General introductory remarks

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1 JAPANESE RISK ASSESSMENT ON ANTIMONY AND ITS COMPOUNDS - SUGGESTIONS I2A ON MUTAGENICITY/GENOTOXICITY, REPRODUCTIVE TOXICITY, CARCINOGENICITY AND OEL VALUE- (JANUARY 2013) Abbreviations: ATO = diantimony trioxide (CAS ); SHHA = sodium hexahydroxoantimonate (CAS ); APO = diantimony pentoxide (CAS ); ATC = antimony trichloride (CAS ); APC = antimony pentachloride (CAS ) General introductory remarks i2a politely wishes to note that in the context of EU chemicals risk assessment (EU-RAR, performed under Council Regulation (EEC) 793/931), only oral, dermal and inhalation exposures are considered, since these are the only relevant exposure routes for chemicals, and are as such used further in this document to assess human health effects of antimony. In contrast, whereas other application routes (such as i.p., s.c. etc.) may be of vital importance for example for pharmaceuticals or medical devices, their uptake and distribution kinetics are usually remote from those of the aforementioned three physiological routes. In this document, we will focus on some endpoints that are identified to be different from the scientific data gathered by i2a: mutagenicity/genotoxicity, reproductive toxicity and carcinogenicity. The final conclusions of the EU-RAR of ATO and the REACH registration process of the i2a Sb substances, as summarized in below table, are discussed more in detail in following sections: Summary of hazard assessments for Sb substances discussed more in detail below Human health hazards Mutagenicity/genotoxicity Reproductive toxicity Carcinogenicity Conclusion Sb substances are non-clastogenic and non-mutagenic. Sb substances do not present a reproductive toxicity hazard. (derived critical concentrations: NOAEL =1686 mg/kg (oral) and NOAEC=6.3 mg/m³ (inhalation)) ATO can be regarded as a threshold carcinogen (NOAEC = 0.51 mg/m³; OEL : 0.5 mg/m³ One remark on data quality: for the EU-RAR of ATO and the REACH registration process, i2a has gathered and reviewed all relevant international scientific publications, and has subsequently performed new studies for those endpoints for which adequate information (according to OECD guidelines and GLP compliant) was lacking. To ensure that only good quality and reliable scientific data are used to assess chemicals, a critical review process of the scientific literature was performed. The most relevant aspects 1

2 for this review process are quality, reliability and relevance of the studies (eg information on purity and identity of test substance, details of study methods used, provision of raw data, guideline and GLP compliance ). The reliability criteria applied are described by Klimisch et al. (1997). The use of such study quality indicators is generally required in the EU registration process, and has also been applied in the preceding EU and OECD (SIDS) assessment reports. In this way, the regulatory process ensures that data quality is established and documented. i2a supports and encourages the use of above mentioned quality assessments for scientific literature to ensure that only high quality and reliable scientific data are used for chemical assessment of Sb and antimony substances worldwide. Reproductive / Developmental Toxicity Similar to the Japanese Risk Assessment, i2a has previously assessed two non-standard fertility studies in animals (Belyaeva (1967) and Omura et al (2002)), and one human occupational report (Belyaeva, 1967). However, none of these studies were performed according to standard guidelines, and they all suffer from numerous shortcomings. For this reason, no conclusions on the effects of Sb(III) substances on female fertility could be drawn based on these studies. In the Japanese Risk Assessment, two other studies are additionally considered in the assessment for this endpoint: Grin et al (1987) and Alkhawajah et al (1996). i2a has in the meantime reviewed both of these studies, and concludes that both studies have to be considered inconclusive due to the following critical shortcomings: -Grin et al (1987): - it is not clearly documented whether the studied substance was indeed ATO or perhaps APO (only reported as antimony oxide ) - neither purity nor particle size is reported. - study was reported in 1987 in a journal which may or may not have a peer-review procedure ( Gigiyena I Sanitariya ), and is summarised only very briefly in a two-page publication, thus missing a lot of essential details relevant for a quality screening. - the study not performed according to any standard guidelines. - it was not reported how the aerosol was generated or analytically characterised. - with regard to the concentration of the antimony oxide aerosol, it is notable that the variations in concentration at the low exposure levels (0.027 and mg/m³) were 14 % and 6% of mean value (the unit of the variation is not stated), whereas the variation at the highest exposure level (0.27 mg/m³) was 155 %. It is therefore 2

3 doubtful whether the extremely low concentrations could actually be technically generated with the stated precision. - considering 24 h exposure per day, it is assumed that it was whole-body exposure, but there is no information on how the animals were actually exposed (ventilation rate, etc). It is in fact quite uncommon to expose animals for such an extensive period 6h per day is a more reasonable daily exposure period. Such an extended exposure is very likely to exert unnecessary stress factors to all exposed animals. -Alkhawajah et al (1996): - this study describes experiments involving the repeated i.m.-injection of pentavalent antimonials as well as ATC; this route of administration is considered relevant only for pharmaceuticals, but not relevant for chemicals. In contrast, the only human health concern for ATO is via inhalation - none of the findings are considered to be relevant for read-across to the poorly soluble, trivalent ATO. For the reasons above, i2a politely suggests not to include these studies in the assessment for reproductive/developmental toxicity, and also not to consider them to derive critical threshold concentrations. In contrast, i2a politely notes that in the EU/OECD assessment, it was concluded that antimony substances are NOT reprotoxic, for the following reasons: (I) in a 90-day oral feeding study of ATO, Wistar rats were fed diets containing ATO (Hext et al., 1999; cfr repeated dose toxicity in i2a s Summary of available scientific data 1 ) at doses by far exceeding 1,000 mg/kg bw/d. The study was performed according to current guidelines and reports all parameters required for a full appraisal. Complete macroscopic and histopathological investigations were performed on all rats, including also the following tissues of organs with reproductive function: -epididymes and testes were weighed -epididymes, testes, prostate gland, seminal vesicle, ovary and uterus were examined for macroscopic lesions -epididymes, testes, prostate gland, seminal vesicle, ovary and uterus were fixed in 10 % neutral buffered formalin or other appropriate fixative. Tissues from the controls and the top dose group were examined microscopically. As an outcome, no changes were seen in the female or male reproductive organs, and an oral NOAEL of 1686 mg/kg (based on absence histopathological changes for female (ovary and uterus) and male (epididymis, testes, prostate gland, seminal vesicle) reproductive organs) is suggested. In a toxicokinetic study, Sb tissue levels in reproductive organs were extremely low, providing supportive information that organs of reproductive function are not preferential target organs for Sb upon ingestion of ATO. (II) for the sake of completeness, i2a is currently performing a Prenatal Developmental Toxicity Study with rodents (OECD 414) using SHHA as test substance (reporting expected end 2013) for 3

4 the purpose of read-across to all other Sb(V) substances. The dose-range finder study (14- days oral gavaging, doses of mg/kg(bw), 3 females/group and 2 litters/group) did not show any adverse effect at 1000 mg/kg. For exposure of humans via the environment, ingestion of food and water are the most relevant routes. For thermodynamic considerations, ambient environmental antimony will transform to the (soluble) pentavalent form Sb(V); any such material being transformed from ATO released to the environment may therefore be considered covered by this data. (III) for developmental toxicity of ATO itself, there is one recent methodically reliable rat inhalation study available (Schroeder, 2003; 6 h/day exposure throughout gestation). The highest exposure concentration corresponds approximately to 10-fold the OEL value, and the high dose gives rise to mild maternal toxicity. The study does not show statistically significant developmental toxicity up to the highest concentration (6.3 mg ATO/m³). Although a slight increase of resorptions and postimplantation loss was observed in the highest dose group, these values did not differ statistically from controls (p = 0.11) and were within the range of recent historical control data (4-8%, mean 6%). This study suggests that an NOAEC for developmental toxicity can be established at or above 6.3 mg ATO/m³. Because of the poor oral, dermal and inhalation absorption of Sb substances and the results of the toxicokinetic study, any quantitatively relevant exposure of reproductive organs in male and female mammalian species to ATO can be ruled out. In addition, there were no macroscopic or histopathological findings in a 90d feeding study (rats) at very high doses (>>1,000 mg/kg bw/d). The EU/OECD assessment concluded that based on these results, any specific effects on reproduction are not to be expected. Therefore, it is scientifically not justified to conduct any further developmental toxicity or two-generation reproduction studies in rats, in compliance with the 3R-rules (Replacement, Reduction and Refinement) for animal welfare. Based on the weight of evidence from the available long-term toxicity studies in rodents and the relevant information on the toxicokinetic behaviour in rats, it may be concluded that ATO (and other Sb(III) substances in the group) does not present a reproductive toxicity hazard. Derived critical concentrations are NOAEL =1686 mg/kg (oral) and NOAEC=6.3 mg/m³ (inhalation) for poorly soluble Sb(III) substances 4

5 Mutagenicity / Genotoxicity For Sb(III) substances, both negative and positive results were obtained via in vitro testing: -Negative results were obtained in: - two Ames tests (Elliot et al., 1998; Kuroda et al., 1991) - a study using the spot technique (Kanematsu et al., 1980) - the Mouse Lymphoma TK± assay (Elliot et al., 1998). -Positive results were obtained in: - two rec± assays for DNA damage (Kuroda et al., 1991; Kanematsu et al., 1980) but it is difficult to draw conclusions on the reliability of the results on the basis of the study details provided. - a chromosomal aberration study (Elliot et al., 1998) - two studies investigating the induction of SCE (Gebel, 1997; Kuroda et al., 1991); Elliot et al (1998; Ames test, Mouse Lymphoma TK± assay, CA study) was performed according to OECD guidelines. Both negative and positive results were obtained via in vivo testing: -Negative results were obtained in: - the studies of Elliot et al (1998) and Whitwell (2006) (OECD and GLP compliant) - the mouse bone marrow chromosomal aberration test using a single dose protocol (Gurnani, 1992) -Positive results were obtained in: - the mouse bone marrow chromosomal aberration test using the repeated oral exposure using male mice (Gurnani et al., 1992) Due to the questionable reliability of Gurnani et al (1992), these study results were not considered for the hazard assessment, so that the overall conclusion on in vivo clastogenicity testing using mice and rats was negative. This finding was supported by a recent toxicokinetic study (OECD and CLP conform) using repeated oral ATO administration at 1,000 mg/kg showing a low oral uptake of ATO, and tissue distribution data confirmed that the bone marrow was exposed by comparion higher than any other tissue (De Bie and Salmon-te Rietstap, 2005). Considering the results obtained in above studies, their individual quality and reliability, it was concluded by weight-of-evidence that (i) ATO does not induce gene mutations in vitro, and (ii) whereas ATO has some potential to induce structural chromosome aberrations in mammalian cells in vitro, the invivo verification testing was negative. This reasoning of the EU Risk Assessment was adopted also by OECD under the ATO-SIAP. For the sake of completeness, in vivo testing with SHHA (as a pentavalent Sb substance) did not induce micronuclei in cultured human peripheral blood lymphocytes (Stone 2010) and did not induce mutation at the tk locus of L5178Y mouse lymphoma cells (Whitwell, 2010). Kuroda et al (1991 Klimisch 2) showed no effects of APC on bacteria. 5

6 The above mentioned studies for Sb(III) substances have actually all been used in the Japanese RA. However, in the Japanese RA, we were surprised that it was concluded that studies with ATO, ATC, APO and APC were positive for mutagenicity/genotoxicity, whereas i2a (and via the SIAP process also the OECD) concluded the opposite: It is concluded that ATO and other Sb(III) substances do not induce gene mutations in vitro. The induction of structural chromosome aberrations in cultured mammalian cells observed in vitro is considered overruled by negative in vivo studies in rats and mice. This is supported by a study showing that ATO does not cause systemic mutagenicity after oral administration. It is concluded that SHHA (and other Sb(V) substances via read-across) are non-clastogenic and nonmutagenic. Important considerations supporting i2a/oecd s viewpoint: -metal specificities: tests on the mutagenic potential of antimony compounds in bacteria are considered dispensable for principal considerations, since inorganic metal compounds are frequently negative in this assay due to limited capacity for uptake of metal ions (ECHA Guidance on information requirements and chemical safety assessment, Chapter R.7a, p. 387; HERAG facts sheet mutagenicity, Chapter 2.1). -acidification of the medium: Antimony chloride molecules react with water molecules upon dissolution as 2 SbCl n + n H 2 O Sb 2 O n + 2n HCl, hereby releasing protons and thus leading to a sharp ph decrease in solution (this corresponds to the classification as corrosive which is related to the same ph effect). Where appropriate control treatments for such a reactive substance are not included, results should be regarded with caution. -potential adverse cytotoxic effect of precipitates: upon dilution in water, antimony chlorides will hydrolyse, and the hydrolysis products may either spontaneously bind to hydroxyl-ligands, or form Sb (hydr)oxide precipitates (Sb(OH) n or Sb 2 O n ), especially at physiological (neutral or slightly alkaline) ph. Dissolved Sb concentrations in solution are mostly not measured / reported, so that it is impossible to relate the reported effects to effective Sb concentrations. Also, human data do not support the mutagenic/genotoxic potential of ATO: the genotoxicity of ATO in lymphocytes of occupationally exposed workers was assessed by the sister chromatid exchange (SCE) and micronucleus (MN) test and the enzyme (Fpg)-modified comet assay (Cavallo et al, 2002). No inductions of MN or SCE were seen when comparing the two exposed groups with the unexposed group. In the enzyme modified comet assay, workers of the high exposure group showed a significantly higher oxidative DNA damage in their lymphocytes than the control group. However, the workers were exposed to various chemicals, the exposure to antimony is only in the ambient air exposure range (ie mg/m³) and no monitoring was performed on the control group. Therefore, the correlation between higher oxidative DNA damage and antimony exposure is uncertain. 6

7 Please check the document i2a s Summary of available scientific data for mechanistic information, and more remarks regarding testing metals for mutagenicity/genotoxicity) Carcinogenicity Three chronic inhalation studies in rats are available for the carcinogenicity assessment of ATO. Watt ( mg ATO/m³ produced lung neoplasms in 44 % of the tested animals) and Groth et al. ( mg ATO/m³ produced pulmonary neoplasms in 32 % of the female rats, none in male rats) showed positive results. Newton et al. (1994) showed no ATO-related lung tumours, neither in males nor in females, at any dose level up to 4.5 mg/m³. Re-evaluation of histopathology slides by the pathologist who evaluated the Watt and Groth slides confirmed a lack of ATO-related neoplastic changes. Possible reasons explaining the differences between Watt/Groth and Newton: - exposure levels in Watt (1983) higher than reported? Exposed rats in Watt had more lung damage and considerably more antimony deposited in the lungs than in Newton et al (1994). Given that the dose level in Groth (1986) is 10 times higher and also the dose levels in the study by Watt were likely much higher than 1.9 and 5.0 mg/m³ (based on a retrospective analysis of particle size and Sb lung burdens), the dose levels in the Newton study most probably were below the threshold that may elicit lung tumours. - different particle generation techniques or different rat strains. - use of different techniques: The particle size was similar among the studies although they were all measured using different techniques. Particle overload hypothesis: Newton et al (1994) showed that ATO reduced the pulmonary clearance rate in a dose dependent manner, and interpreted this as a toxic effect of ATO rather than a general effect due to pulmonary overload. However, it is well known that reduced lung clearance at chronic exposure of rats to poorly soluble particles (PSPs) can result in pulmonary overload, subsequently followed by an inflammatory response, epithelial cell hypertrophy and/or hyperplasia and squamous metaplasia. The persistence of these tissue responses over chronic time periods can lead to secondary development of lung tumours (Hext, 1994). Thus, it could be speculated that the neoplastic effects seen in the Watt and Groth et al studies is a result of pulmonary overload and an inflammatory response to particulate ATO. This hypothesis is supported by the assessment of the total lung load during exposure. Once the load is at or above the threshold level of 1 mg/g(lung tissue) (1000 nl/g at relative density of 1), lung clearance by alveolar macrophages is affected (Oberdörster, 1995). Calculating this lung burden for the three inhalation studies reveals: -Newton et al (1994): 1460 µg/g ( 300 nl/g; basis data MMAD 3,7 µm - loading 1,5 mg/g lung - relative density 5,5) at highest exposure level (< threshold value) 7

8 -Watt (1983) : likely 2-3 fold higher than Newton et al (1994) (3 mg/correponding to 550 nl/g) coming close to the threshold level -Groth (1986): significantly higher than threshold level (25.6 mg/g and 4.5 mg) ATO produced lung cancer in female rats, not in male rats, but a higher concentration of ATO was found in lungs from male rats and there appeared to be more inflammatory cells in the male rat lung than in the female rat lung (Groth et al, 1986) indicating that the tumour response was not only a function of lung tissue concentration of ATO. Also, Groth et al (1986) observed a 32 % incidence of lung neoplasms in female rats, no in male rats although pulmonary interstitial fibrosis was seen in both males and females. In the majority of studies with particle exposure, it appears that females develop the higher incidences of lung tumors (Lee et al, 1985). This may be attributed to a more potent response to particles in females or to the fact that in a number of studies the females had a greater survival rate. Even a relatively small increase in longevity in one sex may result in an apparent disproportional increase in tumour incidence as the tumours develop towards the end of the life span of the rat (Hext, 1994). The overall expert judgement by TC NES (Technical Committee for New and Existing Substances) is that the most likely mechanism for carcinogenicity appears to be impaired lung clearance and particle overload followed by an inflammatory response, fibrosis and tumours. Consequently, ATO can be regarded as a threshold carcinogen (NOEC for cancer: 4.5 mg/m 3 ); as a highly conservative starting point for a quantitative risk characterization, a NOAEC of 0.51mg/m 3 derived for local repeated dose toxicity was derived in the EU Risk Assessment, and also used for carcinogenicity (cfr i2a s Summary of available scientific data 1 ). This reasoning was accepted by OECD for the ATO-SIAP. However, this conservative value disconsiders the high incidence of pulmonary disease even in the controls, rendering most of the toxicological findings as obsolete and without dose-response. No data on the carcinogenic potential of Sb(V) substances are currently available. However, given that the overload mechanism is intrinsically coupled to poor solubility, it may be anticipated that the highly water soluble Sb(V) substances do not have the potential to be carcinogenic considering the scientific information for toxicokinetics, acute toxicity data and the dose-range finding study of the currently running repeated-dose toxicity via oral exposure to SHHA. The overall expert judgement of the EU Risk Assessment was that the most likely mechanism for carcinogenicity appears to be impaired lung clearance and particle overload followed by an inflammatory response, fibrosis and tumours. Consequently, ATO can be regarded as a threshold carcinogen. The EU derived as a starting point for a quantitative risk characterisation the NOAEC of 0.51 mg/m³ (Newton et al., 1994) derived for local repeated dose toxicity, which was also used for carcinogenicity. 8

9 Derivation of OEL value For the EU REACH registration of Sb substances, DNELs were derived for all relevant exposure routes and target populations. Where national OELs existed, their scientific basis was also considered. A stepwise approach was followed: -selection of the relevant dose-descriptor based on the hazard assessment (cfr i2a s Summary of available scientific data) -modification of the relevant dose descriptor to the correct starting point, if necessary -application of assessment factors (ECETOC, 2003) to obtain an endpoint-specific DNEL for the relevant exposure pattern, if necessary. The long-term DNEL for inhalation/local effects for ATO was based on the threshold concentration of repeated-dose toxicity: Repeated inhalation exposure to ATO gives local toxic effects in the lung and a NOAEC of 0.51 mg/m³ is derived from a 12 month inhalation exposure study in rat (Newton et al., 1994), supported by observations of acute pneumonia in a 19 days inhalation developmental toxicity study (Schroeder, 2003). No systemic toxicity is observed after repeated exposure, therefore no quantitative risk characterization is performed for systemic repeated dose toxicity. In accordance with the EU RAR, the NOAEC of 0.51 mg/m³ from a chronic inhalation toxicity study in rats is used as starting point. Because the route of exposure via inhalation is relevant for workers, the starting point was corrected in accordance with the EU RAR on ATO as follows: -for activity driven differences for workers: 6.7/10 = for differences in deposition rate between rats and workers: mean value 4 NOAEC corrected : 0.51 x 0.67 x 4 = 1.4 mg/m³ (rounded value) This DNEL is derived for a local effect, i.e. an effect observed at the site of first contact and caused irrespective of whether the substance is systemically available. Thresholds for local effects are generally driven by the concentration at the target organ rather than by a cumulative/systemic dose. In this case, where the target organ is the lung, the constantly operating clearance mechanisms are not overwhelmed up to a certain local concentration, rather independently of the duration of exposure. Whereas the severity of the effects may increase with increased exposure duration, the minimum threshold concentration (NOAEL) from which the effect starts to occur does not decrease with increasing exposure duration. Thus, a modification of the starting point with regard to different duration of exposure in the laboratory animals relative to humans via the factors 6h/8h for workers can be neglected for this local DNEL. An assessment factor of 3 is applied for workers for intra-species variability (ECETOC, 2003). This assessment factor is introduced since it is expected that a greater variability in response from the most to least sensitive human would be seen, relative to an experimental animal population. ECETOC (2003) has reviewed scientific literature on the distribution of human data for various toxicokinetic and toxicodynamic parameters to assess intraspecies variability within the human population, specifically by Renwick and Lazarus (1998) and Hattis et al. (1999). Considering that the data analysed by these authors includes both sexes, a variety of disease states and ages, the use of the 95th percentile of the distribution of the 9

10 variability for these datasets is considered sufficiently conservative to account for intraspecies variability for the general population. Based on this, a default assessment factor of 3 (i.e. closer to the 90th percentile of the distribution of the variability for these datasets) is proposed for the more homogeneous worker population. In the worker population, the more susceptible groups are typically excluded and/or may be protected from specific exposures. Thus, and in consideration of normal hygiene practices at the workplace, a lower value for the assessment factor is considered appropriate for workers compared to the general population. The final DNEL is derived by applying the assessment factor to the corrected NOAECs as dose descriptor in the following way: DNEL = NOAEC corrected / overall AF = 1.4 / 3 = 0.47 mg/m³ = 0.5 mg/m³ (rounded value) This value agrees with the current OEL value that is applied in most EU countries, and which is proposed by US ACGIH as the TLV (Threshold Limit Value) for antimony. In the Japanese RA, the studies of Grin et al (1987) and Brieger et al (1954) have been cited as key studies to lower this value from 0.5 to 0.1 mg/m³ based on effects on embryos/foetuses and cardiac effects respectively. These studies suggest that the 0.5 mg/m³ OEL would not be sufficiently protective. i2a has reviewed Grin et al (1987) and considers this study inconclusive (cfr. Reproductive / Developmental Toxicity section): -lacking data/information on test animals such as age, species -lacking information on purity/composition of test substance -lacking information on testing conditions (housing/diet/ ) -there is no control treatment included, and only 1 dose is applied per test -study is not compliant with today s standards (no protocol mentioned, likely not GLP compliant) -limited amount of test results reported Brieger et al (1954) describes: -workers exposure and effects in an abrasive industry plant where resinoid grinding wheels are manufactured. Key activities are mixing, molding and pressing of inert abrasive granules. During the study period, wheels were produced from a phenol formaldehyde resin and ATS (ATS replaced lead for safety reasons). -data of inhalation exposure of rats, rabbits and dogs to the same substance as above mentioned workers. Animals were exposed to a single concentration for various exposure times (from 5 days to 10 weeks). Focus of these animal data were effects on cardiac performance based on the workers exposure data. Neither the data from the workers exposure nor the animal data provide solid scientific evidence for further lowering the OEL value: 10

11 -lacking information on exposure conditions of workers (eg time of exposure, co-exposure to other substances such as As?) as well as on eg their medical background -lacking information on the exposure/test substance (composition, exact particle size) -lacking quantitative exposure information for workers (only qualitative such as most heavily exposed ) -limited amount of housing conditions of testing animals reported -there is no control population included for the workers and the animals -limited amount of test results reported -animal exposure only at concentrations about times the current EU OEL and US ACGIH TLV value of 0.5 mg/m³ Based on the above, i2a politely suggests not to include -Grin et al (1987) as scientific evidence for the occurrence of effects on embryos and foetuses -Brieger et al (1954) as scientific evidence for the occurrence of cardiac effects upon inhalation exposure to antimony. I2a politely suggests to only consider the lung effects observed in rat studies after chronic inhalation exposure to antimony dust to derive the TLV, and not lower the threshold concentration from 0.5 mg/m³ to 0.1 mg/m³ based on the Grin et al (1987) and Brieger et al (1954) studies. I2a s recent assessments for the REACH registration dossiers of its members considers most recent scientific data, and confirms that the value previously proposed by eg US ACGIH is still accurate, and sufficiently protective to ensure long-term workers health. This is supported by a biomonitoring campaign at an antimony production plant. The results of lung capacity tests of the workers in strongly suggest that there are no effects on workers health when complying with the current OEL value of 0.5 mg/m³, and confirms that the theoretically derived value above is effectively protecting workers health on the longterm. Due to the relatively low amount of data, it is impossible to draw any statistically conclusions from the data. However, considering the relatively long duration of this monitoring campaign ( ), and the absence of any visual evolution of the tests during this period, we believe the data strongly suggest that the current OEL is sufficiently protective, and that no change is required. Moreover, it can be questioned whether the effects caused by pulmonary overload with rats is relevant for humans: Positive (Hext, 1994; Oberdorster, 1995) and negative (Tran and Buchanan, 2000; Kuempel et al, 2001) findings of particle overload in human lungs are reported. Macrophage transport of particles into the alveolar interstitium is the major clearance mechanism in humans but of minor importance to the rat. These species differences between humans and rats are related to morphological features of the lung, i.e. to the relative short pathway length from the alveoli to the ciliated terminal bronchioles in rats (Bailey et al, 1989; Kreyling, 1990; Kreyling et al, 1991). In the absence of mechanistic data to the contrary, it must be assumed that the rat model of tumorigenicity can identify potential carcinogenic hazards to humans and the rat 11

12 presently remains the appropriate model for both neoplastic and non-neoplastic responses to PSP exposure (ILSI Risk Science Institute Workshop Participants, 2000). Due to the deviations from the OECD guidelines and the critical shortcoming in all three inhalation bioassays with ATO, US NTP (National Toxicology Program) has embarked on a testing programme leading to a new, full 2-year bioassay. A 14d range-finder on rats and mice was already conducted at the end of 2007 and preliminary reporting was already conducted and will be further evaluated for inclusion into the REACH dataset for ATO (and via read-across to other Sb(III) substance). The chronic toxicity studies in both rats and mice have already been finished in 2010, and reporting is expected in

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