Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

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.

Read-across from sodium selenite to zinc selenite

Since no data on reproductive toxicity is available specifically for zinc selenite, in the first instance 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 of bioavailability:

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 references

According to the evaluation criteria used by the experts of ATSDR (2003), a set of studies on reproductive toxicity of 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. Two key studies performed with sodium selenite were identified in which effects on female fertility and in one of those also effects on male fertility are reported: Abdo, 1994 and Nobunaga, et al. 1979 (data entry in IUCLID section 7.8.2).

In the NTP studies (Abdo, 1994), treatment of male and female mice via drinking water with concentrations of 2, 4, 8, 16 and 32 ppm sodium selenite (corresponding to 0.14, 0.3, 0.5, 0.9 or 1.6 mg Se/kg bw/d) caused significant increases in oestrus cycle lengths in female mice of the 32 ppm group (1.6 mg Se/kg bw/d). Because the next lower group treated with 16 ppm (0.9 mg Se/kg bw/d) was not evaluated for fertility parameters, the dose level of 8 ppm Na2SeO3or 0.5 mg Se/kg bw/d can be regarded as NOAEL for female fertility. This value corresponds to 1.22 mg/kg bw/d ZnSeO3(based on molecular weight). Treatment of male and female rats via drinking water with concentrations of 2, 4, 8, 16 and 32 ppm Na2SeO3(corresponding to 0.08, 0.13, 0.2, 0.4 or 0.8/0.9 mg Se/kg bw/d) caused increases in oestrus cycle lengths in female rats of the 16 ppm group (0.4 mg Se/kg bw/d) (32 ppm not evaluate), which was regarded as treatment related. All other findings at high exposure concentrations were regarded as confounded by dehydrated and unthrifty conditions of the animals. Thus, the dose level of 8 ppm Na2SeO3or 0.2 mg Se/kg bw/d (corresponding to 0.49 mg/kg bw/d ZnSeO3, based on molecular weight) can be regarded as lowest NOAEL for female fertility resulting from this study. The effect on oestrus cycle length was regarded as treatment related, because it was seen in rats and mice at dose levels that caused less than 10% body weight depression.

In the same NTP studies (Abdo, 1994), there is also some information on male fertility. No treatment- related effects were observed on spermatid and epididymal spermatozoal measurements in treated groups of male rats and mice. In male rats, epididymal sperm concentrations were slightly, but significantly decreased in all groups (4, 8, 16, 32 ppm Na2SeO3) without dose-relation, and this effects was therefore regarded as not treatment related. Thus, no treatment related effect on male fertility could be observed up to a dose of 32 ppm Na2SeO3 (corresponding to 3.9 and 2.0 mg/kg bw/d ZnSeO3respectively for mice and rats, based on molecular weight).

In addition, results from a developmental toxicity study (Nobunaga, et al. 1979) confirmed effects on oestrus cycle length at 0.6 mg Na2SeO3x 5 H2O/kg bw/d (corresponding to 0.18 mg Se/kg bw/d or 0.44 mg/kg bw/d ZnSeO3, based on molecular weight), but no maternal toxicity and effects on conception rates and the average time until conception as well as fertility in general were observed.

Thus, based on a weight of evidence approach of the studies presented above there is some evidence of treatment-related effects on female oestrus cycle length in rats and mice with an NOAEL of 0.18 mg Se/kg bw/d or 0.44 mg/kg bw/d for ZnSeO3(based on molecular weight), but no clear evidence for impaired fertility are available. In comparison, the NOAEL of 0.12 mg Se/ kg bw/d or 0.29 mg ZnSeO3/kg bw/d for systemic toxicity is somewhat lower and is used for risk assessment purposes.

The three supportive studies investigating male fertility (Kaur, 1994; Kaur, 2005; and Shalini, 2008) are considered inadequate for the evaluation of this endpoint (rated as not reliable RL=3), because of their limitations with respect to study animals and dose selection. In the study reported by Kaur (1994), the ingestion of 2 and 4 ppm sodium selenite via diet was investigated in house rats (Rattus rattus) captured from poultry houses with no information on age, body weight and health status of animals. Only 6 animals per group were used and the results showed a very high variability between animals. In two studies conducted in mice (Kaur 2005, Shalini 2008), male mice were fed diets either with an adequate Se status (0.2 ppm), deficient (0.02 ppm) or excess Se (1 ppm) amount of Se over up to 8 weeks. However, these studies were not designed to evaluate a dose–response relationship of sodium selenite on the fertility of male mice, because only one dose level with selenium in access of the adequate group was given, and these two groups were compared to each other.

No relevant human data are available for reproductive toxicity effects of selenites, including zinc selenite.

The data requirement for a screening study as laid down in regulation (EC) 1907/2006, Annex VIII, Column 1, Section 8.7.1 is nearly fulfilled by applying a weight-of-evidence approach to the two key studies Abdo (1994) and Nobunaga (1979).

According to the data requirements as laid down in regulation (EC) 1907/2006, Annex IX, Column 1, Section 8.7.3 a reproductive toxicity study needs to be conducted only if the 28-day or 90-day studies indicate adverse effects on reproductive organs or tissues. However, although there are some indications of an effect on female oestrus cycle length observed in subchronic toxicity studies and in a developmental toxicity study, the registrant does not consider the conduct of a 2-generation or extended 1-generation toxicity study to be required, since a 3-generation study with sodium selenate and a 2-generation study with potassium selenate are available in theATSDR Toxicological Profile on Selenium (2003). Based on the information evaluated by a renowned scientific body as described in the ATSDR Toxicological Profile on Selenium (2003), the results from the above mentioned studies may readily be included for risk characterisation purposes, assuming read-across to zinc selenite based on the metabolic diagram according to Sunde, 1990 (see attachment below).

The reasoning for this can be briefly summarised as follows: inorganic selenium is assumed to be reduced stepwise to the key intermediate hydrogen selenide; thus, “selenates” are transformed via “selenites” which are ultimately further reduced to “selenides”. Furthermore, according to "WHO (2001): Human Vitamin and Mineral Requirements. WHO, Food and Agriculture Organization of the United Nations, p. 240", absorption rates of selenates and selenites by humans are similar.

Based on the above, as cited in the ATSDR (2003), read-across from sodium or potassium selenate to zinc selenite is considered to be feasible without restriction: in ATSDR (2003), a three generation study with sodium selenate and a 2-generation study with potassium selenate are described as follows: “In a three-generation reproduction study, selenium administered as sodium selenate (0.57 mg selenium/kg/day) in the drinking water of breeding mice produced adverse effects on reproduction (Schroeder and Mitchener 1971b). The most notable observed effects included the failure of about half of the F3 generation pairs to breed successfully. In a two-generation study using rats, selenium administered as potassium selenate had no effect on reproduction at a dose of 0.21 mg selenium/kg/day for 1 year; however, decreased fertility and pup survival were noted at 1.05 mg selenium/kg/day (Rosenfeld and Beath 1954). At 0.35 mg selenium/kg/day for 1 year, the number of young successfully reared by the females was reduced by 50%, and the body weight of the females was approximately 20% less than that of the control females (Rosenfeld and Beath 1954).”

Furthermore, a short term reproductive study with sodium selenate is presented in ATSDR (2003), which should be included as supportive information in the evaluation of the effects on fertility: “A short-term reproductive study of the effects of sodium selenate in drinking water on rats reported some female reproductive toxicity (reduced corpora lutea, reduced implants per litter, shorter estrous cycle), but only at doses (0.418 mg selenium/kg/day) that produced signs of severe maternal toxicity, including a large reduction in water consumption (NTP 1996).”

Summarising the results of the three cited studies, the following NOAELs were concluded by ATSDR:

3-generation study: no NOAEL derived; LOAEL: 0.57 mg selenium/kg/day

2- generation study: NOAEL: 0.21 mg selenium/kg/day

30-day study: no NOAEL derived; LOAELreproduction: 0.5 mg selenium/kg/day for female rats

Since no NOAEL could be derived from the 3-generation study, the lowest available NOAEL (rat) resulting from the 2-generation study is 0.21 mg selenium/kg bw/d (corresponding to 0.51 mg zinc selenite/kg bw/day, based on molecular weight). This no-adverse effect level is in the same range as the NOAELs derived from the two studies (Nobunaga, 1979; Abdo, 1994) conducted with sodium selenite (0.18 mg Se/kg bw/d).

Based on the above, the conduct of a new study is not considered necessary, since reliable data fulfilling the requirements of the REACH regulation are available in the ATSDR Toxicological Profile on Selenium (2003). 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.

The NOAEL obtained for effects on fertility was 0.2 mg Se/kg bw/d from the 90 day study will be used for risk assessment. This NOAEL 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:

--> NOAEL = 49 mg ZnSeO3/kg bw/d (test type: subchronic study; species: rat; effect on oestrus cycle length)


Short description of key information:
Weight of evidence approach is performed (calculation for ZnSeO3 based on molecular weight; absorption properties disregarded):
k_Abdo (1994): NOAEL mice, female Se (element) = 8 ppm: 0.5 mg/kg bw/d -->NOAEL mice ZnSeO3 = 1.22 mg/kg bw/d
k_Abdo (1994): NOAEL rats, female Se (element) = 8 ppm: 0.2 mg/kg bw/d -->NOAEL rats ZnSeO3 = 0.49 mg/kg bw/d
k_Abdo (1994): NOAEL rats male Se (element) = 32 ppm: 0.8 mg/kg bw/d -->NOAEL rats ZnSeO3 ≥ 1.95 mg/kg bw/d
k_Abdo (1994): NOAEL mice, male Se (element) = 32 ppm: 1.6 mg/kg bw/d -->NOAEL rats / mice ZnSeO3 ≥ 3.90 mg/kg bw/d
k_Nobunaga (1979): NOEAL mice, female Se (element) = 0.18 mg/kg bw/d (3 ppm Na2SeO3*5 H2O) -->NOAEL mice ZnSeO3 = 0.44mg/kg bw/d

--> lowest NOAEL: 0.44 mg ZnSeO3/kg bw ( = 44 mg ZnSeO3/kg bw/d incl. 1 % absorption factor)

Effects on developmental toxicity

Description of key information
Oral drinking water:
k_Nobunga (1979): mice NOAEL = 3 ppm: 0.6 mg/kg bw/d Na2SeO3 x 5H2O -->NOAEL mice ZnSeO3 = 0.44mg/kg bw/d ( = 44 mg ZnSeO3/kg bw/d incl. 1 % absorption factor)
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.

Read-across from sodium selenite to zinc selenite

Since no data on reproductive toxicity is available specifically for zinc selenite, in the first instance 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 references

According to the evaluation criteria used by the experts of ATSDR (2003), several studies on developmental 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. No relevant human data are available on developmental toxicity of selenites, including zinc selenite.

One key study was identified for developmental toxicity and teratogenicity: Nobunaga (1979). Treatment of female mice with sodium selenite pentahydrate in drinking water (3 and 6 ppm Se) for 30 days before gestation and following mating until day 18 of gestation did not cause maternal toxicity, but oestrus cycle length was increased in comparison to control in the high dose group (6 ppm). Beside a statistically significant decrease in foetal body weights in high dose animals (6 ppm), no further signs of embryo-/foetotoxicity or teratogenicity were observed. Thus, the lower dose level of 3 ppm represents a NOAEL. This corresponds to 0.6 mg/kg bw/d Na2SeO3x 5H2O (0.18 mg Se/kg bw/d), and can be recalculated to 0.44 mg/kg bw/d ZnSeO3(based on molecular weight).

This study has some restrictions because it was conducted at a time when OECD guidelines were not available and reporting of results is not comparable to information coming from a recently conducted OECD and GLP toxicity study. However, since there are no indications of effects of treatment with sodium selenite on development of mice, from the available data, the registrant does not foresee the conduct of an OECD developmental toxicity study.

The ATSDR Toxicological Profile on Selenium (2003), which is the most comprehensive review on selenium compounds, contains an evaluation of the toxicity information performed by a renowned scientific body. Based on the possibility of read-across between the different selenium anions (Sunde, 1990; see above, discussion of “Effects on fertility” and see attachment, below), the summary on developmental toxicity of selenium compounds as given in ATSDR is taken into consideration concerning the requirement of any new animal study: “Developmental studies using the oral route of administration indicate that excessive sodium selenate or sodium selenite intake can result in fetal toxicity and reduced growth in experimental mammals (Dinkel et al. 1963; Ferm et al. 1990; NTP 1996; Rosenfeld and Beath 1964; Wahlstrom and Olson 1959a), but generally only at doses that produce maternal toxicity. Developmental effects were not observed in macaque fetuses from mothers given toxic oral doses of L-selenomethionine during gestation (Tarantal et al. 1991). Intravenous injection of sodium selenite in mice did not indicate that the compound is teratogenic in rodents (Yonemoto et al. 1984). Intravenous injections of sodium selenate, D,L-selenomethionine, and D,L-selenocystine into neonatal rats indicated that some selenium compounds can contribute to the formation of one type of cataracts (Ostadalova and Babicky 1980). Cataracts were not observed in the offspring of macaques treated orally with L-selenomethionine during gestation (Tarantal et al. 1991). Additional developmental toxicity studies of selenium compounds in mammals do not seem to be necessary at this time.”

Thus, based on the study results cited above and the conclusions drawn by the experts of ATSDR, the conduct of a new OECD developmental toxicity study is not considered necessary.

Since no further relevant developmental effects (at concentrations without maternal toxicity) are described in ATSDR (2003), the lowest NOAEL obtained for developmental effects was0.18 mg Se/kg bw/d. This NOAEL was 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:

--> NOAEL = 44 mg ZnSeO3/kg bw/d (test type: subchronic study; species: mouse; decrease in foetal body weights)

Justification for classification or non-classification

In the classification system of Regulation (EC) No 1272/2008, reproductive toxicity includes adverse effects on sexual function and fertility in adult males and females, as well as developmental toxicity in the offspring. Classification as a reproductive toxicant should be made on the basis of an assessment of the total weight of evidence. Evaluation of substances chemically related to the substance under study may also be included, particularly when information on the substance is scarce. If, in some reproductive toxicity studies in experimental animals the only effects recorded are considered to be of low or minimal toxicological significance, classification may not necessarily be the outcome.

Since the available data on selenites are not considered as sufficient to allow a conclusive decision for classification or non-classification, study results from related selenium compounds as cited in ATSDR (2003) were also included in the assessment of the total weight of evidence. ATSDR summarises the reproductive effects of various selenium compounds as follows: “Very high amounts of selenium have caused decreased sperm counts, increased abnormal sperm, changes in the female reproductive cycle in rats, and changes in the menstrual cycle in monkeys. The relevance of the reproductive effects of selenium exposure in animals studied to potential reproductive effects in humans is not known. Selenium compounds have not been shown to cause birth defects in humans or in other mammals.

For the highly soluble sodium selenite, effects on oestrus cycle lengths of females were observed in standard toxicity studies in rats and mice and in a developmental toxicity in mice. However, no evidence for an impairment of fertility was seen in the developmental study. The available reliable developmental study showed no significant adverse effects on foetal development and no indications of a teratogenic potential of sodium selenite were observed. Based on the possibility of read-across from sodium selenite to zinc selenite this information can also be considered to be valid for zinc selenite.

However, in consideration of the comparatively poor bioavailability of zinc selenite compared to the highly soluble other selenite and selenate substances as discussed above, it is concluded that the currently available data is not sufficient to require any classification and labelling of zinc selenite for reproduction toxicity.