efsa-opinion-chromium-food-drinking-water
efsa-opinion-chromium-food-drinking-water efsa-opinion-chromium-food-drinking-water
7.2.1.3. Developmental and reproductive toxicity Chromium in food and drinking water Adverse reproductive effects have been observed in rats and mice exposed orally to Cr(III) compounds, although conflicting results have been reported. The NOAELs and lowest-observed adverse effect levels (LOAELs) from the relevant studies are reported in Table 13 and the studies are described in details in Appendix H (Table H2). A series of studies was conducted to determine the effects of chromium chloride on reproduction in rats and mice following 12 weeks of exposure via drinking water (Bataineh et al., 1997; Elbetieha and Al-Hamood, 1997; Al-Hamood et al., 1998). Histopathology was not performed in these studies. Fertility was assessed by mating exposed animals of each sex with unexposed animals of the other sex. Decrease in body weight and absolute testes, seminal vesicles and preputial glands weights as well as inhibitory effect on sexual and aggressive behaviour, without a decrease in fertility, were observed in male Sprague-Dawley rats at exposure concentrations up to 1000 mg/L (30 mg Cr(III)/kg b.w. per day) (Bataineh et al., 1997). Decreased body weights, testes, and preputial gland weights were reported in mice at exposure concentrations of 5000 mg/L (246 mg Cr(III)/kg b.w. per day) and decreased seminal vesicle weight at 1000 mg/L (49 mg Cr(III)/kg b.w. per day). Decrease fertility was also observed in males at 5000 mg/L (Elbetieha and Al-Hamood, 1997). In both studies, increased number of resorptions and dead fetuses were also observed in females mated with treated males. Increases in ovarian weights and reduction in uterine weights were reported in female mice at doses ≥ 2000 mg/L (98 mg Cr(III)/kg b.w. per day). No effect on fertility was noted, however, there was a decrease in the number of implantations and of viable fetuses and an increase in the number of resorptions in treated females (Elbetieha and Al-Hamood, 1997). Impairement of reproductive function and fertility in adulthood was observed in male mice of F1 generation following exposure of dam to 1000 mg/L (79 mg Cr(III)/kg b.w. per day) during gestation and lactation (Al-Hamood et al., 1998). Bataineh et al. (2007) observed a slight decrease in the number of pregnant rats compared to controls after exposure by gavage of mated female rats during gestation days 1-3 to 25 mg chromium chloride/rat (corresponding to 33.6 mg Cr(III)/kg b.w. per day. Results of these studies should be interpreted with caution due to concerns regarding experimental methods. Mice exposed for 7 week to chromium sulphate (9.2 mg Cr(III)/kg b.w. per day) through the diet had reduced sperm count and degeneration of the outer cellular layer of the seminiferous tubules. Morphologically alterated sperm occurred in diets providing 46 mg Cr(III)/kg b.w. per day (Zahid et al., 1990). Serious questions have been raised regarding the design and conduct of this study (Finley et al., 1993; NTP, 1996a, b, 1997; U.S. EPA,1998a). The methods utilized by Zahid et al. (1990) are considered to be insufficient to identify spermatogonia, likely generated nonreproducible counts of epididymal sperm, and resulted in the biologically implausible conclusion of reduction in spermatogonia numbers concurrent with unchanged spermatocyte and spermatid numbers. Moreover there are inconsistencies regarding the number of mice used in the study, the sizes of the experimental groups do not satisfy minimal requirements for such toxicity study and inappropriate statistical methods were used. Therefore, the CONTAM Panel did not take into account the results of this study in its evaluation of the reproductive toxicity of Cr(III). Delayed vaginal opening was observed in mice exposed during gestation and lactation to 1000 mg chromium chloride/L (79 mg Cr(III)/kg b.w. per day) (Al-Hamood et al., 1998). A significant increase in the incidence of bifurcated cervical arches was observed, in the absence of maternal toxicity or an effect on maternal fertility, in the offspring of pregnant CD-1 mice fed diets containing 200 mg chromium picolinate/kg (25 mg Cr(III)/kg b.w. per day) from gestation days 6 to 17 (Bailey et al., 2006). However, this effect was not reproducible in other studies (Bailey et al., 2008a,b). Other studies do not show show evidence of reproductive or developmental toxicity. There were no changes in testis or epididymis weights in rats following treatment with chromium picolinate or chromium chloride (9 mg Cr(III)/kg b.w. per day) in the diet for 24 weeks (Anderson et al., 1997). There was no evidence of reproductive or developmental toxicity in male or female rats following dietary exposure to chromium oxide (50000 mg/kg diet equivalent to 1806 mg Cr(III)/kg b.w. per day) EFSA Journal 2014;12(3):3595 72
Chromium in food and drinking water for 60 days prior to gestation and during gestation (Ivankovic and Preussmann, 1975). In the 3-month studies on rats and mice following administration of chromium picolinate in the diet up to 50000 mg/kg diet (equivalent to 506 mg Cr(III)/kg b.w. per day in rats and 1090 mg Cr(III)/kg b.w. per day in mice), there were no significant changes in reproductive organ weights in male or female animals, in sperm parameters, or in estrous cyclicity (NTP, 2010). Developmental effects were not observed following dietary treatment of female mice with 200 mg chromium chloride/kg b.w. (39 mg Cr(III)/kg b.w. per day) (Bailey et al., 2006). Dietary exposure of male mice to 200 mg chromium picolinate/kg b.w. per day (25 mg Cr(III)/kg b.w. per day) before mating had no effect on fertility, prenatal mortality, fetal weight or skeletal morphology (McAdory et al., 2011). In summary, conflicting results on reproductive effects of Cr(III) compounds have been reported; some studies do not show show evidence of reproductive or developmental toxicity, whereas in other studies effects on fertility, organ weights, embryo- and fetotoxicity have been observed. The difference in results might be related to experimental methods, including exposure media (drinking water versus feed) or to differences in toxicity of the specific Cr(III) compounds evaluated. The CONTAM Panel noted that a majority of studies have methodological limitations, and were not designed for establishing reference doses (only one dose tested). However, in the absence of adequate data, the results of these studies must be taken into account as they identify potential adverse effects of oral Cr(III) exposure. In the studies where effects on reproduction and development have been observed, the lowest LOAELs were in the order of 30 mg/kg b.w. per day. EFSA Journal 2014;12(3):3595 73
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Chromium in <strong>food</strong> and <strong>drinking</strong> <strong>water</strong><br />
for 60 days prior to gestation and during gestation (Ivankovic and Preussmann, 1975). In the 3-month<br />
studies on rats and mice following administration of <strong>chromium</strong> picolinate in the diet up to<br />
50000 mg/kg diet (equivalent to 506 mg Cr(III)/kg b.w. per day in rats and 1090 mg Cr(III)/kg b.w.<br />
per day in mice), there were no significant changes in reproductive organ weights in male or female<br />
animals, in sperm parameters, or in estrous cyclicity (NTP, 2010).<br />
Developmental effects were not observed following dietary treatment of female mice with<br />
200 mg <strong>chromium</strong> chloride/kg b.w. (39 mg Cr(III)/kg b.w. per day) (Bailey et al., 2006).<br />
Dietary exposure of male mice to 200 mg <strong>chromium</strong> picolinate/kg b.w. per day<br />
(25 mg Cr(III)/kg b.w. per day) before mating had no effect on fertility, prenatal mortality, fetal<br />
weight or skeletal morphology (McAdory et al., 2011).<br />
In summary, conflicting results on reproductive effects of Cr(III) compounds have been reported;<br />
some studies do not show show evidence of reproductive or developmental toxicity, whereas in other<br />
studies effects on fertility, organ weights, embryo- and fetotoxicity have been observed. The<br />
difference in results might be related to experimental methods, including exposure media (<strong>drinking</strong><br />
<strong>water</strong> versus feed) or to differences in toxicity of the specific Cr(III) compounds evaluated. The<br />
CONTAM Panel noted that a majority of studies have methodological limitations, and were not<br />
designed for establishing reference doses (only one dose tested). However, in the absence of adequate<br />
data, the results of these studies must be taken into account as they identify potential adverse effects of<br />
oral Cr(III) exposure. In the studies where effects on reproduction and development have been<br />
observed, the lowest LOAELs were in the order of 30 mg/kg b.w. per day.<br />
EFSA Journal 2014;12(3):3595 73