Copper dichromium tetraoxide

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Studies with more water-soluble chromium (III) compounds have shown effects on spermatogenesis and reproductive performance in mice and rats.

Effect on fertility: via oral route

Dose descriptor:

NOAEL

2 000 mg/kg bw/day

Effect on fertility: via inhalation route

Dose descriptor:

NOAEC

30 mg/m³

Additional information

Screening studies performed with chromium (III) oxide No effects on male fertility, female fertility or embryofoetal development were seen in rats mated following exposure to dietary levels of up to 5% chromium (III) oxide for 60 days (Ivankovic & Preussmann, 1975), equivalent to mean achieved intakes in excess of 2000 mg/kg bw/d. No effects on testes or ovary weights were seen following administration at this dose level for 2 years. No effects on sperm parameters were seen in male rats exposed by inhalation to chromium oxide dust at concentrations of up to 30 mg/m3 in a 90-day study (Derelanko et al, 1999). The available information therefore do not indicate any adverse effect of chromium (III) oxide administration on either the reproductive organs or on reproductive function. Kinetic data show that this substance is poorly absorbed. Chromium (III) is an essential element and highly water-soluble forms (such as the picolinate complex) are used as dietary supplements; data indicate that chromium (III) supplementation may be of benefit in controlling insulin-dependent diabetes and it has been suggested that chromium (III) supplements may be of benefit in the control of gestational diabetes. Based on the results of the screening studies, the very low systemic availability of chromium (III) oxide and the essentiality of chromium it is not proposed to perform any additional studies of reproductive toxicity. The performance of a two-generation reproductive toxicity study is not justified for scientific reasons or on animal welfare grounds.Other literature studies No additional studies are available for chromium oxide, however studies are available for other chromium (III) salts. These studies are of limited value due to methodological deficiencies and/or the relevance of the route of administration, however they are summarised here for completeness. The following summary and conclusion is taken from the 2006 FIOH review Summary of reproductive toxicity studies reviewed by the FIOH No guideline-based reproductive toxicity studies were found for any trivalent chromium compound and there are only a few other studies of the reproductive toxicity of trivalent chromium compounds.  No studies of the effects of metallic chromium on fertility are available but it can be assumed that the reproductive toxicity of metallic chromium resembles that of chromium(III) oxide.  In the case of water-insoluble chromium(III) oxide no compound-related effects on sperm parameters or testicular and ovarian weights were seen after inhalation exposure of rats to chromium(III) oxide 6 hours per day 5 days per week over 13 consecutive weeks at the concentration levels of 3, 10 or 30 mg Cr3+/m3 (Derelanko et al,  1999).  Also, the study by Ivankovic & Preussmann (1975) did not show any adverse effects on the reproductive performance of rats treated orally with very high doses of chromium(III) oxide.  Based on these studies and the toxicokinetic knowledge of the poor bioavailability of water-insoluble chromium(III) oxide it is concluded that chromium(III) oxide does not cause a hazard for fertility.  Although one old rabbit study (Behari et al, 1978) with chromium nitrate claims that intraperitoneally administered water-soluble trivalent chromium compounds may cause even more marked testicular effects than hexavalent chromium, this is not supported by another study performed with i.p. administration of chromium chloride (Ernst, 1990).  In addition, because i.p. injection can lead to unrealistically high testicular chromium levels due to the direct uptake of chromium into the peritoneal organs (Sipowicz et al, 1997) studies using inhalation exposure or oral administration are considered more relevant for the assessment of reproductive risks of trivalent chromium.  There are four oral studies with water-soluble trivalent chromium compounds suggesting effects on male and/or female reproductive performance (Zahid et al, 1990; Elbetieha & Al Hamood 1997; Bataineh et al, 1997; Al Hamood, Elbetieha et al, 1998).  The study by Zahid et al suggests effects on spermatogenesis at dose levels of 3 mg Cr3+/kg/day.  However, this study suffers from serious deficiencies and from the obscurity concerning the identity and the purity of the test substance. In other oral (drinking water) studies, effects on reproductive performance were seen in mice and rats at dose levels ≥24 mg/kg/day of Cr3+as chromium chloride hexahydrate.  However, due to deficiencies in study designs and execution it is not possible to conclude whether these effects were real, specific effects on the reproductive system or not. On the other hand, the possibility of adverse reproductive effects caused by highly excessive trivalent chromium intake cannot to be totally excluded.  According to toxicokinetic studies, chromium can reach the testis and is found mainly in the interstitial compartment of the testis.  The interstitial compartment of testis contains testosterone-producing Leydig cells. Since trivalent chromium is an essential nutrient involved in cellular glucose and lipid metabolism, it is possible that the excessive uptake of trivalent chromium into the interstitial compartment perturbs the chromium balance of Leydig cells and results in changes in testosterone production as suggested by Al-Hamood et al, and Elbetieha & Al-Hamood 1997.  Nevertheless, according to the 13-week inhalation toxicity study by Derelanko et al,  no compound-related effects on sperm parameters, testicular or ovarian weights were seen after exposure of rats to basic chromium sulphate 6 hours per day at concentration levels of 3,10 and 30 mg/m3 of Cr3+(corresponding to inhaled doses of 0.7-6.6 mg Cr3+/kg/day).  This study suggests that trivalent chromium does not cause effects on fertility at dose levels up to 6.6 mg Cr3+/kg/ day. 6.6 mg Cr3+/kg/day (30 mg Cr3+/m3) is selected as a NOAEL for fertility effects. 24 mg Cr3+/kg/day is selected to represent a LOAEL for reproductive toxicity.  This is based on the effects on reproductive organ weights and sexual behaviour seen in the study by Bataineh and co-workers (Bataineh et al, 1997).  However, it should be noted that at the same dose level, a clear reduction in the body weight gain of treated animals was also seen and therefore it is unclear whether the observed effects were real and specific to the reproductive system or not. The FIOH review concluded that the studies with chromium (III) oxide have not demonstrated any adverse effects on reproductive organs or reproductive function.

Short description of key information:
No standard reproductive toxicity studies are available. An assessment of fertility and teratogenicity was included in a dietary toxicity study. Sperm parameters were assessed in a 13-week inhalation toxicity study.

Effects on developmental toxicity

Description of key information

No evidence of teratogenicity was seen in the offspring of rats exposed to chromium oxide in the diet at dose levels of up to ~2000 mg/kg bw/d for 60 days.  No evidence of developmental toxicity was seen in a study in mice performed using water-coluble complexes of Cr (III).  A negative in vitro screening study is also available.

Effect on developmental toxicity: via oral route

Dose descriptor:

NOAEL

2 000 mg/kg bw/day

Additional information

In vitro screening study with chromium (III) chloride No evidence of embryotoxicity was seen in a screening study using the water soulble Cr(III) compound chromium trichloride. Screening study with chromium (III) oxide

No effects on embryofoetal development were seen in rats mated following exposure to dietary levels of up to 5% chromium (III) oxide for 60 days (Ivankovic & Preussmann, 1975), equivalent to mean achieved intakes in excess of 2000 mg/kg bw/d.

Other literature studies

No additional studies are available for chromium oxide, however studies are available for other chromium (III) salts. These studies are of limited value due to methodological deficiencies and/or the relevance of the route of administration, however they are summarised here for completeness. The following summary and conclusion is taken from the 2006 FIOH review:

No studies of the effects of metallic chromium on development are available. However, it can be assumed that the developmental toxicity of metallic chromium resembles that of chromium(III) oxide. In a 90-day feeding study by Ivankovic and Preussmann (1975), no malformations were seen in the offspring of chromium(III) oxide fed female rats. The study was limited only to a small number of animals and provided no quantitative data.  However, based on this study and the toxicokinetic knowledge of the poor bioavailability of water-insoluble chromium(III) oxide it is concluded that chromium(III) oxide is unlikely to cause developmental toxicity.  According to toxicokinetic studies trivalent chromium accumulates in the placenta but only a low proportion of chromium in maternal serum crosses the placenta to the foetus. The transfer is far more limited than for hexavalent chromium.  The only studies available concerning the developmental toxicity of water-soluble chromium compounds are non-standard studies using high-dose parenteral (i.p. or s.c.) administration, which cannot to be used in the developmental risk assessment of trivalent chromium. One meeting abstract suggests developmental abnormalities in rabbits treated orally with chromium chloride during the period of organogenesis.  Due to the lack of any quantitative data or a better description of the study, the study cannot to be assessed. Therefore, no conclusions for the developmental toxicity of water-soluble trivalent chromium can be made.

Study with water soluble complexes of Cr (III)

A recent developmental toxicity study (Bailey et al, 2008) has been performed with the water souble Cr (III) complexes chromium picolinate and [Cr3O(O2CCHCH3)6 (H2O)3]+ (Cr3). No evidence of teratogenicity, foetotoxicity or developmental toxicity was seen in this study at dose levels of 200 mg/kg bw/d chromium picolinate (equivalent to 25 mg/kg bw/d Cr(III)), 15 or 120 mg/kg bw/d Cr3 (equivalent to 3.3 and 26 mg/kg bw/d Cr(III) respectively). Given the much higher systemic availability of these compounds, it can be deduced that the NOAEL values for chromium (III) oxide wil be considerably higher.

Conclusion

Based on the results of the screening studies, the very low systemic availability of chromium (III) oxide and the essentiality of chromium it is not proposed to perform any additonal studies of developmental toxicity. The lack of developmental toxicity seen in a study with chromium (III) compounds of much higher bioavailability is also noted. The performance of a developmental toxicity study is not justified for scientific reasons or on animal welfare grounds.

Toxicity to reproduction: other studies

Additional information

A number of studies using water-soluble trivalent chromium compounds have been summarised in the FIOH review (see above). A number of deficiencies have been identified in these studies including dose level relevance, relevance of the route of administration and identity of the test material. It is conclude that the effects on the reproductive system are unclear.

Justification for classification or non-classification

The available information on chromium oxide suggests no adverse effect on reproduction and no developmental toxicity. No classification is therefore proposed.