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Endpoint Summary Information from the European Union Risk Assessment for Nickel Chloride (2008/2009):

Inhalation Absorption:

No studies providing specific information about the absorbed fraction of nickel following inhalation or intratracheal instillation of nickel chloride have been located. Three studies in experimental animals indicate that absorption from the respiratory tract does occur as low retention of nickel in the lungs and extensive excretion in the urine have been observed following intratracheal instillation of nickel chloride in rats. The absorption from the respiratory tract might be extensive in rats as indicated by a urinary elimination of 96.5% of the initial body burden at day 21 post-instillation in the study by Carvalho & Ziemer (1982), an average of 70% of the instilled nickel being excreted by the third day after instillation in the study by English et al. (1981), and 90% of the instilled nickel being excreted, mainly in the urine (75%) by 72 hours after instillation in the study by Clary (1975). However, the experimental design in these studies could not distinguish between nickel absorbed from the lungs and nickel cleared from the lungs, swallowed, and absorbed from the gastrointestinal tract. No human data are available. The absorbed fraction of nickel following inhalation exposure to nickel chloride cannot be quantified based on the available data. The deposition of particles in the respiratory tract depends on the particle sizes (MMADs) as well as on other characteristics of the particles, and the absorption of nickel from the respiratory tract into the blood stream depends on the solubility of the nickel compound inhaled. Soluble nickel compounds, such as nickel chloride, are expected to be absorbed from the respiratory tract following inhalation exposure. This is supported by data from the studies in rats using intratracheal instillation of nickel chloride, which indicate that up to approximately 97% of a dose of nickel chloride can be absorbed from the respiratory tract. By assuming that the absorption of nickel following inhalation exposure to nickel chloride is similar to absorption following intratracheal instillation, the absorption of nickel from the respiratory tract following inhalation of nickel chloride might be as high as up to about 97%.

In conclusion, the available data on nickel chloride and nickel sulphate indicate that the absorption of nickel following inhalation of these nickel compounds might be as high as up to 97-99%; it should be noted that the fraction absorbed apparently depends on the concentration of the nickel compound in the inhaled air as well as on the duration of exposure. For the purpose of risk characterisation, a value of 100% will be taken forward to the risk characterisation for the absorbed fraction of nickel from the respiratory tract following exposure by inhalation of nickel chloride for particulates with an aerodynamic diameter below 5 µm (respirable fraction). For nickel particulates with aerodynamic diameters above 5 µm (non-respirable fraction), the absorption of nickel from the respiratory tract is considered to be negligible as these particles predominantly will be cleared from the respiratory tract by mucociliary action and translocated into the gastrointestinal tract and absorbed. Hence, for the non-respirable fraction, 100% clearance from the respiratory tract by mucociliary action and translocation into the gastrointestinal tract is assumed and the oral absorption figures can be taken.

An inhalation study by Benson et al. (1995) showed that clearance of nickel sulphate from the lungs of rats and mice is extensive (up to 99% in rats and 80 to 90% in mice). By assuming that the clearance of nickel sulphate particles (respirable particles, MMADs ranging from 2.0 to 2.4 μm) from the lungs in the inhalation study is due to absorption rather than to deposition or by mucociliary action, the absorption of nickel from the lungs following inhalation of nickel sulphate might be as high as up to 99% (at concentrations up to 0.11 mg Ni/m3 in rats and up to 0.22 mg Ni/m3 in mice). For further details, the reader is referred to the Risk Assessment Report on nickel sulphate as well as to the Background document in support of the individual Risk Assessment Reports.

For the purpose of risk characterisation, as described in the European Union Risk Assessment for Nickel Chloride (2008/2009) a value of 100% is taken forward for the risk characterisation as the absorbed fraction of nickel from the respiratory tract following inhalation exposure to nickel chloride (respirable size, 100% deposition) in rats.

Endpoint Summary Information from the European Union Risk Assessment for Nickel Chloride (2008/2009):

Oral Absorption:

Absorption of nickel following oral ingestion of nickel chloride has been evaluated in a few studies in experimental animals. When non-fasting rats were dosed by gavage with nickel chloride, 3 to 6% of the nickel was absorbed regardless of the administered dose (Ho & Furst 1973; also quoted in TERA 1999 and IPCS 1991). Another study in rats (Ishimatsu et al. 1995) showed an absorption of 9.8% when nickel chloride was administered in a 5% starch saline solution. In mice, the intestinal absorption was estimated to be 1.7 to 10% when nickel chloride was administered orally by gastric intubation (Nielsen et al. 1993). A study on volunteers (Nielsen et al. 1999a), in which the nickel compound administered was not specified, showed that 25.8% of the administered dose was excreted in the urine following administration of nickel in drinking water to fasting individuals compared with 2.5% when nickel was mixed into a meal. Based on experimental data from various human studies, Diamond et al. (1998) have used a biokinetic model to estimate nickel absorption; the results showed that estimated nickel absorption ranged from 12-27% of the dose when nickel was ingested after a fast, to 1-6% when nickel was administered either in food, in water, or in a capsule during (or in close proximity to) a meal. For further details, the reader is referred to the Background document in support of the individual Risk Assessment Reports. In conclusion, the available data indicate that the absorption of nickel following administration in the drinking water to fasting individuals might be as high as up to about 25-27% and about 1-6% when administered to nonfasting individuals and/or together with (or in close proximity to) a meal.

For the purpose of risk characterisation, as described in the European Union Risk Assessment for Nickel Chloride (2008/2009) a value of 30% is taken forward for the risk characterisation as the absorbed fraction of nickel from the gastrointestinal tract following oral exposure to nickel chloride under fasting conditions. For absorption of nickel from food, soil, dust and from water consumed with food, a value of 5% will be used. When extrapolating rat exposures from the oral route to the inhalation route, a value of 11% is used for absorption by the oral route (Ishimatsu et al., 1995) and 100% for the inhalation route (respirable size, 100% deposition).

Endpoint Summary Information from the European Union Risk Assessment for Nickel Chloride (2008/2009):

Dermal Absorption:

When considering dermal absorption, a distinction should be made between penetration of nickel into skin and percutaneous transport, where nickel is transported through the skin and into the blood stream. For further details, the reader is referred to the Background document in support of the individual Risk Assessment Reports. No humanin vivostudies providing information about the absorbed fraction of nickel following dermal contact to nickel chloride have been located. One study in guinea pigs (Lloyd 1980 also quoted in IPCS 1991) indicate that nickel chloride can be absorbed following dermal contact, but only to a very limited extent (indicated by low levels in blood plasma and in urine up to 24 hours of exposure). In an in vitro study (Tanojo et al. 2001) using human skin (stratum corneum from cadaver leg skin), 98.7% of the dose was recovered in the donor solution after 96 hours, with about 0.7% in the receptor fluid and 0.2% in the stratum corneum. Limited data obtained from in vitro studies using human skin (Fullertonet al. 1986, Spruit et al. 1965 - quoted from IPCS 1991) indicate that absorption following dermal contact may have a significant lag time; the study by Spruit et al. (1965 - quoted from IPCS 1991) also showed that nickel was bound by the dermis.

Absorption of nickel chloride can take place following dermal contact; however, the absorption seems to be lowwith a large part of the applied dose remaining on the skin surface or in the stratum corneum. Recent human in vivo studies of nickel sulphate and nickel metal (Hostýnek et al. 2001a, 2001b) has shown that a large part of the administered dose remained on the surface of the skin after 24 hours or had penetrated into the stratum corneum. For further details, the reader is referred to the Risk Assessment Reports on nickel sulphate and nickel metal.

In vitro studies using human skin support the findings in the human in vivo studies as most of the dose remained in the donor solution and only minor amounts were found in the receptor fluid; the in vitro studies also indicate that absorption following dermal contact may have a significant lag time. For further details, the reader is referred to the Background document in support of the individual Risk Assessment Reports.

In conclusion, the available data indicate that absorption of nickel following dermal contact to various nickel compounds can take place, but to a limited extent with a large part of the applied dose remaining on the skin surface or in the stratum corneum. The data are too limited for an evaluation of the absorbed fraction of nickel following dermal contact to nickel chloride. The in vitro study of soluble nickel compounds (nickel sulphate, nickel chloride, nickel nitrate, and nickel acetate) using human skin (Tanojo et al. 2001) showed about 98% of the dose remained in the donor solution, whereas 1% or less was found in the receptor fluid and less than 1% was retained in the stratum corneum. According to the revised TGD, the amount absorbed into the skin, but not passed into the receptor fluid, should also be included in the estimate of dermal absorption. For the purpose ofrisk characterisation, a value of 2% will be taken forward to the risk characterisation for the absorbed fraction of nickel following dermal contact to nickel chloride.

For the purpose of risk characterisation, as described in the European Union Risk Assessment for Nickel Chloride (2008/2009) a value of 2% is taken forward to the risk characterisation for the absorbed fraction of nickel following dermal contact to nickel chloride.

 

Distribution and Elimination:

Following intratracheal instillation of nickel chloride to rats or oral administration by gavage to mice, the highest concentrations of nickel were found in the lungs and in the kidneys. The major route of excretion of nickel in rats following intratracheal instillation of nickel chloride was in urine with 70 to 80% of a dose being eliminated via the urine within 3 days following instillation and approximately 97% by 21 days after instillation. No data on excretion of nickel chloride in experimental animals following other exposure routes have been located.

Generally, nickel tends to deposit in the lungs of workers occupationally exposed to nickel compounds and in experimental animals following inhalation or intratracheal instillation of nickel compounds. The tissue distribution of nickel in experimental animals does not appear to depend significantly on the route of exposure (inhalation/intratracheal instillation or oral administration) although some differences have been observed. Low levels of accumulation in tissues are observed (generally below 1 ppm). A primary site of elevated tissue levels is the kidney. In addition, elevated concentrations of nickel are often found in the lung, also after oral dosing, and in the liver. Elevated nickel levels are less often found in other tissues. Limited information exists on tissue distribution in humans.

Absorbed nickel is excreted in the urine, regardless of the route of exposure. Most ingested nickel is excreted via faeces due to the relatively low gastrointestinal absorption. In humans, nickel excreted in the urine following oral intake of nickel sulphate accounts for 20 -30% of the dose administered in drinking water to fasting subjects compared with 1-5% when administered together with food or in close proximity to a meal. From biological monitoring in small groups of electroplaters exposed to nickel sulphate and nickel chloride, the half-life for urinary elimination of nickel has been estimated to range from 17 to 39 hours.

Inhaled nickel particles can be eliminated from the respiratory tract by absorption, by deposition in the lung tissues, by removal via the mucociliary action and subsequently swallowed into the gastrointestinal tract, and by exhalation.