Sodium chromate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DMEL (Derived Minimum Effect Level)

Value:

0.01 mg/m³

Most sensitive endpoint:

carcinogenicity

Acute/short term exposure

Hazard assessment conclusion:

DMEL (Derived Minimum Effect Level)

Value:

0.01 mg/m³

Most sensitive endpoint:

carcinogenicity

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Acute/short term exposure

DNEL related information

Additional information - workers

Grouping of the water-soluble hexavalent chromium compounds

The compounds in this group (chromium (VI) trioxide, sodium (VI) dichromate, sodium (VI) chromate and potassium (VI) dichromate as well as potassium (VI) chromate) are considered to be sufficiently similar in terms of their toxicology to enable grouping of the compound and to allow read-across between toxicity studies performed using any compound in this group. Additionally, read-across from this group to other water-soluble Cr (VI) compounds is also appropriate.

The only potential difference in the toxicology of the members of this group is a consequence of the greater corrosivity of chromium (VI) trioxide. While all of the members of this group are classified according to Directive 67/548/EEC as corrosive, chromium (VI) trioxide is classified as (R35) 'Causes severe burns' whereas the other compounds are classified as (R34) 'Causes burns'. The more marked corrosive effects of chromium (VI) trioxide potentially results in more severe toxicity at the site of contact and, theoretically, may result in more extensive absorption where corrosivity occurs. More marked effects at the site of contact are apparent in studies of skin and eye irritation and acute dermal and inhalation toxicity with chromium (VI) trioxide. Chromium (VI) trioxide is classified as a Category 1 carcinogen, whereas the other members of the group are classified as Category 2 carcinogens. The more severe classification of chromium (VI) trioxide for carcinogenicity is a consequence of findings of increased incidence of respiratory tract tumours following occupational inhalational exposure to chromic acid (aqueous chromium (VI) trioxide) mists, and is considered to be a consequence of both the inherent genotoxic activity of the compound and also of its local irritancy/corrosivity.  While the other members of the group are also genotoxic in vitro and in vivo, and have been shown to be carcinogenic in animal studies, relatively extensive epidemiological investigations have not demonstrated carcinogenicity due to occupational exposure.

Once systemically absorbed, and beyond any effects specific to the site of contact, the four compounds in this group are considered to be essentially identical in terms of toxicokinetics and toxicodynamics.  All compounds are highly water soluble and will therefore dissociate in the aqueous physiological environment to liberate chromate (VI) or dichromate (VI) ions.  The chromate and dichromate ions exist in equilibrium in aqueous environments and, with the exception of the site of contact effects discussed above, it can be seen that the four compounds in this group are toxicologically identical.

Toxicokinetics

A relatively large number of literature studies investigating the toxicokinetics of the water-soluble hexavalent chromium compounds. The findings of these studies (in experimental animals and human volunteers) show that the bioavailability of Cr (VI) is relatively low followig oral and dermal exposure, but higher following inhalation exposure. Once absorbed, distribution is relatively rapid and extensive; accumulation is seen in the erythrocyte due to binding to haemoglobin caused by the intracellular glutathione-mediated reduction on Cr (VI) to Cr (III). Extensive reduction to Cr (III) also occurs in the gastrointestinal tract, plasma and in other cells and is caused by reaction with glutathione, ascorbate or cytochrome P450. As a consequence of this reduction, absorbed Cr (VI) is excreted (in urine and faeces) in the form of glutatione complexes of Cr (III).

Acute toxicity

All four of the compounds in this group were found to be very toxic by inhalation and toxic by the oral route. Chromium trioxide was found to be toxic by the dermal route, compared to the other compounds in this group which were found to be harmful. The difference in dermal toxicity is attributable to more severe local corrosive effects caused by chromium trioxide.

Irritancy

The results of screening studies in vivo indicate that chromium trioxide is corrosive to skin and a severe eye irritant. The results of studies with sodium dichromate. Potassium dichromate and sodium chromare indicate that these compounds are skin irritants when mixed with water (due to low pH). Experience from occupational use with the water-soluble hexavalent chromium compounds indicate that they may be corrosive. No eye irritation studies are available, however severe irritancy is assumed.

Sensitisation

Experience from occuaptional exposure indicates that the water-soluble Cr (VI) compounds are both skin and respiratory sensitisers. Evidence from animal studies also indicates that these compounds are skin sensitisers.

Repeat-dose toxicity

Short-term toxicity studies in the rat and mouse were performed using oral administration of potassium dichromate and sodium dichromate. The results of these studies show local irritant effects on the gastrointestinal tract and red blood cell findings (microcytic anaemia) consistent with an effect on iron homeostasis or haemoglobin synthesis. The results of repeated exposure inhalation studies in the mouse with chromium trioxide show local irritant effects on the respiratory tract.

Genotoxicity

There is a very large body of evidence indicating that the Cr (VI) ion in solution is directly mutagenic in in vitro systems. Extensive in vitro testing of highly water-soluble Cr(VI) compounds has produced positive results for point mutations and DNA damage in bacteria, point mutations, mitotic crossing-over, gene conversion, disomy and diploid in yeasts, and gene mutation, DNA damage, chromosome aberrations, sister chromatid exchanges and unscheduled DNA synthesis in mammalian cells. The in vitro genotoxicity of Cr (VI) was diminished considerably by the presence of reducing agents, in the form of tissue S9 or S12 fractions, gastric juice or reducing agents such as glutathione, ascorbate or sulphite. These all serve to reduce Cr (VI) to Cr (III) outside the cell therefore greatly reducing entry of chromium into the cell. The genotoxicity of Cr (VI) compounds in vivo has been less extensively studied. Parenteral administration of sodium or potassium dichromate or potassium chromate to rats or mice resulted in significant increases in chromosome aberrations and micronucleated cells in the bone marrow and DNA single-strand breaks, interstrand cross-links and DNA-protein cross-links in the liver, kidneys and lung. A mouse spot test involving intraperitoneal injection of potassium chromate gave positive results. Oral studies have been negative but these employed lower dose levels and absorption is known to be poor by the oral route. Overall, water soluble Cr (VI) compounds are in vivo somatic cell mutagens in animal studies. A significant increase in post-implantation deaths in a dominant lethal assay was reported in mice following intraperitoneal injection of potassium dichromate. A few studies have been conducted in which circulating lymphocytes have been isolated from chromium-exposed workers and examined for chromosome aberrations, micronuclei, SCE and changes in chromosome numbers. In general, the results from the better-conducted and reported studies including chromium plating workers in Japan and SS-MMA welders in Scandinavia have been negative. Evidence of genotoxicity has been reported in several other studies of chromate production workers in Eastern Europe and chromium plating workers in Italy. However the manner in which these were conducted and reported precludes full assessment of the significance of the findings. Given the available database on the genotoxicity of chromium (VI) compounds and the conclusion that this group of compounds is mutagenic, it is considered that further testing (specifically in guideline and GLP-compliant studies is not required.

Carcinogenicity

A large number of studies are available, however most of the available studies of carcinogenicity performed using chromium (VI) compounds have not been performed to GLP or to recognised guidelines, however the provisional results of two NTP studies (in the rat and mouse) performed using sodium dichromate in the drinking water are available. These studies showed increased incidences of tumours of the oral cavity (rats) and tumours of the small intestine (mice); findings indicate a site-of contact effect associated with chronic irritation. The NTP have provisionally concluded that these studies both provide 'clear evidence' of carcinogenicity. The results of two published studies in female mice (Adachi et al, 1987; Adachi, 1988) exposed by inhalation to mists of chromic acid (aqueous chromium trioxide) for up to 12 months showed marginally (but not statistically significantly) increased incidences of lung tumours. The findings in these studies were associated with chronic irritation and corrosion of the respiratory tract. Similar findings of marginally increased tumour incidences were reported in one of two rat studies performed using intrabronchial implantation of pellets containing chromium (VI) trioxide (Laskin et al, 1970; Levy et al, 1986). A slight increase in the incidence of respiratory tract (lung and pharynx) tumours was seen at the highest exposure concentration in rats exposed to aerosols of sodium dichromate (Glaser et al, 1986). A clear increase in the incidence of lung tumours was seen in a study using intratracheal instillation of sodium dichromate (Steinhoff et al, 1985).

The carcinogenicity of chromium (VI) trioxide and other chromium (VI) salts have been extensively reviewed by the UK Health and Safety Executive (HSE, 1989); the UK Institute of Occupational Health (IOH, 1997) and most recently in the EU RAR (2005). The EU RAR discussion of the carcinogenicity of chromium (VI) compounds is shown below; this review discusses the results of the inhalation carcinogenicity studies performed with chromium (VI) trioxide, as well as studies with other chromium (VI) salts and incorporates the studies previously reviewed by the HSE and IOH. Occupational (inhalation) exposure to chromium (VI) trioxide has been linked to increased incidences of lung cancer, therefore this compound was considered by the EU RAR to be a human carcinogen. Water-soluble hexavelent chromium compounds are genotoxic in vitro and in vivo. However the reduction of Cr (VI) to Cr (III) in the body (saliva, gastric juice, erythrocye) may explain the lack of carcinogenicity of Cr (VI) at sites distant from the site of exposure.

Reproductive and developmental toxicity

Studies of reproductive and developmental toxicity have been performed with potassium dichromate.

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 also 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).

Observations in humans

Reports of occupational exposures in humans confirm the local irritant and corrosive nature of this group of compounds. The compounds in this group are all classified as corrosive and severe and persistent eye and skin effects (including ulcers) have been observed in humans following single or repeated exposures. There is also clear evidence that the chromium (VI) compounds are skin sensitisers. Respiratory tract sensory irritation has been reported in workers exposed to mists of aqueous chromium (VI) trioxide ('chromic acid'); it is possible that the other compounds in this group may produce similar effects, although it is recognised that the acidity of chromium (VI) trioxide will be an important contributory factor. It is also recognised that the inhalation of chromium (VI) compounds can cause occupational asthma. Inflammation in the lower respiratory tract and nasal septum perforation can occur following repeated inhalation exposure to Cr(VI) in the workplace. In the case of nasal septum damage, an important confounding factor is the possible transfer of Cr (VI) in solution from fingers to the nose due to poor personal hygiene. Some kidney toxicity related to occupational exposure has also been reported.

A number of epidemiological studies are also available, which have investigated the association between occupational exposure to chromium (VI) compounds and the incidence of lung cancer. Chromium (VI) trioxide is regarded as a human carcinogen. Evidence from epidemiological studies has shown an excess in lung cancer. However, this excess cannot be related to particular airborne Cr (VI) levels in any reliable manner. The evidence for the other four chromium (VI) compounds is less clear, but on balance, taking into account all the human and animal evidence, together with their genotoxicity profile, they are also likely to have carcinogenic potential, at least at the site of contact.

DNEL/DMEL derivation

Hexavalent chromium compounds have recently been considered by the Scientific Committee on Occupational Exposure Limits (SCOEL).  The SCOEL recommendation (SCOEL/SUM/86; 2004) has been published.

The health effects of occupational exposure to hexavalent chromium compounds are identified as carcinogenicity (and specifically respiratory tract carcinogenicity), skin and respiratory tract sensitisation, renal toxicity, local irritant and corrosive effects.  SCOEL identified the critical effect of occupational exposure to hexavalent chromium compounds as being the induction of lung cancer. 

While it was not considered possible to reliably rank the carcinogenic potency of hexavalent chromium compounds due to the quality of the epidemiological data available, SCOEL recognised that the soluble hexavalent chromium compounds in this group generally had a higher carcinogenic potency than the less soluble compounds.

SCOELs preferred risk assessment is based on a published review of ten published epidemiological studies by Steenland et al (1996); it has been estimated that about 5-28 excess lung cancers will occur in a cohort of 1000 male workers, followed-up from age 20 to age 85 and occupationally exposed to 50 µg/m3 of hexavalent chromium until retirement at age 65. The corresponding number of excess lung cancers has been estimated to be 2-14 for an exposure level of 25 µg/m3, 1-6 for an exposure level of 10 µg/m3, 0.5-3 for an exposure of 5 µg/m3 and 0.1-0.6 for an exposure level of 1 ug/m3.  It is important to note that these estimates are based on linear extrapolation (i.e. assuming no threshold), whereas the (threshold) irritant and inflammatory reactions caused by these corrosive compounds are likely to be contributory factors in the development of lung tumours.  Linear extrapolation to low doses may therefore overestimate the true cancer risk, however the extent of the overestimation cannot reliably be quantified.  Similarly, the ability of the respiratory tract to detoxify hexavalent chromium by reduction to trivalent chromium is not taken into account by linear extrapolation.

Based on the consideration of the available epidemiological data (primarily the Steenland review), SCOEL recommended consideration of exposure limits of 10 or 25 µg/m3 for the soluble hexavalent chromium compounds.  An inhalation exposure limit of 10 µg/m3 is therefore proposed.  Dermal exposure limits are not proposed and cannot be reliably quantified due to the corrosive nature of the substance. Dermal exposure will be minimised by the use of appropriate engineering controls and personal protective equipment.

No additional data, published since the SCOEL conclusion and which would affect the OEL derivation, has been identified. It is therefore proposed to set the long-term DMEL at this level; it is proposed that the inhalation DMEL is also set at this level.

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure

DNEL related information

General Population - Hazard via oral route

Systemic effects

Acute/short term exposure

DNEL related information

Additional information - General Population

Significant exposure of the general population to hexavalent chromium compounds is not predicted. Inhalation exposure is not predicted. Dermal exposure limits are not proposed and cannot be reliably quantified due to the corrosive nature of the substance; dermal exposure should be minimised due to the potential for sensitisation reactions. Oral exposure is likely to be minimised by the environmental reduction of hexavalent chromium to trivalent chromium.