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Rationale for use of NiSO4 data in the NiF2 dossier


 


Data on the bioaccessibility of Ni fluoride in biological fluids as a surrogate for bioavailability can be found in Section 7.1.1 of this IUCLID file (Kirby I and II, NiF2, 2008 and Bioaccessibility data, KMHC, NiSO4, 2010). This document demonstrates that Nickel fluoride can be grouped in the class of soluble Nickel Compounds, represented by Nickel sulfate which is the most extensively examined.


In situations where the bioavailability of a metal substance is not known or not feasible to determine experimentally, the amount of ion “available for absorption” may be measured using in vitro methods.  In the references mentioned above, the dissolution (e.g., elution or extraction) of metal ion from surrogate (synthetic) tissue fluids is measured. The resultant value is termed bioaccessibility and is defined as the amount of a substance (e.g., metal ion) available for absorption.  These reports measured bioaccessibility of nickel substances as a surrogate for bioavailability.


In the following table, highest values for both salts are reported:


 















































 Time

% Nickel release /Nickel content


Nickel fluoride


Average of two replicates



% Nickel release /Nickel content


Nickel sulfate


Average of two replicates


 Simulated Gastric fluid 72h  86.4100 (5H)
 Simulated Alveolar Fluid 72h 42.148.2
 Artificial Perspiration 72h99.31011
 Lysosomal Fluid 2h104.1594.6
Simulated Interstitial Fluid 72h50.2557.4
 Simulated Intestinal Fluid 5h77.4 46

 


All values are very similar, with nickel release from nickel sulfate always higher. The only value where nickel sulfate seems significantly lower than nickel fluoride is in the Simulated Intestinal fluid.


Being less bioavailable than Nickel sulfate, most of the data collected for this substance can be used in read-across in a conservative way, as nickel fluoride is less bioavailable.


 


Toxicokinetics assessment based on NiSO4 data 


Inhalation Absorption


Endpoint Summary Information from the 2008/2009 European Union Risk Assessment for Nickel Sulphate:


The absorbed fraction of nickel following inhalation exposure to nickel sulphate 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 sulphate, are expected to be absorbed from the respiratory tract following inhalation exposure. This is supported by data from the study by Medinsky et al. (1987), which showed that 50 to 80% of a dose (dependent on the dose) of nickel sulphate can be absorbed from the respiratory tract. By assuming that the absorption of nickel following inhalation exposure to nickel sulphate is similar to absorption following intratracheal instillation, the absorption of nickel from the respiratory tract following inhalation of nickel sulphate might be as high as up to 80%. Furthermore, the inhalation study by Benson et al. (1995) showed that clearance of nickel sulphate from the lungs of rats and mice is rapid and extensive (up to 99% with a half-time of 2-3 days in rats and 80 to 90% with a half-time of less than one day 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). Other inhalation studies in rats (Benson et al. 1988, NTP 1996) indicate that lung nickel burdens increase with increasing concentrations of nickel sulphate (at least up to about 0.8 mg Ni/m3) in the inhaled air as well as with duration of exposure.


In conclusion, the available data on nickel sulphate and nickel chloride 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 nitrate 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.


For the purpose of risk characterisation, as described in the 2008/2009 European Union Risk Assessment for Nickel Sulphate 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 sulphate (respirable size, 100% deposition) in rats.


 


Oral Absorption


Endpoint Summary Information from the 2008/2009 European Union Risk Assessment for Nickel Sulphate:


 


A study on volunteers (Nielsen et al. 1999), 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.


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, a value of 30% will be taken forward to the risk characterisation for the absorbed fraction of nickel from the gastrointestinal tract following oral exposure to nickel nitrate in the exposure scenarios where fasting individuals might be exposed to nickel nitrate. In all the other exposure scenarios, a value of 5% will be used for the absorbed fraction of nickel from the gastrointestinal tract.


 


For the purpose of risk characterisation, as described in the European Union Risk Assessment for Nickel Sulphate (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 ion (from nickel sulfate, and applied to nickel fluoride) 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).


Dermal absorption


Endpoint Summary Information from the 2008/2009 European Union Risk Assessment for Nickel Sulphate:


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.


In a recent human in vivo study of nickel sulphate (Hostýnek et al. 2001), a large part of the administered dose remained on the surface of the skin after 24 hours or, according to the authors, is adsorbed in the uppermost layers of the stratum corneum. In an in vitro study (Tanojo et al. 2001) using human skin (stratum corneum from cadaver leg skin), about 97% of the dose was recovered in the donor solution after 96 hours, with about 1% in the receptor fluid and 0.6% in the stratum corneum. Limited data obtained from other in vitro studies using human skin (Fullerton et al. 1986, Samitz & Katz 1976 – quoted from IPCS 1991) indicate that absorption following dermal contact may have a significant lag time.


Studies in experimental animals indicate that nickel can be absorbed through the skin of rats (Mathur et al. 1977 – quoted from IPCS 1991) and guinea-pigs and rabbits (Norgaard 1957 – quoted from IPCS 1991). Another study in guinea pigs (Lindberg et al. 1989 – quoted from NiPERA 1996) showed that nickel only penetrated into the stratum corneum.


Absorption of nickel can take place following dermal contact to nickel fluoride, based on the nickel sulphate assessment; however, the absorption seems to be low with a large part of the applied dose remaining on the skin surface or in the stratum corneum.


A recent human in vivo study of nickel metal (Hostýnek et al. 2001) 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.


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.”


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 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 of risk characterisation, a value of 2% is taken forward to the risk characterisation for the absorbed fraction of nickel following dermal contact to nickel sulphate.


For the purpose of risk characterisation, as described in the 2008/2009 European Union Risk Assessment for Nickel Sulphate, a value of 2% will be taken forward to the risk characterisation for the absorbed fraction of nickel from nickel fluoride, based on the nickel sulphate assessment.


In addition to the above information and summaries from the European Union Risk Assessment, data on the bioaccessibility of nickel difluoride and nickel sulphate in biological fluids as a surrogate for bioavailability are reported within Section 7.1.1 of this IUCLID file.


 


Discussion on bioaccumulation potential result:


ENDPOINT SUMMARY INFORMATION FROM THE 2008/2009 NICKEL SULPHATE RISK ASSESSMENT


 


Two inhalation studies in rats (Benson et al. 1988, NTP 1996) indicate that lung nickel burdens increase with increasing concentrations of nickel sulphate (at least up to around 0.8 mg Ni/m3) in the inhaled air as well as with duration of exposure. The study by Benson et al. (1988) indicates that the lung nickel burden may rise to a steady state level as the lung nickel burdens were almost similar in rats exposed to 15 or 30 mg/m3. A third study (Dunnick et al. 1989) found similar concentrations of nickel in the lungs of rats and mice after 4, 9, and 13 weeks of inhalation to nickel sulphate (0.02 to 0.4 mg Ni/m3). Of nickel remaining in the body after 96 hours following a single dose of nickel sulphate administered by intratracheal administration, over 50% was in the lungs. The deposition of nickel in the lungs of rats is apparently greater than in the lungs of mice. No human data 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 either by exhalation, by absorption from the respiratory tract, or by removal due to mucociliary elimination.


 


For further details, the reader is referred to the Background document in support of the individual Risk Assessment Reports.


 


In addition to this summary from the EU Risk Assessment, data on the bioaccessibility of Ni sulfate and Ni fluoride in biological fluids as a surrogate for bioavailability are reported within Section 7.1.1 of this IUCLID file.

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