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Description of key information

  • An LLNA-test with disodium selenite indicated some potential skin sensitizing properties for this substance
  • Selenite-related sensitizing effect has been reported in a human clinical case study
  • Disodium selenite has a harmonised classification as Skin sensitizer (Cat.1)
  • An LLNA-test with zinc selenite showed that this substance is not a skin sensitizer

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion
Additional information:

Background

 

A read-across category-approach is used for the assessment of the toxicological properties of selenium and selenium compounds. The following Se-substance are included in the category:

  • Se-metal (massive, powder)
  • Disodium selenate
  • Disodium selenite
  • Selenium dioxide / selenious acid
  • Zinc selenite
  • Barium selenite

A detailed rationale for the read-across hypothesis has been outlined in the read-across report that was generated according to the principles laid out in the Read-Across Assessment Framework (RAAF). In summary, the physico-chemical behavior of elemental selenium (once it has formed an ion-from its metal state), disodium selenite, disodium selenate and selenium dioxide/selenious acid is the same with regard to their metabolic fate. All selenium compounds (organic and inorganic, including elemental selenium), do share the very same metabolic fate in that after their resorption, reduction to the selenide moiety [Se2-], which is the single common precursor for its further metabolic conversion, takes place.

Therefore, there seems to be good evidence that different selenium moieties will behave very similar also for their ability to form reactive species which may play a decisive role in the generation of cytotoxicity followed likewise by unspecific and secondary clastogenicity and read-across can be made from the available data for disodium selenite. It is concluded that additional testing for each individual member of the proposed Se-category is not necessary and scientifically not meaningful.

In the case of inorganic salts like barium selenite and zinc selenite, uptake is always associated with a dissolution of the substance, i.e. dissociation into the metal cation (Zn2+, Ba2+) and the selenite anion (SeO32-). It can safely be assumed that the selenium/selenite moiety of barium/zinc selenite is generally of higher toxicological relevance than the zinc/barium cations. Therefore, the subsequent assessment of the toxicity of barium/zinc selenite focuses on the selenium moiety. As no in vivo toxicokinetic data or in vitro bioaccessibility data are available for a comparative assessment of relative bioavailability of various selenite substances, water solubility is adopted as a surrogate for bioavailability. Disodium selenite is readily soluble, with a water solubility of 800-900 g/L at 20°C. Barium selenite and zinc selenite, on the other hand, are poorly soluble salts (water solubility at 20°C of 66.7 mg/L and 16 mg/L, respectively, i.e. a difference of four/five orders of magnitude). Based on that, an intrinsically very conservative read-across from highly soluble forms to the poorly soluble barium/zinc selenite is proposed as the latter are assumed to have a lower solubility. It should also be noted that selenite anions in the tests with disodium selenite are formed under most physiological relevant conditions (i.e. neutral pH), thus facilitating unrestricted read-across between the various substances. In slightly acid conditions (pKa:8.32) the hydrogen selenite ion (HSeO3-) is formed whereas in more acidic conditions (pKa:2.62) the formation of selenious acid is observed (H2SeO3). Based on such existing equilibrium conditions, read-across between selenites, hydrogen selenites and selenious acid (solubility of 1670 g/L at 20°C) is justified.

 

Read-across from sodium selenite and selenious acid to barium/zinc selenite

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. Comparing the DNELs for the zinc/barium ion itself with the zinc/barium levels that are associated with the DNELs for barium/zinc selenite (based on selenite-data) indicated significantly higher values (in the range of factor 10 to 20) for the DNELs derived for the barium/zinc ion itself. Therefore, the subsequent assessment of the toxicity of barium/zinc selenite focuses on the selenium moiety.

In an OECD Guideline 429 study (Skin Sensitization: Local Lymph Node Assay), groups of four female CBA/J Rj mice were treated with 1, 0.5, 0.25 and 0.1% (w/v) sodium selenite in propylen glycol (PG). The solutions of the test item were applied on the dorsal surface of ears of experimental animals (25 µg/ear) for three consecutive days (Days 1,2,3). There was no treatment on Days 4,5 and 6. On Day 6, the cell proliferation in the local lymph nodes was measured by incorporation of tritiated methyl thymidine (SHTdR) and the values obtained were used to calculate stimulation indices (SI).

 

The highest dose group of 1% (w/v) was excluded from the evaluation as during the experiment one animal was found dead on Day 4/ This finding suggests that sodium selenite may be dermally relatively toxic (cfr significant skin irritation properties. No mortality, signs of systemic toxicity or body weight loss were observed during the study for the remaining dose groups. No treatment related effects were observed on animal body weights in any treated groups. Very slight erythrema (score 1) was observed in 1% (w/v) test item treated groups animals on Day 3 and in one or two animals in positive control group on Days 2 and 3.

 

Stimulation index values of the test item were 3.2, 2.0 and 2.1 at treatment concentrations of 0.5, 0.25 and 0.1% (w/v), respectively. A value of 3 is considered as a positive response. In conclusion, under the conditions of the present assay sodium selenite (Batch No.225

07) tested in PG as vehicle, was shown to have a sensitization potential (sensitizer) in the Local Lymph Node Assay.

However, the positive response at the highest concentration was slight and metals are known to have a lower predictivity in the LLNA than organic molecules.

 

 

In addition, a positive patch test with sodium selenite in one female technician who frequently worked with a selenite-cystine enrichment broth, was recorded and reported in a scientific journal (Senff et al, 1988). RadioAllergoSorbent Tests (RASTs) for common inhalants using peptone and selenite were negative, and the same tests in 15 control subjects were also negative.

 

 

As Se is an essential element, and no other sensitizing effects in industrial environments have been publishing in publicly accessible scientific journals, the observed sensitizing properties require to be thoroughly scrutinized.

Sodium selenite is dermally relatively toxic, and testing for skin irritation has shown that it is a significant skin irritant, i.e. sodium selenite may lead to “hyperreactivity” and be a ”non-specific stimulis” (as has been described by Basketter et al. (1998) for “difficult” substances). Secondly, "Non-specific cell activation as a result of inflammatory processes” has been discussed by Ulker et al. (2011) as a possible confounding factor for a false positive result. “Ear weight determination” is described by Ehling et al. (2005) for the identification of “skin irritation properties of the test item” in LLNA. The effect on ear weights as observed in the preliminary range finding study with sodium selenite has shown a clear correlation of test concentrations with the SI, i.e. observation of the borderline SI of 3.2 occurred at clearly elevated ear weights (even though these were within the range of historical controls according to the study author). Test results with sodium selenite (water solubility is 898 g/L) indicate that the SI is of only a (very) borderline nature (2 times clearly below 3 and only one time slightly above 3) and the resulting concentration-response curve is not clearly positive (medium concentration reveals SI below the lowest concentration). Slightly positive SI at 0.5 % may have been only observed due to proximity to “toxic” concentration(s) because one animal died at a concentration of 1.0 %, i.e. the concentration-response curve may be incompatible with an unbiased biological response (as has been commented by Chamberlain et al., 1996)).

 

Many elements, including copper and selenium, are essential elements (micronutrients) for animals and humans, and therefore its sensitizing potential can be difficult to establish. This was the case for copper chloride for which a positive outcome was recorded in the LLNA whereas it was negative in the Guinea Pig Maximization Test (GPMT) and in the Buehler Assay both with rabbits (as has been reported in summarizing format by Basketter et al., 1996).

 

Based on this assessment, it must be considered that sodium selenite is not a significant skin sensitizing agent, and there is a possibility that the LLNA-test gave a false positive result due to several (confounding) factors.

 

 

Treatment with zinc selenite at concentrations of 0.25%, 0.5%; 1.0% and 2.5% did not reveal statistical significantly increased values for lymph node cell count. The stimulation indices of the lymph node cell count did not exceed the threshold level of 1.4. Hence, the test item is classified as not sensitizing. The threshold level for the ear weight of 1.1 was not exceeded and the lymph node weights were not increased in a dose-related way, i.e. no irritating properties were noted. In conclusion, under the present test conditions, zinc selenite did not reveal any sensitizing properties in the local lymph node assay. Thus, the classification criteria according to Regulation (EC) No. 1272/2008 as skin sensitizer are not met.

Respiratory sensitisation

Endpoint conclusion
Additional information:

Substances shall be classified as respiratory sensitizers (Category 1) in accordance with the following criteria:

a)    if there is evidence in humans that the substance can lead to specific respiratory hypersensitivity and /or

b)   if there are positive results from an appropriate animal test.

 

According to the CLP Regulation Annex I, Section 3.4.2.1 substances fulfilling the criteria for respiratory sensitization will be classified as such in Category 1. As no such information is available for any of the selenium compounds that are included in the read-across category, no classification is proposed on respiratory sensitization. Furthermore, based on industry experience, during long-year industrial practice, no cases of hypersensitivity till now by workers exposed exclusively to any of the Se-compounds that are relevant to this read-across category.

 

Justification for classification or non-classification

Disodium selenite is subject to a legally binding harmonised classification. As included in the CLP Regulation (EC) No 1272/2008, Annex VI, Table 3.1, the following classification with regard to skin sinsitizing properties is mandatory:

Disodium selenite (Index-Nr 034 - 003 - 00 - 3): Skin.Sens. Cat.1 - H317 - May cause an allergic skin reaction

 

Based on the available data, and taking into account the harmonised classifications, the following substance-specific classification is determined:

 

Disodium selenite:

Skin.Sens. Cat.1 - H317 - May cause an allergic skin reaction

(Harmonized classification)

 

Additional supporting information: the published documentation on the German OEL (Occupational Exposure Limit: see German MAK Commission: Toxikologisch-arbeitsmedizinische Begründungen von MAK-Werten “Selen und seine anorganischen Verbindungen”, 2011, concluded that for Selenium and its inorganic compounds no assignment with "Sa" (potency for sensitization of airways) nor "Sh" (potency for sensitization of skin) should follow.

 

 

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