PUBLIC CONSULTATION ON RMO ANALYSIS OF NICKEL OXIDE AND NICKEL SULFATE

Transcription

1 PUBLIC CONSULTATION ON RMO ANALYSIS OF NICKEL OXIDE AND NICKEL Comments of the (NiPERA) October 8, 2014

2 NiPERA appreciates the opportunity to provide comments on the RMO analysis of nickel oxide and nickel sulfate to the Ministry of Ecology, Sustainable Development and Energy. The comments below focus on the concerns expressed by the French Agency for Food, and Occupational Health & Safety (ANSES) on the DNEL derivation for nickel compounds. ANSES has done a thorough job of reviewing the toxicity and carcinogenicity data available for Ni oxide and Ni sulphate (Sections 3.3 of the respective documents). In Section 3.4 Derivation of Reference Values of these documents, ANSES discusses the derivation of workplace DNELs for acute and chronic exposures via dermal and inhalation routes. NiPERA appreciates ANSES detailed review of the dossiers and their thought-provoking comments. Although ANSES has not identified any major flaws in the long-term inhalation DNEL derivation based on human data, their comments on the complementary (animal-based) calculations have already led to improvements in the CSRs documents. The NiPERA comments herein address exclusively ANSES s comments on the workplace longterm DNELs. The concerns raised by ANSES are nearly identical in the RMO for Ni sulphate and for Ni oxide; thus, NiPERA s response applies to both documents. Dermal Route Regarding the dermal route (Section 3, Chronic Exposure, Dermal Route), please see comment and response in Table 1 below. Table 1. ANSES comments on NiPERA s Dermal DNEL (Ni sulphate and Ni oxide) and NiPERA s response to these comments. Section in ANSES Response NiO RMO comment (page 84) For dermal route, registrants only considered local effects as relevant, taking into account the sensitizing of the substance (readacross with Ni sulphate). However, sensitization is more often considered as a non-threshold effect, and available data cannot permit to assess quantitatively the risk, thus no DNEL can be derived. A qualitative risk assessment is ECHA Guidance on Information Requirements and Chemical Safety Assessment Part E: Risk Characterisation states the following: It is to be stressed that when data are available that allow the derivation of a DNEL or DMEL for an endpoint (including irritation/corrosion, sensitisation, acute toxicity, carcinogenicity and mutagenicity), the quantitative or semi-quantitative approach (see Section E.3.3) should be followed. Having DNELs or DMELs for all the required and available data on a substance makes it fairly easy to identify the leading health effect for that substance for the relevant exposure patterns. In a footnote in the same page it states: Note that for skin sensitisers the qualitative approach (risk characterisation) to define the RMMs and OCs should be the first step and the derivation of a DNEL (if possible) should be performed to judge the remaining/residual likelihood of risks after these RMMs and OCs are implemented At the individual level, both the induction of dermal Ni sensitization and the elicitation of dermatitis in sensitized people are threshold events. At a population level, there is a wide range of immune responses among individuals; however, an Page 2 of 18

3 therefore considered as relevant for this effect, with appropriate risk management measures and operating conditions. exposure level can be defined that will minimize the percent of Ni-sensitized individuals that would have a positive response to Ni. This concept is the basis for the REACH regulation (Annex XVII of REACH, entry 27) that states that nickel and its compounds are not to be used in certain post assemblies for piercing and certain other articles unless the Ni release rate is less than 0.5 µg Ni/cm 2 /week for articles in direct & prolonged skin contact, and 0.2 µg Ni/cm 2 /week for skin piercing material. This regulation acknowledges that if the Ni-containing materials release Ni below a certain level (i.e., threshold), they will not induce or elicit sensitization in the majority of the population. Furthermore, the CLP (section , note 7) states that Alloys containing nickel are classified for skin sensitization when the release rate of 0.5 µg Ni/cm 2 /week, as measured by the European Standard reference test method EN 1811, is exceeded. The thresholds noted above were derived to assure protection of all non-sensitized individuals and most of the sensitized ones. This is the approach used by NiPERA in the derivation of the dermal DNEL for Ni sulphate which is based on results from patch testing Ni-sensitive individuals. In general it is accepted that the Ni exposure required to sensitize a person is higher than the exposures required to elicit a response once that person is sensitized (Arts et al., 2006). Thus, basing the DNEL on protecting from elicitation of dermatitis also protects from induction of dermal sensitization. The DNEL of mg Ni/cm 2 (based on the study by Fischer et al., 2005) is considered to be sufficiently protective for dermal effects associated with Ni exposure. It is also acknowledged in the REACH regulation that the higher the amount of Ni a substance releases in sweat, the higher its potential to elicit a dermal reaction will be. Thus, the DNEL for Ni oxide was derived by adjusting the DNEL for Ni sulphate (highest Ni release) taking into account the relative release of Ni from Ni oxide and Ni sulphate in synthetic sweat (as described in Appendix B3 to the Oxide CSRs). In summary there is precedent in the REACH regulation and guidance documents for the use of a threshold approach to prevent dermal sensitization to nickel and a quantitative approach to risk assessment seems warranted. Further, as stated by ANSES, in the nickel case skin sensitization is not the leading health effect and the risk is considered controlled when gloves are used (e.g., section , page 119 of the nickel oxide RMO). Inhalation Route Regarding chronic exposures via the inhalation route (Section 3.4, Chronic Exposure, Inhalation route), ANSES reviewed the SCOEL SUM85 doc detailing the derivation of an inhalable OEL for Ni compounds (0.01 mg Ni/m 3 ) (Section 3.4.The SCOEL approach) as well as Appendix C2 to the May 2013 CSRs detailing the derivation of a long term inhalation inhalable DNEL for Ni compounds (0.05 mg Ni/m 3 ) (Section 3.4.The Registrants approach). As a background to NiPERA s response to ANSES comments in Section 3.4, ANSES Page 3 of 18

4 approach, please see below a comparison of the basic approaches taken by SCOEL and NiPERA in the inhalable OEL-DNEL derivations based on human cancer data (Table 2). Table 2. Derivation of Inhalable IOEL of 0.01 mg Ni/m 3 (SCOEL) or Inhalable DNEL of 0.05 (NiPERA) mg Ni/m 3 for Ni compounds. SCOEL 2011 NiPERA 2014 Health effect selected as basis for Inhalable OEL/DNEL derivation Protection from lung cancer effects (with support from nasal effects) observed in epidemiological studies (SCOEL SUM 85) Protection from lung (& nasal) cancer effects observed in epidemiological studies (Oller et al., 2014; Goodman et al., 2011; Appendix C2, REACH dossier, 2014) Dose-response (D-R) Practical threshold Practical threshold Cohort (s) Kristiansand (w/ support from Harjavalta for nasal) 13 cohorts including Kristiansand & Harjavalta Size of cohort 5,000 workers >100,000 workers Exposure type Exposure aerosol fraction Point of departure Fold-factor applied Soluble Ni compounds (in presence of insoluble Ni compounds) Nominal (not inhalable) Exposure measured with 37-mm sampler that undersampled the inhalable fraction by ~ 2-fold 1 The LOAEC (Low Observed Adverse Effect Concentration) for lung cancer was derived from a median cumulative exposure of 1.6 mg Ni/m 3 x years (Table 5, Grimsrud et al., 2002), considering a 40 year exposure. The exposure level associated with the LOAEC for cancer in this cohort was calculated as1.6/40= 0.04 mg Ni/m 3 (37-mm sampler) or ~0.08 mg Ni/m 3 (inhalable sampler) as soluble Ni in the presence of insoluble Ni compounds. The LOAEC (0.04 mg/m 3 ; 0.08 mg Ni/m 3 inhalable) was considered by SCOEL as very conservative because of supralinear dose-response (SUM85, page 36). This number is much lower than the LOAEC from Harjavalta (0.25 mg Ni/m 3 soluble Ni). The LOAEC of 0.08 mg Ni/m 3 (inhalable) is similar to the value considered by NiPERA as a practical threshold (0.1 mg Ni/m 3, inhalable) based on 13 cohorts. The LOAEC of 0.08 mg Ni/m 3 is higher than the final NiPERA derived value of 0.05 mg Ni/m 3 A 4-fold factor was applied by SCOEL to LOAEC of 0.04 mg Ni/m 3 (37-mm sampler, soluble Ni). If the same factor was applied to a LOAEC of 0.08 mg Ni/m 3 (inhalable), the OEL would have been 0.02 mg Ni/m 3 (soluble Ni, inhalable). This is still conservative when applied to total Ni Soluble Ni compounds (in presence of insoluble Ni compounds) Corrected Inhalable 1 A NOAEC (No Observed Adverse Effect Concentration) (0.1 mg Ni/m 3, inhalable) soluble Ni (in presence of insoluble Ni compounds) was considered as a practical threshold for lung cancer based upon linear Poisson regression analysis of relationships between cancer risk ratios and exposures in the 13 cohorts comprising an expanded database of 100,000 workers with an average duration of exposure of 12 years. A 2-fold factor was applied to the inhalable NOAEC of 0.1 mg Ni/m 3 to take into account duration of exposure. The factor is lower than the one used by SCOEL because the starting value considered is a NOAEC instead of a LOAEC and the size of the combined human cohorts is much larger Final value 0.01 mg Ni/m 3 (assigned to total Ni, inhalable) IOEL 0.05 mg Ni/m 3 (assigned to total Ni, inhalable) DNEL Values in blue are those measured with a 37-mm sampler; values in red are inhalable exposures and reflect the difference in sampling efficiency between the 37-mm and the inhalable sampler. 1 Exposures measured with a 37-mm sampler were converted to inhalable exposures using the measured differences in aerosol collection efficiency for the 37-mm cassette compared to the IOM inhalable sampler in nickel exposure data collected at Ni producing and using facilities (Tsai et al., 1985; 1996a, 1996b; 1996c; Vincent et al., 1995; Werner et al., 1996; 1999; Ramachandran et al., 1996; Vincent, 2007). Page 4 of 18

5 In Section 3.4, ANSES approach, the document states that The DNEL worker proposed by the registrant in the oxide [NiSO 4 ] CSR cannot be endorsed for the following complementary reasons. ANSES s complementary reasons are listed in Table 3 below. In general, it is apparent that the documentation in support of the inhalable DNEL derivation contained in Appendix C2 to the 2013 REACH nickel Chemical Safety Reports (CSRs) was not clear enough. In reading it, ANSES understood that the approach taken by NiPERA for the derivation of an inhalable DNEL was very different from that followed by the SCOEL in the derivation of the inhalable OEL. In reality both derivations are very similar. Both derivations are based on human epidemiological lung cancer data. NiPERA additionally a) considered a greater number of lung cancer cohorts and epidemiological lung toxicity data and b) used the MPPD model to derive Human Equivalent Concentrations (HECs) protective of respiratory toxicity and tumor effects observed in rats, as parallel complementary analyses to assure that the inhalable DNEL value based on human cancer data would also be protective for toxicity effects. In other words, the inhalable DNEL is not primarily based on the animal data and the application of the MPPD model, but it is based on the human epidemiological data. The comments provided by ANSES have been helpful to improve the description of the DNEL derivation contained in Appendix C2 of the nickel CSRs. The 2014 version of this appendix more clearly describes the approaches taken to the nickel DNEL derivations. Table 3 below includes ANSES main reasons for not endorsing the NiPERA approach to inhalable DNEL derivation and NiPERA s response to ANSES comments. Table 3. ANSES comments on NiPERA s inhalable DNEL (Ni sulphate and Ni oxide) and NiPERA s response to these comments. ANSES Comment (section ) NiPERA Response No clear data have been presented by As shown in Table 2, the main driver for the derivation of the the NiPERA supporting the use of the inhalable DNEL (and for the inhalable OEL) was cancer, MPPD model as a validated tool for the with the DNEL (and OEL) based on epidemiological lung nickel particles. Some MPPD models cancer data. The MPPD model played no role in this exist that are validated for few particle derivation. compounds; MPPD models are specific to compounds and shall be validated ANSES comments seem to be quite appropriate for a from field data; it is not acceptable to physiologically-based pharmacokinetic (PBPK) model, which apply a generic model to a specific is specific to each compound modeled. The MPPD model is compound without considering the a model for the deposition of poorly soluble particles based physico-chemical parameters of the upon empirical studies and established principles of aerosol considered particle compound. physics that are independent of particle composition and thus do not require validation for each compound modeled. The MPPD model calculates deposition of solid particles in lung airways of rats or humans. Deposition is a function of the physical properties of the particles (such as diameter and density) and the breathing parameters of the subject and does not depend on other compound-specific chemical properties such as solubility. These properties would affect the subsequent absorption of the deposited material into the bloodstream but do not affect the site of initial deposition. The model has been applied to predict deposition of diverse particles such as particulate matter, quartz, silica, diesel exhaust, titanium dioxide, carbon black, cadmium chloride (e.g., Jarabek et al., 2005; Cassee et al., 2002, Brown et al., 2005; Maruyama et al., 2006). No citations are provided by Page 5 of 18

6 ANSES for substance-specific MPPD models but NiPERA would be curious to learn about them. NiPERA complemented the DNEL derivation based on human cancer and non-cancer data by also evaluating whether the DNEL value would be protective of the lung tumors and toxicity seen in rat studies. The MPPD model was used by NiPERA to calculate an inhalable Human Equivalent Concentration (HEC) comparable to the rat Ni sulphate (and oxide, subsulphide, metal) levels at which no toxicity and/or no tumors were observed after exposure for 6h/day, 5d/week for 2 years (lifetime). The parameters used in the model (particle size, density, retention T1/2) were specific to each animal study (as recommended by Greim et al., 2001). The predicted rat lung burdens using the model were comparable to the measured lung burdens after 15 months of exposure to Ni oxide and Ni sulphate in the rat studies (Oller et al., 2014); as such the MPPD model was demonstrated to be a valid predictor of retained Ni doses in rats for Ni compounds spanning the widest range of possible water solubilitis. The human MPPD model is based upon deposition curves for particles of low solubility and low toxicity established after many years of study by the International Council for Radiological Protection (ICRP) and has been validated against experimental lung deposition data (Subramaniam et al., 2003). There is no a priori reason to suspect that nickelcontaining particulate aerosols will exhibit deposition properties that vary from the predictions of the MPPD model. Verifying that the model is applicable to Ni particles is naturally more difficult since there is little data on human lung burdens in well-defined exposure situations. However, the respiratory toxicity data from refinery workers is consistent with the HECs that are calculated using the MPPD model and support our complementary use of the model and parameters to predict retained doses in humans. The use of the MPPD model has been increasing in the last 5 years (e.g., Gangwal et al., 2011; Geraets et al., 2012; Miller et al., 2013), with the MAK Commission and the UAIII Working Party in Germany as well as NIOSH (2011, 2013) in USA using this model to derive OELs for different inorganic substances. Furthermore, dosimetric adjustments have been applied by U.S. EPA to derive ambient air reference concentrations (RfC) for a variety of substances since 1994 (U.S. EPA, 1994) SCOEL also recognized that when animal respirable data was used exclusively to derive an OEL, it is not appropriate to simply define that OEL as inhalable. Thus, SCOEL derived a second respirable OEL, giving some consideration to the appropriateness of using dosimetric approaches (see Table 4). As indicated by ANSES, the problem for the REACH dossiers is that there are no respirable exposure Page 6 of 18

7 data available to compare with a respirable DNEL. For the above reasons NiPERA used the MPPD model and animal data as a complementary analysis conducted in parallel to the derivation of an inhalable DNEL based on human epidemiological data. In this way, equivalent animal and human exposure values could be compared and the animalderived HECs (inhalable) could be used together with the human respiratory cancer and non-cancer exposure data (inhalable) to assure that the inhalable DNEL would be protective of both cancer and non-cancer respiratory effects. MPPD model was originally developed/validated for particles with aerodynamic diameter up to 10 μm and its application to particles up to 61 μm (if this assumption is correct) with important standard deviation (SD) cannot be performed without an extensive validation step. Again this comment refers to the parallel complementary analyses carried out by NiPERA based on rat toxicity or tumor data; this comment does not address the main derivation of the inhalable DNEL based on epidemiological lung cancer data. ANSES refers to the application of the MPPD model to calculate deposited doses in humans using the particle size distribution (PSD) of inhalable workplace aerosols (ranging in MAAD from µm with GSD ranging from 1.1 to 3.5). [MMAD stands for Mass Median Aerodynamic Diameter 2 and GSD stands for Geometric Standard Deviation]. ANSES is correct that the MPPD human model has been validated for particles from 0.01 to 20 µm in diameter (version However, the model is valid for particles outside of this size range as well. Deposition of microparticles (particle sizes > 1 µm) primarily depend on the inertial impaction mechanism in the upper lung airways where velocities are high. For particles in this size range, deposition is a function of the inertial parameter, ρ x d 2 x Q, (ρ is density, d is diameter, Q is flow rate). As particle size increases, particle inertia also increases, thereby increasing deposition in the upper lung airways or even in the upper respiratory tract before entering the lung. Studies have shown that particles > 10 µm will predominantly deposit in the nasal passages, with deposition increasing as particle size increases (Kelly et al., 2004). Thus, the model developers maintain that the deposition predictions are valid for aerosols up to 100 µm in MMAD and a GSD equal to, or less than, 5 (Brown et al., 2013; Owen Price, ARA, personal communication). Input parameters to the MPPD model are the particle size distribution of the aerosol (MMAD, GSD) as well as the density of the material. From this distribution (of particles with different aerodynamic diameter) the model considers the degree of deposition associated with each particle diameter present in the distribution and integrates them to calculate an overall deposition. Figure 1 shows that particles with diameter > 20 µm will have no deposition in the alveolar or trachea-bronchial (TB) regions of the human respiratory tract, which are the regions relevant for the present 2 MMAD=Median of the distribution of airborne particle mass with respect to the aerodynamic diameter. Page 7 of 18

8 calculations of inhalable DNELs based on lung cancer and toxicity data. Thus the application of the MPPD with workplace PSD conducted by NiPERA is reasonable. Moreover other important physical properties of the particles as density for instance, are not taken into account in this model. The MPPD model does take the particle density into account. Particle composition, PSD, and particle density are important parameters to calculate the deposited or retained dose in workers exposed to aerosols generated at specific worksites (e.g., copper example in Miller et al., 2014). As indicated in previous comment, deposition is primarily dependent on density and diameter of the inhaled particles. So the density is taken into account in all lung deposition calculations using the MPPD model. However, in the derivation of the Ni DNEL the question NiPERA addresses is: what is the HEC for Ni sulphate (or other Ni substance), as inhalable or respirable aerosol, that will result in the same retained dose per surface area as the NOAEC in rats? To answer this question it is appropriate to use the density of the pure Ni sulphate (or of the other Ni substances) and the PSD of the workplace (under the assumption that Ni sulphate will be distributed among all particles sizes in a manner analogous to total Ni). This was done for each of the 4 main chemical forms of Ni, each with its own toxicity and each with its own density. Then all the HEC values were considered and the final selected DNEL was protective of the most toxic of these substances. In this way, when the DNEL is applied to a workplace where exposure is 100% to Ni sulphate, the workers are protected but if the exposure is 100% to Ni oxide they are also protected, and they are also protected if the exposure is to a mixture of these two compounds (as a mixture of particles or even as a mixtures in a particle). In Table 5 of Oller et al. (2014) it can be seen that the deposited dose in the thoracic region of the human respiratory tract calculated for Ni oxide (density =6.6 g/cm 3 ) and Ni sulphate (density =2.1 g/cm 3 ) using the same workplace PSDs, differ by 12%. Furthermore, if the workplace real particle density is lower than the one for pure substances used in the MPPD model, the real deposition will be lower and the calculations of HECs will be even more conservative. This could be the situation for example for alloy manufacturing facilities where the density of Nicontaining alloys is lower than the density of pure metallic Ni (8.9 g/cm 3 ). Additionally, because elevated risk of lung and nasal sinus cancer among nickel workers has been demonstrated it does not seem correct to ignore the toxic effect of the fraction of particles not reaching the pulmonary tract. Again the use of the MPPD model relates to the complementary analyses carried out by NiPERA based on rat toxicity or tumor data, not on the main derivation of the inhalable DNEL based on human epidemiological data. As noted by ANSES, the epidemiological studies of sulphidic Ni ore refinery workers indicated increased cancer risks for the nose and the lung. The SCOEL based its derivation of inhalable OEL on the lung cancer data, and so did NiPERA. Page 8 of 18

9 Both SCOEL and NiPERA considered that based on existing data (e.g., ICNCM, 1990), workplace inhalable exposure levels at which no excess lung cancer risks are expected will also be protective from nasal cancer risks. In fact, there is no epidemiological study where nasal cancers were observed at an inhalable exposure level several fold above the DNEL of 0.05 mg Ni/m 3. Since neither SCOEL nor NiPERA judged nasal tumor incidence to be a sensitive endpoint appropriate for DNEL derivation there was no obvious need to present extrathoracic deposition predictions. This is also consistent with the animal data where nasal toxicity effects in rats were always observed at higher exposure levels than lung effects (with no nasal tumors observed in rats). Thus, we have not ignored the nasal effects, but rather determined (as SCOEL did) that protecting from lung effects would also protect from nasal effects. At the end, the proposed mathematic equations to add a clearance function to this model are disproportionately simplistic to describe the clearance mechanisms both in humans and rats, and their differences between species. The granulometry data included in the MPPD model are not considered as generalizable (coming from a limited number of working sites/jobs with a questionable methodology, non-publicly available report from Vincent JH 1996 for instance) While particle deposition is not substance specific, particle retention is. The clearance parameters used for rats were based on measured retention T1/2 values for each of the main Ni substances specific to the studies from which the toxicity values were derived. The predicted lung burdens in rats after 15 month of exposure to Ni sulphate and Ni oxide using these mathematical equations matched reasonably well the measured lung burdens (Oller et al., 2014). In the case of Ni metal, Ni oxide and Ni subsulphide, the clearance parameters are derived from exposure levels at which some toxicity is observed and thus clearance may be impaired. This is a conservative approach since faster non impaired clearance is expected to operate at lower, non-toxic doses (NAEC). The clearance parameters for humans were either based on actual measured data (Ni oxide) or were estimated using very conservative and reasonable assumptions (10- fold slower mechanical particle clearance in humans than in rats). The information on PSD for the workplace is indeed limited (n = 5). These data were collected with a Personal Inspirable/Inhalable Dust Spectrometer (PIDS) sampler (or similar samplers) following state of the art methodology. The report from Vincent (1996) is available from NiPERA and the vast majority of the data collected during this study has been published (Tsai et al., 1985; 1993; 1995; 1996a, 1996b; 1996c; Vincent et al., 1995; Werner et al., 1996; 1999; Ramachandran et al., 1996; Vincent, 2007). In addition, these PSD data have been used in several publications (Oller and Oberdörster, 2010; Yu et al., 2001; Oller et al., 2014). Importantly, the intersampler comparison (37-mm & IOM inhalable samplers) carried out in parallel at the same refinery at which the PSD measurements were taken has shown results consistent with a variety of Ni workplaces (producing and using nickel), as discussed in many of the publications from Vincent s group listed above as well as in Oller and Oberdörster (2010). Thus, although Page 9 of 18

10 a larger dataset of measurements would be desirable, the PSD values employed in the HEC calculations appear to be representative for a large number of Ni worksites. As a generalization, occupational aerosols in other nonferrous metal facilities appear to be quite coarse and are similar to those observed in the nickel studies. For example, more extensive studies of lead (Spear et al., 1998; Vincent, 2007) and zinc (Battersby and Boreiko, 2003) production and use sectors are all characterized by aerosols similar in size to those reported for nickel with some variation being observed as a function of the metallurgical process being studied (Vincent, 2007, chapter 22.3). At least all these reasons/doubts should support the use of an additional assessment factor for interspecies extrapolation based on MPPD model. The possible toxicodynamic differences between human and rat should be taken into account by a specific assessment factor (different from 1) due to the fact that MPPD extrapolation only takes into account possible toxicokinetic differences The assumption that retained pulmonary doses, are more relevant for chronic, long-term toxicity/pulmonary effects of nickel particles should be more supported by scientific evidence and mechanism of toxicity. Independently of retained dose, possible heterogeneity of the particles deposition in lung of rats/humans NiPERA agrees with ANSES that possible toxicodynamic differences between human and rat should always be considered when deriving a DNEL or an OEL for a given substance. Note that both SCOEL and NiPERA have used the same total assessment factor (factor of 3) in their respirable OEL/DNEL derivation (see Table 4). In the specific case of Ni, NiPERA considered what would be an appropriate toxicodynamic assessment factor by comparing the animal data to the human data and by considering the wealth of existing information on the chronic response of rats to inhalation of inorganic particles. These comparisons, for both the predicted dose to target tissue and for cohort mortality epidemiology studies compared to animal bioassay results, indicate that humans are as (or even less) sensitive to the chronic effects of Ni compounds than rats (discussed in Oller et al., 2014). Thus a substancespecific toxicodynamic assessment factor higher than 1 was not justified for the specific case of nickel substances. Risk assessment methodologies consider that for effects such as respiratory chronic toxicity (e.g., chronic inflammation, lung fibrosis) and tumor development (multistage process) after inhalation, it is the retained dose in a given region of the respiratory tract that is associated with the observed effects and the retained particles are the ones that can interact with the tissue to cause adverse effects (U.S. EPA, 1994, 1996; Snipes et al., 1997; Jarabek et al 2005; Maruyama et al., 2006; Brown et al., 2005; Oberdörster, 1996; Driscoll et ai., 1997; Tran et al., 2000; Duffin et al., 2002; NIOSH, 2011, 2013). Thus if it is possible to measure (e.g., lung burden) or calculate (e.g., considering differences between exposure and observation periods, normalizing doses appropriately) the retained dose; this dose will be more relevant to the observed effects than the simple exposure level or the cumulative exposure level (concentration x years). Only for immune effects (e.g., asthma) it is important to consider peak exposures. However, SCOEL notes that contact sensitization and sensitization of the respiratory tract are not Page 10 of 18

11 (hotspots) and its influence on cancer development should be discussed taken into account in the setting of the OEL. The exact same approach was taken by NiPERA in the derivation of the DNELs. In the case of Ni and respiratory tumors, neither the deposited nor the retained Ni dose in rats, by itself, is predictive of tumor outcome across all compounds. The nature of the substance in which Ni is present (soluble, oxidic, sulphidic) has a much greater influence on tumor outcome (Goodman et al., 2011). The calculation of retained doses, however, provides a good long term metric to compare health outcomes between rats and humans exposed to the same compounds. The issues of particle heterogeneity and hotspots are relevant if the rat tumor data had been the sole source of information used to derive the inhalable DNEL. However, as indicated before, the HEC calculations were used only as complementary analyses, with the inhalable DNEL being based on lung cancer data from workers exposed to the real heterogeneous particles and workplace PSDs. In a conservative approach, the lowest OEL proposed by the SCOEL would be used for the risk characterization in this dossier. However, this value of mg Ni/m3 is based on animal studies with inhalation exposure to respirable aerosols which are of small particle size and of great homogeneity. At the workplace, particles are not limited to the respirable fraction, and workers are usually exposed to coarser and more heterogeneous aerosols. Therefore, an OEL based on animal aerosols of MMAD < 10 μm is not directly comparable to the workplace exposures and may overestimate the risk associated with the coarser workplace nickel exposures. On this basis, the OEL of 0.01 mg Ni/m3 set by the SCOEL for the inhalable fraction is considered as more relevant for the risk characterization. This value is based on a significant increase in cancer incidence in a refinery workers cohort NiPERA concurs with the ANSES view that it would not be appropriate to include a respirable DNEL (based upon the animal studies) in the CSRs since the exposure data in the REACH GES workplaces is for coarser aerosols different from the respirable aerosols used in the rat studies. However, NiPERA did not want to ignore the animal toxicity data when tools were available that would permit interspecies dosimetric comparisons. Rather than applying an inhalable DNEL (based on cancer human data) that does not take into account the toxicity inhalation effects observed in animals, NiPERA employed the available dosimetric tools with nickel-specific information and conservative assumptions to evaluate whether the inhalable DNEL would be adequate to also protect for the respiratory toxicity effects observed in animals. Regarding the heterogeneity of aerosols, as mentioned by ANSES, the Ni industry faces the issue that many workplaces listed, e.g., under Ni sulphate GES, include exposures to other forms of Ni as mixtures of particles in the aerosol or as mixtures within particles. To address this problem NiPERA derived a DNEL that covers toxicity of the aerosol whether it is, for example, 100% Ni sulphate or any percent of Ni sulphate mixed with any other form of Ni. As shown in Table 2, the approaches taken by SCOEL and NiPERA to the derivation of an inhalable OEL or DNEL are nearly identical and both use cancer epidemiological data. However, unlike the SCOEL approach, which relies on the estimated dose-response from a single epidemiological cohort, the NiPERA approach utilizes the totality of the Nirelated epidemiological data (13 cohorts, 100,000 Page 11 of 18

12 (Grimsrud et al., 2002) and is therefore directly comparable to exposure estimates that are presented by the registrants in the dossiers. However, it has to be noted that this value covers the risk of cancer incidence, and also the reproductive effect, but it does not take into account the respiratory chronic inflammations observed at lower doses in animal exposed to respirable fraction of nickel compounds (NTP, 1996). workers) to quantify the dose-related response. The SCOEL OEL was defined as inhalable, but it is not a true inhalable aerosol fraction exposure value. It is a value based on data collected with 37-mm samplers and thus is about 2-fold lower than the corresponding inhalable exposure value (please see many references by J. Vincent s group, cited in previous comment). The SCOEL OEL value of 0.01 mg Ni/m 3 (based on just one cohort) would correspond to an inhalable value of 0.02 mg Ni/m 3. In the early stages of REACH registration of nickel substances a guidance document was prepared by IOM (UK) for the Institute. This document describing how best to collect inhalable and respirable exposure data for the GES was provided to the companies. Companies were also encouraged to collect data on PSD of workplace aerosols (already noted above as a data need). NiPERA agrees that this value, as well as NiPERA s DNEL value, cover risks from reproductive and genotoxic effects. In this statement it appears that ANSES is comparing directly the inhalable OEL exposure value to the respirable exposure values ( lower doses ) in animal studies. Yet, ANSES noted earlier that this comparison was not appropriate. The direct comparison of these values is not appropriate given the differences in dosimetry (rat, human) and PSD of rat and human aerosols. Furthermore, the SCOEL-proposed inhalable OEL of 0.01 mg Ni/m 3 is indeed a lower absolute number than the NOAEC or calculated NAEC (No Adverse Effect Concentration) in animal studies (~ 0.03 mg Ni/m 3 ). If ANSES was referring to lower doses as deposited or retained doses, then this is puzzling given ANSES critique of the use of the MPPD model by NiPERA. For respiratory toxicity effects, the existing human epidemiological data indicates that the values of 0.01 mg Ni/m 3 (OEL) and 0.05 mg Ni/m 3 (DNEL) are well below the exposure levels at which increased adverse respiratory toxicity effects have been observed in epidemiological studies. This is confirmed by the fact that there has not been any evidence of widespread pneumoconiosis among Ni workers, compared to exposures to other dusts such as crystalline silica. So even without considering the complementary animal data and the use of the MPPD model, the weight of evidence from the available human data indicates that the inhalable DNEL of 0.05 mg Ni/m 3 would be protective of respiratory toxicity effects in humans. Nevertheless, NiPERA (as the SCOEL did) also derived a respirable DNEL (0.01 mg Ni/m 3 ) that is used in the REACH dossiers as a guidance value for workplaces where exposures to respirable size aerosols are expected. This value was derived from the calculated respirable HECs Page 12 of 18

13 using the MPPD model with the same PSD for humans as present in the rat aerosol (MMAD~2 µm; GSD ~2. Please see Table 4 below. Figure 1. Deposition fraction in various regions of the respiratory tract of humans and rats as a function of particle diameter. Page 13 of 18

14 Table 4. Derivation of respirable IOEL of mg Ni/m 3 (SCOEL) or respirable DNEL of 0.01 (NiPERA) mg Ni/m 3 for Ni compounds and Ni metal based on animal respiratory toxicity data. SCOEL 2011 NiPERA 2014 Health effect selected as basis for OEL/DNEL derivation Protection from respiratory toxicity effects observed in rodent lifetime inhalation studies (SCOEL SUM 85) Protection from respiratory toxicity effects observed in rodent lifetime inhalation studies (Oller et al., 2014; Appendix C2, REACH dossier, 2014) Dose-response Threshold (NOAEC for Ni sulphate) Threshold (NOAEC for Ni sulphate) [and LOAEC for other Ni compounds & Ni metal] Study (s) Chronic inhalation study in rats exposed to Ni sulphate Chronic inhalation study in rats exposed to Ni sulphate [and Ni oxide, Ni subsulphide and Ni Point of departure Dosimetric adjustment NOAEC = 0.03 mg Ni/m 3 (MMAD = 2 µm) Ni sulphate for effects in pulmonary region Not applied but considered. SCOEL (SUM85, page 34) indicates that the rat NOAEC (0.03 mg Ni/m 3 ) corresponds to a human equivalent concentration (HEC) of mg Ni/m 3 (MMAD = 2 µm) when equivalent deposited doses are considered, citing Oller and Oberdörster, (2010). Unfortunately, this calculation utilized a rat pulmonary surface area value that has been recently found (Miller et al., 2011) to be incorrect and resulted in an underestimate of the HEC Fold-factor applied A 3-fold factor was applied to HEC of mg Ni/m 3 to cover long-term retention for more insoluble particles and possible toxicodynamic differences as well as intraworker variability in response. If the same factor would have been applied to the updated HEC based on deposited & retained equivalent doses ( mg Ni/m 3 ), the respirable OEL would have been 0.01 mg Ni/m 3, equal to NiPERA s derived value Final value mg Ni/m 3 (assigned to total Ni, respirable) - metal] NOAEC = 0.03 mg Ni/m 3 (MMAD = 2 µm) Ni sulphate for effects in pulmonary region, [LOAEC = 0.1 mg Ni/m 3 Ni subsulphide, LOAEC = 0.5 mg Ni/m 3 Ni oxide, LOAEC = 0.1 mg Ni/m 3 Ni metal] Applied. The NOAEC of 0.03 mg Ni/m 3 corresponds to a HEC of mg Ni/m 3 (MMAD = 2 µm) when equivalent deposited doses are considered and using the updated value (Miller et al., 2011) for the surface area of the rat pulmonary region. The NOAEC of 0.03 mg Ni/m 3 corresponds to a HEC of 0.03 mg Ni/m 3 (MMAD = 2 µm) when equivalent retained doses are considered [HEC to NAEC values for subsulphide, oxide and metal for equivalent retained doses are similar] A 3-fold factor was applied to HEC of 0.03 mg Ni/m 3 to cover possible intraworker variability in response. A weight of evidence evaluation of animal and human toxicodynamic differences does not suggest that humans are more sensitive to lung toxicity effects than rats mg Ni/m 3 (assigned to total Ni, respirable) guidance value* IOEL LOAEC = Low Observed Adverse Effect Concentration; NOAEC = No Observed Adverse Effect Concentration; NAEC = No Adverse Effect Concentration (calculated); HEC= human equivalent concentration. * A respirable DNEL was derived but not included in the nickel GESs because there were no respirable exposure data available to compare it to. In summary, NiPERA hopes that our responses to ANSES concerns as well as Tables 2 and 4 comparing side-by-side the approaches taken by SCOEL and NiPERA in the derivation of inhalable and respirable OELs/DNELs can help clarify the basis for the nickel DNEL derivation. In the derivation of the inhalable DNEL of 0.05 mg Ni/m 3, NiPERA used an almost identical approach to that followed by SCOEL, but incorporated more cohorts in the determination of the practical threshold for human lung cancer. NiPERA also conducted a complementary analysis to confirm that the inhalable DNEL of 0.05 mg/m 3 is protective against respiratory toxicity (human and animal studies) using quantitative interspecies extrapolation techniques that are accepted and used my multiple regulatory agencies. For these reasons we consider that ANSES has not identified any major flaws in the nickel DNEL approaches but rather that they have underscore a Page 14 of 18

15 lack of clarity in the documentation in support of the DNEL derivation (Appendix C2). Furthermore we agree with ANSES that more information on the particles size distribution for the various nickel GES would strengthen the complementary analyses based on the animal data. NiPERA is thankful for the opportunity to respond to ANSES concerns on the nickel DNELs and have used their input to revise the DNEL documentation contained in Appendix C2 and make it clearer. NiPERA welcomes ANSES review of the revised 2014 Appendix C2. References cited in NiPERA s comments Arts JH, Mommers C, de Heer C Dose-response relationships and threshold levels in skin and respiratory allergy. Crit Rev Toxicol 36(3): Battersby, R. and Boreiko, C Particle size-dependent deposition behavior of zinc oxide with a perspective for the risk of metal fume fever under occupational settings in the zinc industry. Effect of air contaminants on the respiratory tract interpretations from molecular to meta analysis. INIS Monographs, Fraunhofer IRB Verlag: Brown JS, Wilson WE, Grant LD Dosimetric comparisons of particle deposition and retention in rats and humans. Inhal Toxicol 17: Brown JS, Gordon T, Price O, Ashgerian B Thoracic and respirable particle definitions for human health risk assessment. Particle and Fibre Toxicology 2013, 10:12. Cassee, F. R., Muijser, H., Duistermaat, E., FreijeI', J. J., Geerse, K. B., Marijnissen, J. C. M., and Arts, J. H. E Particle-size dependent total mass deposition in lungs determines inhalation toxicity of cadmium chloride aerosols in rats. Application of a multiple path dosimetry model. Arch. Toxieol. 76: Driscoll, K. E., Deyo, L. C., Carter, J. M., Howard. B. W., Hassenbein, D. G., and Bertram, T. A Effects of particle exposure and particle-elicited inflammatory cells on mutation in rat alveolar type II cells. Carcinogenesis 18: Duffin, R., Tran, C. L., Clouter, A., Brown, D. M., MacNee, W., Stone, V., and Dondaldson, K The importance of surface area and specific reactivity in the acute pulmonary inflammatory response to particles. Ann. Occup. Hyg. 46(suppl.l): Fischer LA, Menne T, and Johanssen JD Experimental nickel elicitation thresholds A review focusing on occluded nikel exposures. Contact Dermatitis; 52: Gangwal S1, Brown JS, Wang A, Houck KA, Dix DJ, Kavlock RJ, Hubal EA Informing selection of nanomaterial concentrations for ToxCast in vitro testing based on occupational exposure potential. Environ Health Perspect Nov;119(11): doi: /ehp Epub 2011 Jul 25. Geraets L, Oomen AG, Schroeter JD, Coleman VA, Cassee FR Tissue distribution of inhaled micro- and nano-sized cerium oxide particles in rats: results from a 28-day exposure study. Toxicol Sci Jun;127(2): doi: /toxsci/kfs113. Epub 2012 Mar 19. Page 15 of 18

16 Goodman JE, Prueitt RL, Thakali S, Oller AR The nickel ion bioavailability model of the carcinogenic potential of nickel-containing substances in the lung. Crit Rev Toxicol 41(2): Greim H, Borm P, Schins R, Donaldson K, Driscoll K, Hartwig A, Kuempel E, Oberdorster G, Speit G Toxicity of fibers and particles-report of the workshop held in Munich, Germany, October Inhal. Toxicol. 13(9): Grimsrud TK, Berge SR, Haldorsen T, Andersen A Exposure to different forms of nickel and risk of lung cancer. American Journal of Epidemiology 156(12): ICNCM (International Committee on Carcinogenesis) Report of the International Committee on Carcinogenesis in Man. Scand J Work Environ Health 16: Jarabek AM, Asgharian B, Miller EJ Dosimetric adjustments for interspecies extrapolation of poorly soluble particles (PSP) Inhal Toxicol 17: Kelly JT, Asgharian B, Kimbell JS, and Wong BA Particle deposition in human nasal airway replicas manufactured by different methods. Part I. Inertial regime particles. Aerosol Sci. Technol, 38: Maruyama W, Hirano S, Kobayashi T, Aoki Y Quantitative risk analysis of particulate matter in the air: interspecies extrapolation with bioassay and mathematical models. Inhal Toxicol 18: Miller FJ, Kaczmar SW, Danzeisen R, Moss OR Estimating lung burdens based on individual particle density estimated from scanning electron microscopy and cascade impactor samples. Inhal Toxicol Dec;25(14): doi: / Miller FJ, Kimbell JS, Preston RJ, Overton JH, Gross EA, Conolly RB The fractions of respiratory tract cells at risk in formaldehyde carcinogenesis. Inhalation Toxicol 23(12): NIOSH (National Institute for Occupational Safety and Health) Current Intelligence Bulletin 63: Occupational Exposure to Titanium Dioxide. DHHS (NIOSH) Publication No NIOSH (National Institute for Occupational Safety and Health) Current Intelligence Bulletin 65: Occupational Exposure to Carbon Nanotubes and Nanofibers. DHHS (NIOSH) Publication No Oberdörster, G Significance of particle parameters in the evaluation of exposure-doseresponse relationships of inhaled particles. In Particle overload in the rat lung and lung cancel': Implications for human risk assessment, eds. J. L. Mauderley and R. J. McCunney, Proceedings of a conference held at the Massachusetts Institute of Technology, March 1995, pp Washington DC: Taylor & Francis. Oller AR and Oberdörster G Incorporation of particle size differences between animal studies and human workplace aerosols for deriving exposure limit values. Regul Toxicol and Pharmacol. 57: Page 16 of 18

17 Oller AR, Oberdörster G, Seilkop S, Derivation of PM10 size-selected human equivalent concentrations of inhaled nickel based on cancer and non-cancer effects in the respiratory tract. Inhal Toxicol, 26(9): Ramachandran, G., Werner, M.A., Vincent, J.H., On the assessment of particle size distributions in workers aerosol exposures. Analyst 121, SCOEL (Scientific Committee on Occupational Exposures Limits) SUM Recommendation from the Scientific Committee on Occupational Exposure Limits for nickel and inorganic nickel compounds. June Snipes, M. B.,James,A. C., and Jarabek, A.M The 1994 ICRP66 human respiratory tract model as a tool for predicting lung burdens from exposures to environmental aerosols. Appl. Occup. Environ. Hyg. 12(8): Spear TM, Werner MA, Bootland J, Murray E, Ramachandran G, Vincent JH Assessment of particle size distributions of health-relevant aerosol exposures of primary lead smelter workers. Ann Occup Hyg Feb;42(2): Subramaniam RP, Asgharian B, Freijer JI, Miller FJ, Anjilvel S Analysis of lobar differences in particle deposition in the human lung. fnl/al. Toxicol. 15(1): Tran, C. L., Buchanan, D., Cullen, R. T., Searl, A., Ones, A. D., and Donaldson, K Inhalation of poorly soluble particles. II. Influence of particle surface area on inflammation and clearance. [nhal. Toxicol.12: Tsai, P.J., Vincent, J.H., Mark D., Maldonado, G., Impaction Model for the Aspiration Efficiencies of Aerosol Samplers in Moving Air under Orientation-Averaged Conditions. Aerosol Science and Technology 22: Tsai, P.J., Vincent, J.H., Impaction Model for the aspiration efficiencies of aerosol samplers at large angles with respect to wind. J. Aerosol Sci. Vol. 24. No.7. pp Tsai, P.J., Vincent, J.H., Wahl, G., Maldonado, G., Occupational exposure to inhalable aerosol in the primary nickel production industry. Occup. Environ. Med. 52, Tsai, P.J., Werner, M.A., Vincent, J.H., Maldonado, G., 1996a. Exposure to nickel containing aerosols in two electroplating shops: Comparison between inhalable and total aerosol. Appl. Occup. Environ. Hyg. 11, Tsai, P.J., Vincent, J.H., Wahl, G.A., Maldonado, G., 1996b. Worker exposure to inhalable and total aerosol during nickel alloy production. Ann. Occup. Hyg. 40, Tsai, P.J., Vincent, J.H., Mark D., 1996c. Semi-empirical model for the aspiration efficiencies of personal aerosol samplers of the type widely used in occupational hygiene. Ann. Occup. Hyg., vol 40, Page 17 of 18

18 U.S. EPA Methods for derivation of inhalation reference concentrations and application of inhalation dosimetry. EPA/600/8-90/066F, Oct U.S. EPA U.S. Protection Agency Dosimetry of inhaled particles in the respiratory tract In Air qualify criteria/or particulate matter, vol. II of III, chap. 10. Office of and Development, Washington, DC. EPA/600/P-95/001 bf. April. Vincent, J.H., Assessment of Aerosol Exposures of Industry Workers, a Final Report to the (NiPERA), October Vincent, J.H (2007). Aerosol Sampling: Science, Standards, Instrumentation and Applications. West Sussex, U.K.: Wiley. Vincent, J.H., Tsai, P.J., Warner, J.S., Sampling of inhalable, thoracic, and respirable dust fractions with application to speciation. Analyst, 120, Werner, M.A., Spear, T.M., Vincent, J.H., Investigation into the impact of introducing workplace aerosol standards based on the inhalable fraction. Analyst 121, Werner, M.A., Vincent, J.H., Thomassen, Y.H., Hetland, S., Berge, S., Inhalable and total metal and metal compound aerosol exposures for nickel refinery workers. Occup. Hyg. 5, Yu, C.P., Hsieh, T.H., Oller, A.R., Oberdörster, G., Evaluation of the human Ni retention model with workplace data. Reg. Toxicol. Pharm. 33, Page 18 of 18