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Administrative data

Description of key information

Oral (calculation of NOAEL for ZnSeO3 based on molecular weight):
k_Abdo (1994), NOAEL rat: 0.4 mg Se/kg bw*d, corresponding to 0.97 mg ZnSeO3/kg bw/d (97 mg ZnSeO3/kg bw/d incl. 1 % absorption factor)
k_Abdo (1994), NOAEL mouse: 0.9 mg Se/kg bw*d, corresponding to 2.19 mg ZnSeO3/kg bw/d (219 mg ZnSeO3/kg bw/d incl. 1 % absorption factor)
s_Bioulac (1992), NOAEL rat: 0.12 mg Se/kg bw*d, corresponding to 0.29 mg ZnSeO3/kg bw/d (29 mg ZnSeO3/kg bw/d incl. 1 % absorption factor)
s_Johnson (2000), NOAEL mouse: 0.36 mg Se/kg bw*, corresponding to 0.88 mg ZnSeO3/kg bw/d (88 mg ZnSeO3/kg bw/d incl. 1 % absorption factor)
No studies on repeated dose toxicity via inhalation or dermal route are available.

Key value for chemical safety assessment

Additional information

General

The ATSDR Toxicological Profile on Selenium (2003), which is currently the most comprehensive review, was used as key source of relevant data on selenium compounds because it contains a detailed evaluation of toxicity data, performed by a renowned scientific body. More recent reviews, e.g. the work conducted for the Canadian Soil Quality Guidelines / Sudbury Soil Study, were also been screened for additional data. The underlying assumption is that the key literature considered by renowned international organisations such as ATSDR has usually already been subjected to a reliability assessment.

Nevertheless, all key references identified by ATSDR for selenites were re-evaluated and re-assessed for use in the REACH dossiers according to Klimisch and with respect to the requirements for risk assessment. Studies which were assessed as not adequate, not relevant or unreliable by expert judgement during the screening procedure were assigned to "disregarded study", and rated as "not reliable" (RL=3), with the rationale being included in the endpoint study record.

In addition, after the evaluation of the ATSDR review and further secondary literature (as documented in IUCLID section 12), a follow-up endpoint-specific literature search was conducted in bibliographic databases restricted to references on repeated dose toxicity by inhalation or the dermal route, published since the beginning of 2000 (as documented in IUCLID section 12). The results of this search were also been screened for use in the REACH dossiers.

Read-across from sodium selenite to zinc selenite

Since no data on reproductive toxicity is available specifically for zinc selenite, read-across from other “selenites” was considered.

Based on a comparison between toxicity reference values of zinc compounds and selenium compounds, it can safely be assumed that the selenium/selenite moiety of zinc selenite is generally of higher toxicological relevance than the zinc cations (for details see IUCLID section 7.1, endpoint summary "Toxicikinetics, metabolism and distribution"). Therefore, the subsequent assessment of the toxicity of zinc selenite focuses on the selenium moiety.

Very little toxicological data exist with the test substance zinc selenite itself. However, for any kind of systemic toxicity, a substance first needs to be taken up systemically. In the case of an inorganic salt like zinc selenite, such an uptake is always associated with a dissolution of the substance, i.e. dissociation into ions. Zinc selenite initially dissociates into zinc cations (Zn2+) and selenite anions (SeO32-). Since toxicological test data are available for sodium selenite (Na2SeO3), the first level of read-across considers extrapolation from this substance to zinc selenite.

Justification:

a) In vivo toxicokinetic data or in vitro bioaccessibility data for a comparative assessment of relative bioavailability of various selenite substances are not available. Thus, water solubility is adopted as a surrogate for bioavailability, as follows:

substance

water solubility

sodium selenite

800-900 g/L

zinc selenite

16 mg/L

Sodium selenite is readily soluble, with water solubilities of 800 – 900 g/L at 20 °C, respectively. Zinc selenite is a salt which is only poorly soluble in water at a concentration of 16 mg/L at 20 °C. Based on that, an intrinsically very conservative read-across from the highly soluble selenite to the poorly soluble zinc selenite is proposed since zinc selenite may reasonably be assumed to have a lower bioavailability than sodium selenite. 

b) Sodium selenite and zinc selenite both liberate the selenite anion upon dissolution. Assuming that (i) sodium selenite and zinc selenite both dissociate in water to SeO32-and the cationic counter-ions, and (ii) the potential effects are caused by SeO32-and not by the cations, the results from the available studies with sodium selenite can be used for read across to zinc selenite. The selenite anions are formed under most physiologically relevant conditions (i.e., neutral pH), thus facilitating unrestricted read-across between these species. In slightly acid condition, the hydrogenselenite ion, HSeO3-, is formed; in more acidic conditions selenous acid, H2SeO3, exists.

H2SeO3<=> H++ HSeO3- (pKa= 2.62)

HSeO3- <=> H++ SeO32-   (pKa= 8.32)

Based on these equilibrium conditions, read-across between the groups of selenites, hydrogenselenites and selenous acid is possible.

Thus, read-across from other “selenites” to zinc selenite seems in principle also possible, if they do not have a bioavailability significantly below zinc selenite or are not associated with any significantly toxic cations.

c) According to ATSDR (2003), selenites are generally readily absorbed after oral administration. Absorption rate of selenites in humans and animals after ingestion often exceeds 80 % of the administered dose. In human studies, absorption rates of 90 – 95 % have been observed (Thomson 1974, Thomson et al. 1977). Absorption in rats after oral administration of sodium selenite was examined to be between 80 – 100 % (Furchner et al. 1975; Thomson and Stewart 1973). However, in a recent publication, Frankenberger & Benson (1994) described a lower absorption rate for sodium selenite administered to humans as food fortificant: „The selenite is a white, water-soluble compound, from which absorption is about 50 %.” However, overall, it may be assumed that oral absorption of selenites is more or less complete (>> 80 %).

Considering the poor water solubility of zinc selenite (16 mg/L), the extrapolation of the above values obtained with highly soluble selenite substances is likely to constitute an intrinsic overestimate of bioavailability. However, due to the lack of information on substance-specific in-vivo toxicokinetic or in-vitro bioaccessibility data related to zinc selenite, read-across from the absorption data of other selenites should be performed. However, since the water solubility is about a factor of > 10 000 lower for zinc selenite compared to sodium selenite, it appears appropriate to introduce a default oral absorption factor.

Due to lack of data, but in order to follow a conservative approach, a default absorption factor of 1% is applied to the NOAELs from the studies with sodium selenite, although the differences in solubility are much higher, to account for the potential differences in bioavailability between the two selenites. Further information on the toxicokinetic properties and the basis for read-across are given in the endpoint summary of IUCLID section 7.1.

Evaluation of relevant references

Repeated dose toxicity, oral:

According to the evaluation criteria used by the experts of ATSDR (2003), a selection of studies on repeated dose oral toxicity with selenites providing reliable, quantitative estimates of No-Observed-Adverse-Effect Levels (NOAELs) or Lowest-Observed-Adverse-Effect Levels (LOAELs) are available (reported in ATSDR, 2003). All these references were obtained and re-evaluated according to the criteria of REACH. 

From the most reliable (RL=1) 90-day toxicity studies (Abdo, 1994: NTP technical report 38) with oral administration of sodium selenite via drinking water conducted in Fischer rats and B6C3F1 mice it can be concluded that the rat is more sensitive than the mouse. Based on mortality, body weight depression, decreased water consumption and renal papillary lesions in rats, the lowest estimated no-observed-adverse-effect level (NOAEL) was 0.4 mg selenium/kg body weight per day, corresponding to 0.97 mg zinc selenite /kg body weight per day. For mice the NOAEL based on body weight depression and decreased water consumption can be established at 0.9 mg selenium/kg body weight per day, corresponding to 2.19 mg zinc selenite /kg body weight per day (based on molecular weight).

Two additional subchronic/subacute toxicity studies are available with a special focus on hepatotoxicity in Sprague-Dawley rats (Bioulac 1992) and immunotoxicity in Balb/c mice (Johnson 2000). In the rat hepatotoxicity study, a somewhat lower NOAEL of 0.12 mg Se/kg bw/d (corresponding to 0.29 mg zinc selenite /kg bw per day, based on molecular weight) was determined based on specific histopathological examinations of livers. However, this study was a dietary study and the difference of the resulting NOAEL to the key study NOAEL might result from the difference in routes of exposure and default calculation of dose levels based on amounts of test item in the diet. The NOAEL of 0.36 mg Se/kg bw/d (corresponding to 0.88 mg zinc selenite /kg bw per day, based on molecular weight) obtained in the immunotoxicity study in mice with administration via drinking water is in the same range as the NOAEL for rats from the NTP study and somewhat lower than the NOAEL for mice from the NTP study (0.9 mg Se/kg bw/d).

Based on the results of these four reliable studies on repeated dose toxicity of sodium selenite it appears appropriate to use the lowest NOAEL of 0.12 mg Se/kg bw/d for risk assessment and it is therefore selected for DNEL derivation.

Thus the NOAEL for sodium selenite is re-calculated to zinc selenite based on molecular weight. In addition, considering the read-across concept described above, a correction factor for the lower oral absorption rate (1 %) is included to account for the lower solubility of zinc selenite compared to sodium selenite resulting in:

No relevant human data are available for repeated dose toxicity of selenites, including zinc selenite.

--> NOAEL = 29 mg ZnSeO3(test type: subchronic study; species: rat), target organ: digestive, liver.

Repeated dose toxicity, inhalation:

For “Repeated dose toxicity, inhalation”, an endpoint-specific literature search was performed (see IUCLID section 12) since in the ATSDR (2003) publication only studies on elemental selenium, selenium dioxide, selenium oxychloride, hydrogen selenide, and dimethyl selenide are cited, which were not considered adequate for risk assessment of zinc selenite. However, also from the literature search, no reliable studies on repeated dose toxicity of selenites via the inhalation route were identified. Therefore, this endpoint needs to be covered by route-to-route extrapolation using multiple path deposition modelling. Route-to-route extrapolation from a 90-day oral toxicity study in rats with sodium selenite and read-across to zinc selenite is performed for the following reasons:

(i) No local effects are expected from inhalation of zinc selenite:

Zinc selenite is only slightly water soluble (ca. 16 mg/L) at a pH around 6. Therefore, no pH-related effects need to be assumed upon contact with respiratory tract epithelia.

During the performance of the acute inhalation toxicity study (see IUCLID section 7.2.2), animals were also observed for possible indications of respiratory irritation such as dyspnoea, rhinitis etc.. The results of the study did not show any evidence of local effects in the lungs following inhalation exposure at any of the tested concentrations. Furthermore, also during skin irritation testing (IUCLID section 7.3) and skin sensitisation testing (IUCLID section 7.4), there are no findings giving any indication of possible irritating or sensitising local effects either. In consequence, local effects are not anticipated for this substance, and thus the derivation of a DNEL for long term systemic effects via inhalation for zinc selenite was considered as a more appropriate.

(ii) Systemic effects for inhalation of (zinc) selenite can be extrapolated from the systemic effects resulting from the oral route of exposure by route-to-route extrapolation:

Any lung overload can be excluded because of the observed behaviour of zinc selenite particles in the dustiness testing. Based on the study results of the dustiness testing and the deposition modelling, a total deposition factor via inhalation for zinc selenite of ca. 54 % was calculated (see IUCLID section 4.5 and 7.1). However, only < 1 % of the airborne particles will be deposited in the pulmonary region and thus, resulting in possible inhalative absorption. The material deposited in the head and tracheobronchial regions (ca. 53 % of the airborne particles) would be translocated to the gastrointestinal tract without any relevant dissolution in view of the low water solubility of zinc selenite (16 mg/L), where it would be subject to gastrointestinal uptake. Thus, since the main portion of the inhaled zinc selenite particles will be swallowed, route-to-route extrapolation from oral data would be an adequate surrogate for describing the systemic toxicity after exposure by inhalation. In accordance with ECHA guidance on information requirements and chemical safety assessment-chapter R.8: characterisation of dose [concentration]-response for human health, May 2008, a DNEL for systemic effects could be derived by route-to-route extrapolation from a 90-day oral toxicity study in rats with sodium selenite (read-across to zinc selenite).

This leads to the conclusion that the initiation of a long term inhalation study in rats is not considered to be required and cannot be justified due to animal welfare reasons.

Repeated dose toxicity, dermal:

For “Repeated dose toxicity, dermal” an endpoint specific literature search has been performed (see IUCLID section 12) since according to the ATSDR (2003) publication, no studies were available for evaluation that provide reliable, quantitative estimates of No-Observed-Adverse-Effect Levels (NOAELs) or Lowest-Observed-Adverse-Effect Levels (LOAELs).However, no reliable studies on repeated dose toxicity of selenites via the dermal route were identified by this literature search.

According to the data requirements as outlined in section 8.6, column 2, Annexes VIII-IX, of Regulation (EC) 1907/2006 a repeated dose toxicity study shall be performed via the most appropriate route of administration, having regard to the likely route of human exposure. However, the inhalation route is considered more appropriate than the dermal route of exposure. Furthermore, the repeated dose dermal toxicity study shall be performed only if inhalation of the substance is unlikely, skin contact in production and/use is likely and the phys. -chem. and toxicological properties suggest potential for a significant rate of absorption through the skin.

Repeated dose toxicity testing via the dermal route is not required for zinc selenite since the physico-chemical and toxicokinetic properties do not suggest any potential for a significant rate of absorption through the skin. Applying HERAG (HERAG fact sheet - assessment of occupational dermal exposure and dermal absorption for metals and inorganic metal compounds; EBRC Consulting GmbH / Hannover /Germany; August 2007) methodology, one may assume a conservative default of 1% for dermal absorption of zinc selenite, leading to the anticipation of a negligible toxicity via the dermal route (see IUCLID section 7.1 of this technical dossier). Furthermore, during skin irritation testing (IUCLID section 7.3) and skin sensitisation testing (IUCLID section 7.4), no indications of possible local effects were obtained.

Justification for classification or non-classification

Currently no substance-specific harmonised classification exists for zinc selenite. However, in Regulation (EC) No 1272/2008 and subsequent regulations, the substance is formally intrinsically included in a group entry named “selenium compounds with the exception of cadmium sulphoselenide and those specified elsewhere in this Annex“. In the current version of Regulation (EC) No 1272/2008 (1. ATP) this substance group is classified as STOT RE 2; H373**: May cause damage to organs through prolonged or repeated exposure (labelling: GHS08: Health Hazard depending on endpoint). This classification is obviously based on the previously existing classification R33 (based on DSD), even though there is no directly corresponding classification to R33 in Regulation (EC) No 1272/2008. In a weight of evidence approach the following aspects should be considered:

(i) According to Regulation (EC) No 1272/2008 classification in Category 2 is applicable, when significant toxic effects observed in a 90-day repeated-dose study conducted in experimental animals are seen to occur within the guidance value ranges of 10 < effect level < 100 mg/kg bw/d. However, although for sodium selenite some single incidences of liver toxicity or renal findings were observed in studies with laboratory animals, these cannot be regarded as significant health effects for humans, because they are not consistently observed in various studies.

(ii) In addition, information and results of data presented in the peer-reviewed ATSDR (2003) publication is included in the weight of evidence approach. It is stated that in many aspects, similar patterns of toxicity have been reported for selenium in human and animal systems.“However, species-specific differences in toxicity are present (e.g., the main effect of selenium toxicity in rodents is damage to the liver, which is not observed in humans) and this may represent evidence of underlying differences in how selenium is metabolized. [...] The lack of evidence of liver damage in humans due to selenosis, despite the animal data to the contrary, suggests a problem with the animal models of the disease.

According to the weight-of-evidence approach above, no classification is proposed for specific target organ toxicity of zinc selenite.