efsa-opinion-chromium-food-drinking-water

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Chromium in food and drinking water distribution of chromium to the liver and kidney, with liver:kidney ratios being higher in mice than in rats. The tissue data and PBK model predictions indicated a concentration gradient in the small intestines (duodenum > jejunum > ileum). A PBK model for humans orally exposed to Cr(III) and Cr(VI) (Kirman et al., 2013) was also developed. Ex vivo Cr(VI) reduction studies using fasted human gastric fluids were conducted and used to characterize reduction of Cr(VI) in human stomach fluid as a mixed second-order, pHdependent process. Information from the published literature regarding the toxicokinetics for total chromium in human tissues and excreta was used for model development. The PBPK model was shown to provide a good description of chromium toxicokinetics and to be consistent with the available total chromium data from Cr(III) and Cr(VI) exposures in humans. Additional data for Cr(VI) reduction in both humans and rodents were identified as data needs to further develop key assumptions made in the PBPK models, and allow improved health risk assessment. 7.2. Toxicity in experimental animals 7.2.1. Trivalent chromium In general Cr(III) salts present low oral toxicity (ATSDR, 2012). 7.2.1.1. Acute toxicity Table 11 shows the oral LD 50 s reported in the rat. The lower toxicity of Cr(III) acetate compared with Cr(III) nitrate may be related to solubility; Cr(III) acetate is less soluble in water than is Cr(III) nitrate. Signs of toxicity included hypoactivity, lacrimation, mydriasis, diarrhea, and decrease in body weight. Table 11: Oral LD 50 s determined in rats Compound LD 50 (mg Cr(III)/kg b.w.) Reference Chromium acetate 2 365 Smyth et al. (1969) 423 Smyth et al. (1969) Chromium nitrate 200 (males) Vernot et al. (1977) 183 (females) Vernot et al. (1977) Cr(III) dinicocysteinate complex > 2 000 Sreejayan et al. (2010) Chromium propionate complex > 2 000 Staniek et al. (2010) Chromium nicotinate > 622 Shara et al. (2005) 7.2.1.2. Repeat dose toxicity Several studies were located in the literature regarding repeated oral exposure (dietary or via drinking water) to Cr(III). Detailed reviews of these studies have been reported by U.S. EPA (1998a), EFSA ANS Panel (2010a, b) and ATSDR (2012). The no-observed-adverse-effect levels (NOAELs) from the relevant studies are reported in Table 12 and the studies are described in details in Appendix H (Table H1). The NOAELs were always the highest dose tested. EFSA Journal 2014;12(3):3595 70
Chromium in food and drinking water Table 12: Repeated dose toxicity studies with Cr(III) compounds. Results for males (M) and females (F) are reported separately when the data allowed. Study (a) Doses in mg Cr(III)/kg b.w. per day NOAEL mg Cr(III)/kg b.w. per day Reference M: 1419 13-week oral (diet); B6C3F1 mice Rhodes et al. (2005) M/F:0, 2/1.7, 6.2/4.9, 54/44, 273/212, 1419/1090 (b) chromium picolinate monohydrate and F: 1090 NTP (2010) 90-day oral (diet); Becton Dickinson rat Cr 2 O 3 baked in bread M/F: 0, 570/547, 1368/1217 (b) M: 1368 and F: 1217 Ivankovic and Preussman (1975) 14-week oral (diet); F344/N rats chromium picolinate M/F: 0, 0.8/0.7, 2.4/2.4, 19.1/19.1, 95.4/93, 506/507 (b) M: 506 and F: 507 Rhodes et al. (2005) NTP (2010) 90-day oral (diet); Sprague-Dawley rats M: 1.0 Shara et al. (2005) M/F: 0, 0.04/0.04, 0.40/0.42, 1.0/1.1 (c) chromium nicotinate and F: 1.1 24-weeks oral (diet); Harlan Sprague Dawley rats 9 Anderson et al. (1997) 0, 0.45, 2.25, 4.5 and 9.0 (d) chromium chloride or chromium picolinate 52-week oral (diet); Sprague-Dawley rats M: 0.17 (e) Shara et al. (2007) 0.17/0.22 (c) 0 or 25 mg/kg diet chromium nicotinate (0, M/F: 0, and F: 0.22 2-year oral (diet); Becton Dickinson rat Cr 2 O 3 baked in bread 0, 293, 586, 1466 (b) M+F: 1466 Ivankovic and Preussman (1975) 2-year oral (diet); F344/N rats M: 286 NTP (2010) M/F: 0, 10.7/12, 55/61, 286/314 (b) chromium picolinate monohydrate and F: 314 2-year oral (diet); B6C3F1 mice M: 783 NTP (2010) M/F: 0, 3029, 143/143, 783/728 (b) chromium picolinate monohydrate and F: 728 b.w.: body weight; NOAEL: no-observed-adverse-effect level; M: male; F: female. (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): Conversion using the data reported in the original publication. (c): Conversion using drinking water/feed consumption data and average body weight reported in the publication. (d): Conversion using the default correction factor for subacute/subchronic/chronic exposure via drinking water/feed from EFSA SC (2012). (e): The only effects observed were statistically significant decreases in body weight gain, between 5.5 and 14.9 %. In general, Cr(III) displays very little to no toxicity in animals up to the highest dose tested. In the Shara et al. (2007) study, the only effects observed in rats dietary exposed to 25 mg/kg chromium nicotinate were statistically significant decreases in body weight gain, between 5.5 and 14.9 %, which were not considered as adverse by the CONTAM Panel. The lack of toxicity observed at high concentrations of Cr(III) may reflect the poor absorption of Cr(III) by the oral route of exposure. The use of baked bread as a vehicle may have further reduced the absorption of chromium in the Ivankovic and Preussman (1975) study. The studies conducted by the National Toxicology Program (NTP, 2010) have been performed according to present scientific guidances and reported a comprehensive assessment of toxicological endpoints and adequate reporting for estimation of doses in mg Cr(III)/kg b.w. per day. They were considered by the CONTAM Panel to be the most relevant studies to establish reference doses. No adverse effects have been observed in the sub-chronic or long-term toxicity studies in mice or rats at the highest dose tested of 50000 mg CrO 3 or chromium picolinate/kg diet. The relevant NOAELs corresponded to 506 and 286 mg Cr(III)/kg b.w. per day for the sub-chronic and long-term toxicity in the rat, respectively (NTP, 2010). EFSA Journal 2014;12(3):3595 71
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EFSA Journal 2014;12(3):3595 SCIENT
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Human observations Chromium in food
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