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Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
40 mg/kg bw/day
Additional information

A number of studies performed with potassium dichromate are available. Once systemically absorbed, the toxicokinetics and toxicodynamics of the water-soluble Cr (VI) salts are essentially identical, therefore the results of these studies are relevant and can be extrapolated to all members of this group.

In a single generation fertility study in the mouse using administration of potassium dichromate in drinking water, effects on fertility resulting from the exposure of males and females were inidicated by the reduction in the numbers of implantations; findings were apparent following exposure of females to the lowest dose level equivalent to 140 mg/kg bw/d Cr (VI). Changes in reproductive organ weights were also seen in this study but are not considered to be of clear toxicological significance (Elbetieha & Al-Hamood, 1997) as they are associated with bodyweight changes and do not have any pathological correlates. In contrast, no evidence of reproductive toxicity was seen in an NTP continuous breeding study (two generation) in the mouse using potassium dichromate at dose levels of up to 40 mg/kg bw/d Cr (VI).

A number of published developmental toxicity studies performed in mice with potassium dichromate are available. Mice were exposed either throughout gestation (Trivedi et al, 1989), during organogenesis (Junaid et al, 1996a) or prior to mating (Junaid et al 1996b). No evidence of teratogenicity was seen in any study, however adverse effects on fertility (reduced corpora lutea, reduced pre-implantation loss) were seen. Foetotoxicity (post-implantation loss, resorptions) and developmental toxicity (reduced skeletal ossification and subcutaneous haemorrhage) were seen consistently; findings were apparent at dose levels of 20 mg/kg bw/d Cr (VI) and above.

Information on effects of Cr (VI) on the testes is available from repeated oral dose studies. In the rat, testicular degeneration was observed at a dose level (40 mg/kg bw/d (14 mg Cr(VI)/kg bw/d) which caused a large decrease in body weight gain following gavage administration of sodium dichromate for 90 days. A NOAEL of 20 mg/kg bw/d (7 mg Cr(VI)/kg bw/d) was determined for effects on the testis. Other studies found no effects on the testis, following administration of potassium dichromate by the dietary route for 9 weeks. The highest dose levels in these studies were 24 mg/kg bw/d (8 mg Cr(VI)/kg bw/d) in the rat and 92 mg/kg bw/d (32 mg Cr(VI)/kg bw/d) in the mouse (EU RAR, 2005).

Summary and discussion of the available reproductive toxicity studies from the EU RAR (2005)

There are three animal studies available which focus on fertility. Adverse effects were produced in mice receiving potassium dichromate for 12 weeks in drinking water at 333 mg/kg bw/d (120 mg Cr(VI)/kg bw/d) and 400 mg/kg be/d (140 mg Cr(VI)/kg bw/d) and above in males and females respectively. A NOAEL of 166 mg/kg bw/d (60 mg Cr(VI)/kg bw/d) was identified in males, but no NOAEL was found for females as 400 mg/kg bw/d was the lowest dose level tested. An increase in resorptions following treatment of males and a decrease in implantations in treated females were among the findings in this study. In another study, pregestational oral administration of potassium dichromate in drinking water to female mice produced adverse effects on fertility (reduced number of corpora lutea and increased pre-implantation loss) at 500 ppm (119 mg/kg bw/d (40 mg Cr(VI)/kg bw/d)) and above. NOAEL values of 119 mg/kg bw/d (40 mg Cr(VI)/kg bw/d) and 63 mg/kg bw/d (20 mg Cr(VI)/kg bw/d) can be identified from this study for maternal toxicity and fertility effects respectively. In a third study, also in the mouse, at 86 mg/kg bw/d (30 mg Cr(VI)/kg bw/d), the highest dose level tested, there were no effects of treatment on fertility parameters. Fetotoxicity, including post-implantation losses, has been observed in the mouse following administration of potassium dichromate in drinking water during gestation (days 0-19). Significant developmental effects occurred at the lowest dose level tested, 60 mg/kg bw/d (20 mg Cr(VI)/kg bw/d) in the absence of maternal toxicity. Therefore no developmental NOAEL was determined. Qualitatively similar results were obtained in another study in which (350 mg/kg) potassium dichromate (125 mg Cr(VI)/kg) was administered for a shorter period, on days 6-14 of gestation. In a pregestational study in female mice, fetotoxic effects were seen starting from the lowest dose level tested, 250 ppm (63 mg/kg bw/d (22.1 mg Cr(VI)/kg bw/d)) potassium dichromate. Significant levels of total chromium were found in treated animals at sacrifice. No NOAEL could be identified for the developmental effects, which included post-implantation losses. These fetal effects may possibly be explained by the presence of chromium in the dams after the end of treatment. Overall, highly water-soluble chromium (VI) compounds should be considered to be developmental toxicants in the mouse. These findings can be regarded as relevant to humans. It is noted that some of the adverse effects on reproduction observed in animal studies may be related to the germ cell mutagenicity of these chromium (VI) compounds (see Mutagenicity section). No reproductive toxicity studies are available using the inhalation or dermal routes of exposure.

Human data relating to effects on reproduction are limited to poorly reported studies of female workers from which no conclusions can be drawn.


Short description of key information:
A number of studies have been performed uisng potassium dichromate. While the studies are of non-standard design, they are considered (as a whole) to adequately assess reproductive toxicity. The results of the studies are applicable to all of the water-soluble hexavalent chromium compounds in this group.

Effects on developmental toxicity

Description of key information
A number of studies  have been performed uisng potassium dichromate.  While the studies are of non-standard design, they are considered (as a whole) to adequately assess developmental  toxicity.  The results of the studies are applicable to all of the water-soluble hexavalent chromium compounds in this group.
Effect on developmental toxicity: via oral route
Dose descriptor:
LOAEL
20 mg/kg bw/day
Additional information

No studies of the developmental toxicity of chromium (VI) trioxide have been idenitfied, however a number of studies performed with potassium dichromate are available. Once systemically absorbed, the toxicokinetics and toxicodynamics of chromium (VI) trioxide and the other water-soluble Cr (VI) salts are essentially identical, therefore the results of these studies are relevant and can be extrapolated. The available studies investigated both reproductive developmental toxicity endpoints and are discussed above.

Overall, highly water-soluble chromium (VI) compounds should be considered to be developmental toxicants in the mouse. These findings can be regarded as relevant to humans

Justification for classification or non-classification

Chromium trioxide is listed on Annex I of Directive 67/548/EEC with R62 classification (reproductive toxicity Category 3).

Sodium chromate, sodium dichromate and potassium dichromate are listed on Annex I of Directive 67/548/EEC with R60 and R61 (reproductive toxicity Category 2) classification. No changes to these classifications are proposed.