Chromium

Endpoint summary

Description of key information

Oral Repeated Dose Toxicity:

No chronic repeated dose toxicity study with chromium metal is available. However, based on the information available and published in the context of the NTP program (Stout et al., 2010), two chronic repeated dose oral toxicity studies were conducted with chromium picolinate monohydrate using male and female F344/N rats and B6C3F1 mice. The substance was administered ad libitum to groups of 50 male and 50 female F344/N rats in feed at concentrations of 0, 2000, 10000 and 50000 ppm (actually ingested: males: approx. 0, 90, 460 and 2400 mg/kg bw/day; females: approx. 0, 100, 510 and 2630 mg/kg bw/day) for up to 105 weeks.

Average daily doses of Cr III, resulting from chromium picolinate monohydrate exposure in the present 3-month studies, ranged from approximately 1 to 500 mg/kg in rats and 2 to 1,500 mg/kg in mice. Average daily doses in the 2-year studies ranged from approximately 10 to 300 mg/kg in rats and 30 to 800 mg/kg in mice. These doses were up to five orders of magnitude higher than those consumed by humans ingesting typical doses of supplements. According to the authors, chromium picolinate monohydrate did not caused treatment-related effects on clinical signs, mortality, body weights, food consumption and histopathology (neoplastic/non-neoplastic).

No exposure-related lesions occurred in the 3-month studies on rats or mice. In the 2-year study no neoplasms or non- neoplastic lesions were attributed to exposure to chromium picolinate monohydrate.

This finding is supported by a sub-chronic oral repeated dose toxicity study with dichromium trioxide. Thereby, a second study (Ivankovic, 1975) for oral repeated dose toxicity was obtained from a study in which rats were fed chromium (III) oxide baked in bread for 90 days. No signs of toxicity were observed even at the highest dose (for males ca 1368 mg/kg/day and 1216 mg/kg/day for females).

Thereby, it was concluded using a read-across approach and considering the chromium measurement during the study, that chromium III does not present a health hazard to either sex.

Based on the findings from the 2 -year and 3-months studies, the NOEL (No-Observed-Effect-Level) of chromium picolinate monohydrate in male and female F344/N rats is considered to be > 50000 ppm (males and females : approx. equivalent to 300 mg Cr III/kg bw/) due to the absence of any relevant toxicological effects.

Based on the findings from the 2 -year and 3-months studies, the NOEL (No-Observed-Effect-Level) of chromium picolinate monohydrate in male and female B6C3F1 mice is considered to be > 50000 ppm (males and females: approx. equivalent to approx. 800 mg Cr III/kg bw/day) due to the absence of any relevant toxicological effects.

No adverse effects could be observed in none of these studies after the administration of chromium picolinate monohydrate and dichromium trioxide, respectively.

Inhalation Repeated Dose Toxicity:

The LOAEC for inhalation was derived from a guideline subchronic inhalation study with chromium(III) oxide. At the lowest concentration slight inflammation was observed in the lungs.

Dermal Repeated Dose Toxicity:

Due to the low bioavailability of chromium, the dermal route is not relevant for repeated dose toxicity.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Dose descriptor:

LOAEC

3 mg/m³

Additional information

Oral:

No chronic repeated dose toxicity study with chromium metal is available. However, based on the information available and published in the context of the NTP program (Stout et al., 2010), two chronic repeated dose oral toxicity studies were conducted with chromium picolinate monohydrate using male and female F344/N rats and B6C3F1 mice. The substance was administered ad libitum to groups of 50 male and 50 female F344/N rats in feed at concentrations of 0, 2000, 10000 and 50000 ppm (actually ingested: males: approx. 0, 90, 460 and 2400 mg/kg bw/day; females: approx. 0, 100, 510 and 2630 mg/kg bw/day) for up to 105 weeks.

Average daily doses of Cr III, resulting from chromium picolinate monohydrate exposure in the present 3-month studies, ranged from approximately 1 to 500 mg/kg in rats and 2 to 1,500 mg/kg in mice. Average daily doses in the 2-year studies ranged from approximately 10 to 300 mg/kg in rats and 30 to 800 mg/kg in mice. These doses were up to five orders of magnitude higher than those consumed by humans ingesting typical doses of supplements. According to the authors, chromium picolinate monohydrate did not caused treatment-related effects on clinical signs, mortality, body weights, food consumption and histopathology (neoplastic/non-neoplastic).

Furthermore, no treatment-related effects on hematology and clinical chemistry were expected based on findings reported for a 3-months repeated dose oral toxicity (Stout et al., 2010) during which the same concentrations in feed were administered to male and female F344/N rats as in the chronic study. The 3-months study was conducted prior to 2 -year study and was used as a dose range finder for the chronic study.

Based on the findings from the 2 -year and 3-month studies, the NOEL (No-Observed-Effect-Level) of chromium picolinate monohydrate in male and female F344/N rats is considered to be 50000 ppm (males and females: approximatively 300 mg Cr III/kg bw/day) due to the absence of any relevant toxicological effects.

In addition, the National Toxicology Program (Stout et al., 2010) evaluated chromium picolinate monohydrate in a 2-year repeated dose oral toxicity study using mice. The substance was administered ad libitum to groups of 50 male and 50 female B6C3F1 mice in feed at concentrations of 0, 2000, 10000 and 50000 ppm (males and females: approx. equivalent to approx. 800 mg Cr III/kg bw/day) for up to 105 weeks. According to the authors, chromium picolinate monohydrate did not cause treatment-related effects on clinical signs, mortality, body weights, food consumption and histopathology (neoplastic/non-neoplastic).

Furthermore, no treatment-related effects on hematology were expected based on findings reported for a 3-smonth repeated dose oral toxicity (Stout et al., 2010) during which the same concentrations in feed were administered to male and female B6C3F1 mice as in the chronic study. The 3-months study was conducted prior to 2 -year study and was used as a dose range finder for the chronic study.

Based on the findings from the 2 -year and 3-month studies, the NOEL (No-Observed-Effect-Level) of chromium picolinate monohydrate in male and female B6C3F1 mice is considered to be 50000 ppm (males and females: approx. equivalent to approx. 800 mg Cr III/kg bw/day) due to the absence of any relevant toxicological effects.

A 90-day oral toxicity study was performed by Ivankovic (1975) at dietary incorporation levels of 2% and 5%; dose levels are calculated to be equivalent to mean achieved intakes of approximately 700 mg/kg bw/d and 2000 mg/kg bw/d, respectively. No clearly treatment-related findings were seen under the conditions of this study. It is therefore concluded that chromium (III) oxide is of very low oral toxicity. Green-coloured faeces noted in the treated groups indicate that the test material was excreted unchanged; findings are consistent with the toxicokinetic data which indicate very limited oral absorption.

 

Inhalation:

Mild inflammatory reactions were observed with chromium(III) oxide in male and female rats in a 13 -week subchronic inhalation study at all exposure levels. These slight inflammatory changes are likely to be a reflection of a non-specific lung response caused by particle overload, rather than being a response of intrinsic toxicity of trivalent chromium. According to these studies the LOAEC for chromium(III) oxide is 4.4 mg/m3 (corresponding to 3 mg Cr(III) /m3), which is in fact most likely not much higher than the NOAEC for chromium(III) oxide in rats, as the severity and frequency of inflammatory changes in the lungs were minimal. No systemic adverse effects were observed in the inhalation study. The LOAEC of 3 mg Cr(III) /m3 can be used for chromium metal, as its surface is always auto-oxidized to chromium(III) oxide and therefore, in the case of fine chromium dusts, a large proportion of the chromium is in the form of chromium(III)oxide.

 

A 28 -day repeated inhalation study with stainless steel in rats did not cause any signs of toxicity even at the highest dose of 1 mg/L (1000 mg/m3). The release profile of chromium from stainless steel is similar to that of chromium from pure chromium metal. Due to this, the results of the 28 -day study provide strong evidence that inhalation of Cr does not cause any significant effects even at very high concentrations.

Human data showing no significant effects, including no effects on lung function, in a ferrochromium factory support the animal inhalation data.

Repeated dose toxicity: inhalation - systemic effects (target organ) respiratory: lung

Dermal:

Chromium metal is practically insoluble. Chromium does not pass through the skin or enter the systemic circulation and therefore systemic effects via the skin are not expected for metallic chromium.

 

 

Justification for classification or non-classification

3-months and 2-years exposure on two different species data are available with chromium picolinate (NTP, 2010), used as dietary supplement and that are reported to have a higher Cr(III) bioavailability by oral route than insoluble or soluble chromium(III) compounds.

In these animal studies, the absence of any relevant toxicological effects were observed up to 50000 ppm.

Repeated exposures of chromium(III) oxide via the oral or inhalation routes have not resulted in any signs of systemic toxicity. The surface of chromium metal is always rapidly oxidized to chromium(III) oxide, and dissolution studies have shown similar release profiles for chromium metal and chromium(III) oxide. Therefore the results can be directly adopted for the metal.

Mild local effects were observed in rats after repeated inhalation of chromium(III) oxide. These slight effects were most likely non-specific, caused by accumulation of insoluble particles. Rat lungs are known to be sensitive to particle overload, and inflammation is an expected outcome of rat inhalation studies with insoluble particles.

A DNEL for local effects caused by inhalation was derived, but there is no need to suggest classification for this endpoint.