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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.9 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
Overall assessment factor (AF):
18
Modified dose descriptor starting point:
LOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.8 mg/m³
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.9 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
Overall assessment factor (AF):
18
Dose descriptor:
LOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.8 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
Dose descriptor starting point:
LOAEC

Workers - Hazard via dermal route

Systemic effects

Acute/short term exposure
DNEL related information

Workers - Hazard for the eyes

Additional information - workers

Toxicokinetics

Although the behaviour of chromium in biological tissue varies according to degree of water solubility, in general, trivalent chromium compounds (in contrast to hexavalent chromium) are poorly absorbed and taken up by cells when not organically complexed.  Up to 1% of chromium III is absorbed from the normal diet, inhaled chromium III uptake is a very slow process, and chromium III compounds were not shown to be absorbed across the skin into systemic circulation. The prominent tissues for chromium distribution are the liver, kidneys and spleen as well as bone and the remaining carcass (muscle, skin and hair). There is no clear evidence to show the valency of trivalent chromium changes during metabolism and absorbed chromium III is mainly excreted in the urine and to a lesser extent in the faeces.

Acute toxicity

A proprietary acute oral toxicity study is available for the material 'Chromsal B' (chromium hydroxide sulphate / sodium sulphate), which shows low toxicity. This study was reported briefly, but in sufficient detail to enable confident evaluation of the method and the reliability of the results. The calculated LD50 from this study of 3530 mg/kg bw shows that the substance is of low toxicity by this route.  No information on acute dermal toxicity is available, however toxicity by this route can be predicted to be very low based on the low acute oral toxicity and very low dermal penetration of Cr (III) compounds. A waiver is therefore proposed for acute dermal toxicity; testing is not justified on scientific or animal welfare grounds. No information is available on acute inhalation toxicity; testing is proposed for this route which is of relevance to occupational exposure.

Irritation

A proprietary study of skin irritation was performed to a non-standard protocol. However the exposure method used in this study (24 -hour application to the interior surface of the rabbit ear) is noted to be more stringent than specified under the current OECD guideline 404. The finding in this study that the test material is non-irritating to skin is therefore acceptable.  A proprietary study of eye irritation was performed to a protocol broadly comparable to the current OECD guideline 405. The test material was found to be non-irritating under the conditions of this study.  Although the studies are not reported in great detail and are not performed in strict compliance with current guidelines, they indicate that the substance is not irritating to the skin or eyes. This conclusion is supported by the absence of findings of irritation in humans following occupational exposure. Further testing for skin and eye irritation is therefore not justified on scientific or animal welfare grounds.

Sensitisation

No evidence of skin sensitisation was seen in a GLP- and guideline-compliant Buehler study performed with a mixture of chromium hydroxide sulphate and sodium sulphate. The Buehler method is considered to be appropriate given the low dermal penetration of this substance.  It is generally considered that chromium (III) is the active hapten for the chromium (VI) sensitisation which is well recognised and a number of studies with trivalent chromium salts using induction by injection have shown positive results. Therefore it is shown that Cr(III) compounds are much less potent skin sensitisers than Cr(VI) compounds; this difference in potency is attributable to the very low dermal penetration of Cr (III) salts. There are a small number of literature studies which identify skin sensitisation in tannery workers exposed to basic chromium sulphate and also in the general population following close dermal contact to chrome-tanned leather products such as shoes. These cases may concern induction or elicitation, due to leaching of low levels of hexavalent or higher levels of trivalent chromium from the leather. However it is unclear whether these cases involved concomitant exposure to low levels of Cr (VI) contaminants or resulted from cross-reactivity between Cr (III) and Cr (VI). It can be concluded that Cr (III) compounds are probably capable of eliciting sensitisation reactions, but that the potency is very low and that it is related to water solubility. Chromium hydroxide sulphate is of relatively low water solubility and therefore is likely to have a very low skin sensitisation potency. This is supported by the clearly negative response seen in the guideline Buehler study performed with the substance.

Repeated dose toxicity

The NOAEL for systemic toxicity via the oral route is greater than 7 mg/kg/day in the rat based on several studies of water-soluble chromium chloride and chromium picolinate summarized in the FIOH review on trivalent chromium (2006).  The results of subchronic oral studies can be used to assess the risk associated with subchronic dermal exposure. A review of several dermal absorption studies by FIOH (2006) shows that dermal absorption of chromium (III) is very poor. Another review by the UK HSE (1989) found that approximately 2% of administered chromium (III), administered in the form of water-soluble chromium chloride, was dermally absorbed by guinea pigs after 5 hours. Based upon the oral NOAEL and the very limited extent of dermal absoprtion, the dermal NOAEL for systemic toxicity following repeated exposure can be predicted to be high; there is no concern regarding local effects following repeated dermal exposure.   The principle effects observed in a guideline-compliant, 3 -month subchronic inhalation study in rats were primarily noted in the respiratory tract. Rats exposed to water-soluble basic chromium sulphate developed changes in the mediastinal lymphatic tissue, lung, larynx and nasal cavity. Foreign material was absent or decreased after the recovery period in the lungs and was no longer found in the larynx of low- and mid-exposure level rats. This suggests that basic chromium sulphate is most likely rapidly cleared from the respiratory tract due to its high water solubility. Evidence of systemic toxicity was primarily limited to reductions in body weight not related to reduced food consumption. A NOAEC was not established in this study based on the pathological findings in the respiratory tract; the LOAEC for this study was 17 mg/m3 (equivalent to 3 mg/m3 Cr3 +).

Genotoxicity

Trivalent chromium is an essential trace element and highly water-soluble and bioavailable complexes of chromium (III) are used as dietary supplements. In clinical cases, the administration of chromium (III) salts has been shown to improve the efficacy of insulin in diabetic patients. Although some data generated using acellular systems indicate that chromium (III) has the potential to bind to DNA and cause DNA damage in vitrogenotoxicity studies were generally negative in bacteria as seen in the guideline-compliant Ames study (Herbold, 1991) as well as literature reviews which summarize numerous in vitro genotoxicity studies using both soluble and insoluble chromium (III) compounds (De Flora et al, 1990; Eastmond et al, 2008; FIOH, 2006; ATSDR, 2000; HSE, 1989). Studies of in vitrogenotoxicity in mammalian cells gave mixed results; weakly positive results were obtained with water soluble chromium (III) compounds that are taken up by cells and with water-insoluble chromium oxide which cells may phagocytose. The results therefore suggest that the inability of chromium (III) to cross the cell membrane effectively reduces activity in in vitro systems.

Chromium oxide did not induce micronucleated polychromatic erythrocytes in mice in a guideline-compliant study using intraperitoneal dosing (Herbold, 1992). In vivo genotoxicity studies summarized in four literature reviews showed that chromium (III) compounds did not produce DNA strand breaks/crosslinks or chromosomal aberrations in rats and were negative for somatic mutations and recombination in Drosophila (Eastmond et al, 2008; FIOH, 2006; ATSDR, 2000; HSE, 1989).

It is therefore concluded that occupational exposure to chromium (III) hydroxide sulphate will not result in genotoxicity. There is no convincing evidence from biomonitoring studies or from experience of use over a number of years of genotoxic effects resulting from occupational exposure to chromium (III) salts.

Carcinogenicity

No evidence of respiratory tract carcinogenicity was seen in an implantation study using basic chromium sulphate (Levy & Venitt, 1986). A number of literature reviews have summarized information on the carcinogenicity of water-soluble chromium (III) compounds. A drinking water study in rats and mice showed no increase in tumour incidence compared to controls when administered low concentrations of chromium acetate for their lifetime (HSE review, 1989). Intraperitoneal injections of mice with water-soluble chromium (III) sulphate three times per week for eight weeks showed similar incidences of lung adenomas in test and control groups (HSE review, 1989). Occupational exposure to chromium (III) compounds in tanneries, usually to basic chromium sulphate, has not been associated with an excess risk of cancer (ATSDR review, 2000).  Carcinogenicity studies employing various water-soluble chromium (III) compounds and exposure routes have yielded negative results. Both IARC and EPA have classified chromium (III) as Group C and Group D, respectively, that is, not classifiable as to carcinogenic potential (ATSDR review, 2000).  No effects of treatment were seen in a 2 -year dietary study performed at levels of up to 5% chromium (III) oxide, equivalent to approximately 2000 mg/kg bw/d (Ivankovic & Preussmann, 1975). No evidence of carcinogenicity was seen in two inhalation studies performed in the rat (Hueper & Payne, 1961) and mouse (Nettesheim et al, 1970) although both studies have deficiencies in design and reporting. Some evidence of local inflammation of the respiratory tract was seen in the rat study. No evidence of carcinogenicity was seen in two studies using intratracheal or intrabronchial implantation (Levy & Venitt, 1986; Laskin et al, 1970). A poorly reported study (Dvizhkov & Fedorova, 1975) indicates local tumorigenicity following administration of chromium (III) oxide by intratracheal, pleural interstitial or intraperitoneal administration.  Recently completed NTP carcinogenicity studies in the rat and mouse with the water-soluble complex chromium picolinate produced only equivocal evidence of carcinogenicity in the male rat. Rats (50/sex) were administered chromium picolinate in the diet at 0, 2000, 10000 and 50000 ppm; a slight and non dose-related increase in the incidence of preputial gland adenoma in males. No evidence of carcinogenicity was seen in mice (50/sex/group) administered the same dose levels. It is noted that this highly water-soluble complex is an extreme worst case as systemic absorption of Cr (III) is likely to be considerably higher than from the less soluble chromium (III) hydroxide sulphate.

It is noted that occupational exposure to chromium (III) compounds in tanneries has not been associated with an excess risk of cancer. It is noted that both IARC and EPA have classified chromium (III) as Group C and Group D, respectively, that is, not classifiable as to carcinogenic potential.

Reproductive toxicity

A 90-day inhalation study with basic chromium sulphate (Derelanko et al, 1999) showed no effects on sperm parameters at exposure concentrations of up to 168 mg/m3. A number of drinking water studies using chromium chloride have suggested effects on male and/or female reproductive performance, however reviews of these studies have identified a number of deficiencies in these studies and the effects on the reproductive system are unclear. A guideline reproductive toxicity study is proposed for basic chromium sulphate. Administration of high dose levels of chromium chloride in the drinking water (Elbetieha & Al-Hamood, 1997) to mice indicate adverse effects on male and female fertility. The same authors also report effects on fertility and sexual behaviour in male rats. 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 Cr(III) 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 considered to be justified either for scientific reasons or on animal welfare grounds.

Developmental toxicity

Embryo/foetolethality and teratogenicity have been reported in studies with water-soluble chromium chloride in non-standard studies using high-dose parenteral (ip or sc) administration. Toxicokinetic data shows that trivalent chromium accumulates in the placenta but only a low proportion of chromium in maternal serum crosses the placenta to the foetus (FIOH, 2006). The results of an EST assay performed with the water-soluble chromium (III) chloride salt were negative. A guideline-comparable study of Cr (III) toxicity in the mouse (Bailey et al, 2008) performed with two water-soluble Cr (III) complexes do not indicate any teratogenicity, foetotoxicity or developmental toxicity; further testing for developmental toxicity is not proposed for developmental toxicity.

DNEL/DMEL derivation

Dermal DNEL/DMEL

No dermal DNEL/DMEL values are proposed in the absence of data, however it is clear that chromium (III) hydroxide sulphate is of very low toxicity by the dermal route due to the low dermal absorption. Significant local dermal effects resulting from exposure to chromium hydroxide sulphate are not predicted.

Inhalation DNEL/DMEL

The critical effects of inhalation exposure to chromium hydroxide sulphate appear to be local effects on the respiratory tract; little evidence of systemic toxicity was seen in inhalation studies. The absence of systemic effects is likely to be due to the low toxicity and the relatively low bioavailability of trivalent chromium.

An inhalation DMEL can be derived using the LOAEC of 17 mg/m3 chromium hydroxide sulphate (equivalent to 3 mg/m3 Cr (III)) from the 90 -day inhalation study Derelanko et al (1999) as a point of departure (POD). Although a NOAEC was not established in this study due to the microscopic effects observed in the respiratory tract of some animals exposed to the lowest exposure level, the low incidence and minimal severity of the pathological effects suggests that 17 mg/m3 is very near a NOAEC.

It is noted that the current UK WEL (8-hour TWA reference value) for chromium III compounds is set at 0.5 mg/m3 as Cr III (consolidated list, October 2007). The derivation of the WEL value is not detailed, however as the value is designed to cover all chromium III compounds, it is likely to be a reasonable approach with respect to chromium hydroxide sulphate. The toxicity of chromium (III) compounds is generally low, but is related to the solubility of individual compounds. The solubility of chromium hydroxide sulphate means that it is representative of the toxicity of compounds in the group; it is noted that an EU IOEL of 2 mg/m3 has been set for insoluble Cr (III) compounds, which would not cover this substance. The derivation of the UK WEL represents an assessment factor of 6 over the minimal LOAEC from the study of Derelanko et al. No critical data have become available since the derivation of UK WEL for chromium (III) compounds.

Following REACH guidance, the use of the following default assessment factors should be considered:

Assessment factor of 3 for interspecies differences; local effects on the respiratory tract

Although this is a conservative approach, there is no data on the relative sensitivity of rats and humans to the local effects of inhaled chromium hydroxide sulphate. The assessment factor is used to cover potential differences in airway deposition between rats and humans, however the differences are not predicted to be high for the relevant endpoint (local effect).

Assessment factor of 2 for intraspecies differences; extrapolation to workers

The REACH guidance recognises that the use of an assessment factor for local effects is a conservative approach; in this case variation is not predicted to be significant and an asssessment factor of 2 is therefore used.

Assessment factor for exposure duration; extrapolation from a sub-chronic study to chronic exposure

There is no specific information on the increasing severity of effects with increasing exposure time for chromium hydroxide sulphate. However an assessment factor is not used in this case as the relevant effect seen is local.

Additional Assessment factor of 3 to take into account the use of a LOAEC as a starting point

This is not considered to be a major concerns this case, given the minimal nature of the (local) effects seen at the LOAEC and the absence of concern for other (systemic) effects. However as a conservative approach, an additional factor of 3 is used,

Combining the default assessment factors gives an overall assessment factor of 18; applying the overall assessment factor to the LOAEC of 17 mg/m3 results in a long-term DNEL of 0.9 mg/m3. A short-term inhalation DNEL of 2.8 mg/m3 is proposed, in line with REACH guidance and in the absence of specific data, at three times the long-term DNEL value. In the absence of any systemic toxicity in the critical study, the DNEL values for local effects are considered to be suitably protective and seperate value are not proposed.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.45 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
Overall assessment factor (AF):
36
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.4 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
Modified dose descriptor starting point:
NOAEC

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.45 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
Overall assessment factor (AF):
36
Dose descriptor:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.4 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Dose descriptor starting point:
NOAEC

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.07 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.07 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL

General Population - Hazard for the eyes

Additional information - General Population

Significant exposure of the general population to basic chromium sulphate is not predicted.

The general population is exposed to levels of Cr (III) naturally present in food and as a result of the use of dietary supplements; any additional dietary exposure resulting from industrial uses is likley to be minimal. Oral exposure DNEL/DMEL values are therefore not proposed. Inhalation exposure of the general population to chromium hydroxide sulphate likely to be minimal due to the low volatility of these compounds.

Inhalation DNEL values for the general public are proposed on the same basis as those for workers, but with an addtional assessment factor of 2 to account for intraspecies differences. Derma DNEL values are not calculated as dermal absorption is not predicted. Oral DNEL values are calculated from the NOAEL for soluble Cr (III) compounds of 7 mg/kg bw/d and usin an overall assessment factor of 100.

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