No induction of micronuclei was observed following exposure of V79 Chinese hamster lung cells to a variety of Cr(III) complexes, except when Cr(III) imine complexes, which could be oxidized to Cr(V) EFSA Journal 2014;12(3):3595 75
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