Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
43 µg/m³
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
37.5
Dose descriptor starting point:
LOAEL
DNEL value:
5.2 mg/kg bw/day
Modified dose descriptor starting point:
other: LAEC
DNEL value:
1.6 mg/m³
Explanation for the modification of the dose descriptor starting point:

According to RAC/35/2015/09: oral absorption 5%; inhalation absorption 30%; standard respiratory volume 0.384 m³/kg bw/day; breathing rate for workers light activity vs rest 1.5.

Doses refer to Cr(VI), corresponding doses for Dichromium trischromate are 3 fold higher.

Acute/short term exposure
Hazard assessment conclusion:
insufficient hazard data available (further information necessary)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
carcinogenicity
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
43 µg/kg bw/day
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
150
Dose descriptor starting point:
LOAEL
DNEL value:
5.2 mg/kg bw/day
Modified dose descriptor starting point:
other: LAEL
DNEL value:
6.5 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

According to RAC/35/2015/09: oral absorption 5%; dermal absorption 4%

Doses refer to Cr(VI), corresponding doses for Dichromium trischromate are 3 fold higher.

Acute/short term exposure
Hazard assessment conclusion:
insufficient hazard data available (further information necessary)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - workers

Grouping of the water-soluble hexavalent chromium compounds

Dichromium tris(chromate) contains both Cr (III) and Cr (VI) moieties. Cr (III) compounds are generally not classified for health effects; they are poorly absorbed into the body following oral, dermal and inhalation exposure and Cr (III) is an essential nutrient required for energy metabolism. It is predicted that effects of the substance will be almost entirely due to Cr (VI), therefore a read-across is proposed to other water-soluble hexavalent chromium compounds. The compounds in this group (e. g. chromium (VI) trioxide, sodium (VI) dichromate, potassium (VI) dichromate, sodium (VI) chromate and potassium (VI) chromate) are considered to be sufficiently similar in terms of their toxicology to enable grouping of the compounds 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.

Once systemically absorbed, and beyond any effects specific to the site of contact, the Cr (VI) compounds are considered to be essentially identical in terms of toxicokinetics and toxicodynamics. All the compounds are water soluble and will therefore dissociate in the aqueous physiological environment to liberate chromate (VI) or dichromate (VI) ions.

Toxicokinetics

There are 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 following 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 of 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; this metabolic pathway is present in all mammals. As a consequence of this reduction, absorbed Cr (VI) is excreted (in urine and faeces) in the form of glutathione complexes of Cr (III).

Acute toxicity

Dichromium tris(chromate) was found to be toxic by the oral route, but not toxic by the dermal route. Chromium trioxide is toxic by the dermal route. Chromium trioxide, sodium chromate, sodium dichromate and potassium dichromate are all very toxic by inhalation and toxic by the oral route.

Irritancy

Dichromium tris(chromate) 25% solution was not corrosive in the in vitro EPISKIN reconstituted human epidermis assay. No in vivo data are available, and further testing cannot be justified as dichromium tris(chromate) is classified as corrosive to skin according to Regulation (EC) No 1272/2008. Studies with sodium chromate, sodium dichromate or potassium dichromate indicate that these compounds are skin irritants when mixed with water. Aqueous chromium (VI) trioxide (chromic acid) is corrosive due to its 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 occupational exposure indicates that the water-soluble Cr (VI) compounds (e.g. potassium dichromate, sodium dichromate, chromium trioxide) are both skin and respiratory sensitisers. Evidence from animal studies also indicates that these compounds are skin sensitisers. Dichromium tris(chromate) is classified as a skin sensitiser according to Regulation (EC) No 1272/2008, however neither experimental data nor occupational/medical information indicate that dichromium tris(chromate) might be a respiratory sensitiser.

Repeated 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

Dichromium tris(chromate) gave positive results in a GLP and guideline-compliant bacterial reverse mutation test.

The overall body of evidence indicates that Cr(VI) is genotoxic in vivo, resulting in the formation of DNA adducts and oxidative DNA damage. However, clear evidence of mutagenicity in vivo in the target tissues for carcinogenicity (lung and intestine) by relevant routes of exposure is lacking. This supports the contention that Cr(VI) is only weakly mutagenic in vivo and that its mutagenicity is most likely to be only one contributory factor in the carcinogenic process, together with tissue injury/irritation/inflammation and cell proliferation.

Carcinogenicity

The carcinogenicity of 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 in the EU RAR (2005). Chromium (VI) causes lung tumours in humans and animals by the inhalation route and tumours of the gastrointestinal tract in animals by the oral route. These are both local, site-of-contact tumours; there is no evidence that Cr(VI) causes tumours elsewhere in the body. Reference dose response relationships for the carcinogenicity of hexavalent chromium substances are documented in the ECHA publication "Application for authorisation: Establishing a reference dose response relationship for carcinogenicity of hexavalent chromium", Ref RAC/27/2013/06 Rev.1, dated 4 Dec 2013.

Reproductive toxicity

There are a multitude of published studies that address the toxicity to reproduction and developmental toxicity of Cr(VI) substances. As the most sensitive and sufficiently reliable studies, RAC/35/2015/09 identified the study by Li et al. (2001) for fertility effects, and the study by Elsaieed and Nada (2002) for developmental effects. Based on these studies, the Committee for Risk Assessment derived an oral LOAEL of 5.2 mg Cr(VI)/kg bw/d for effects on the testes in rats treated for 6 days (Li et al., 2001), and an oral LOAEL of 7.9 mg Cr(VI)/kg bw/d for a number of foetal effects in rats during gestation (Elsaieed and Nada, 2002). Derivation of the corresponding DNELs is described in RAC/35/2015/09.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
11 µg/m³
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
75
Dose descriptor starting point:
LOAEL
DNEL value:
5.2 mg/kg bw/day
Modified dose descriptor starting point:
other: LAEC
DNEL value:
0.8 mg/m³
Explanation for the modification of the dose descriptor starting point:

According to RAC/35/2015/09: oral absorption 5%; inhalation absorption 30%; standard respiratory volume 1.15 m³/kg bw/day.

Doses refer to Cr(VI), corresponding doses for Dichromium trischromate are 3 fold higher.

Acute/short term exposure
Hazard assessment conclusion:
insufficient hazard data available (further information necessary)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
carcinogenicity
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
22 µg/kg bw/day
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
600
Dose descriptor starting point:
LOAEL
DNEL value:
5.2 mg/kg bw/day
Modified dose descriptor starting point:
other: LAEL
DNEL value:
6.5 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

According to RAC/35/2015/09: oral absorption 5%; dermal absorption 4%

Doses refer to Cr(VI), corresponding doses for Dichromium trischromate are 3 fold higher.

Acute/short term exposure
Hazard assessment conclusion:
insufficient hazard data available (further information necessary)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
carcinogenicity
DNEL related information
Explanation for the modification of the dose descriptor starting point:

According to RAC/27/2013/06 Rev. 1, based on an exposure for 70 years (24h/day, every day) and an 89-year life expectancy and against a human background cumulative lifetime intestinal cancer risk of 9 – 16 per 1000 for the German population, the following risk estimates is derived: An excess lifetime intestinal cancer risk = 8 x 10-4 per μg Cr(VI) /kg bw/day.

Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - General Population

The EU RAR identified no concerns for human health from indirect exposure via the environment other than in relation to genotoxicity and carcinogenicity for which no thresholds could be determined. However, exposure modelling of exposure via the environment indicated very low daily intakes, suggesting low concern.

Direct exposure of the general population from production or use of dichromium trischromate is not expected based on the uses presented in this document. Emission abatement techniques are used to minimise air emissions of chromium trioxide, however indirect exposure to chromium (VI) in the form of particulates may potentially occur. The environmental behaviour of chromium is such that chromium (III) is the relevant form for the consideration of indirect oral exposure.

 

The UK Committee on Medical Aspects of Food and Nutrition Policy (COMA) hassuggested that an adequate level of intake for chromium (III) lies above 0.025 mg/day for adults (0.00035 mg/kg bw/d) and between 0.0001 and 0.001 mg/kg/day for children and adolescents (COMA, 1991). COMA also noted that no adverse effects were observed at intakes of 1000–2000 mg/day trivalent chromium. The US National Research Council (NRC) specify an Estimated Safe and Adequate Daily Dietary Intake (ESADDI) of 0.05–0.2 mg/day for adults and 0.01–0.04 mg/day for infants (0‑0.5 years).

 

There are no data to indicate that dermal exposure to Cr(VI) compounds presents a cancer risk to humans (RAC/27/2013/06 Rev.1).

 

However, since in RAC/35/2015/09 DNEL values for the general population were derived based on the reproductive toxicity of Cr(VI) compounds, these DNEL values are considered in this dossier as well. As the most sensitive and sufficiently reliable studies, RAC/35/2015/09 identified the study by Li et al. (2001) for fertility effects, and the study by Elsaieed and Nada (2002) for developmental effects. Based on these studies, the Committee for Risk Assessment derived an oral LOAEL of 5.2 mg Cr(VI)/kg bw/d for effects on the testes in rats treated for 6 days (Li et al., 2001), and an oral LOAEL of 7.9 mg Cr(VI)/kg bw/d for a number of foetal effects in rats during gestation (Elsaieed and Nada, 2002). Derivation of the corresponding DNELs is described in RAC/35/2015/09.