Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.05 mg/m³

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

7 mg/kg bw/day

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Rationale for and derivation of DNELs (Derived No Effect Level) for Selenium and its inorganic compounds

Basic approach:

Derivation of DNELs normally starts from the effect data (like the NOAEL: No Observed Adverse Effect Level) gained from appropriate studies with experimental animals and is theoretically calculated for the human situation by application of “standard” assessment (uncertainty) factors to realistically take into account for inter- and intraspecies differences and variability respectively.

In those cases where adequate human data exists, in particular when certain toxicological endpoints may have been observed only in humans but not in experimental animals such human data should be used instead of the animal data as is the case for Selenium and its inorganic compounds, where abundant human data exist and where critical human endpoints have never been observed in the experimental animal.

Further, official toxicological evaluations of those potential health hazards by national and/or international scientific bodies should be followed after having being reviewed critically.

Therefore the human data base will be used for the rationale for and the derivation of DNELs also because Selenium is unique as it is an essential micronutrient for mammalian cells.

Rationale for DNELs:

The rationale for the direct use of human DNELs (for the general population and also for workers) is as follows:

Selenium is an essential element for animals and humans, which is needed for the proper function of a number of enzymes and proteins, like for example for glutathione peroxidases, thioredoxin reductase and deiodase and also binding and transport proteins.

Its “therapeutic” window is narrow, such that Selenium deficiency can cause severe adverse health effects, but also overdosing may lead to the clinical manifestation of Selenosis.

Due to its essentiality human dietary intake of Selenium (from foodstuff and drinking water) is necessary (and also “unavoidable”) and has been documented and reviewed with regard to any potential health concerns which may derive from that fact (see below for derivation of DNEL).

Nutritional supplemental Selenium and Selenium added fertilisers are even required in areas with low Selenium concentrations in the soil. Soil which contains 0.02 to 2 mg Selenium/kg is the most important Selenium source for humans (and animals). Since also the amount of Selenium in plants depends on the concentration in soil, diseases of grazing animals have been observed where such levels were low enough {see ref. (1)}.

Due to the facts of essentiality, the “unavoidable” human uptake, the need for nutritional supplementation (in some cases) and the relatively narrow “therapeutic” window accompanied with reliably human effect data national and international scientific bodies have thoroughly evaluated the benefits of Selenium for human health as well as its possible adverse effects.

Therefore in the following for the derivation of DNELs the general population (consumers) and for workers two reviews (besides further supporting documents) will be used mainly, because they are considered to be most relevant due to the facts that they were rather recently published and that they directly address the physiologically necessary oral intake of Selenium (organic and inorganic) for the general populationand the due to the exposure of humans (workers) at the workplace respectively:

· European Food Authority (EFSA):SCIENTIFIC OPINION: L-selenomethionine as a source of selenium added for nutritional purposes to food supplements

Scientific Opinion of the Panel on Food Additives and Nutrient Sources added to Food

Adopted on 14 May 2009,The EFSA Journal(2009) 1082, 1-39

available at:

http://www.efsa.europa.eu/en/scdocs/doc/ans_ej1082_L-Selenomethionine_op_en.pdf

· German MAK Commission: Toxikologisch-arbeitsmedizinische Begründungen von MAK-Werten “Selen und seine anorganischen Verbindungen”, 1999, 2001 and 2010

available at:http://onlinelibrary.wiley.com/book/10.1002/3527600418

Derivation of DNELs:

In the following a short outline is presented for the derivation of the DNELs for the general population and for workers respectively making use of the above mentioned reviews.

Please note that all DNELs (UL) mentioned below are referring to Selenium; the respective DNELs for the substance to be registered takes into account the Selenium moiety based on the respective molecular weight.

For worker:

Also the German MAK Commission derived its MAK value for the workplace (Threshold Limit Value for Selenium and its inorganic compounds) in 1999 and 2001 from the Yanget al.study as mentioned above {see ref. (6), p. 37}.

In 1999 (confirmed in 2001) the MAK value was stated with 0.05 mg/m³equivalentto 7 µg per kg bw per day (for an 8 hour shift) taking into account a lowest relevant NOAEL of 0.15 mg/kg bw per day from a 2-generation study on rats and a LOAEL of < 0.1 mg/kg bw per day from a 4-generation study on mice {see ref. (6): Rosenfeld I and Beath OA (1954): Effect of selenium on reproduction in rats. Proc Soc Exp Biol Med 87: 295—297; Schroeder HA and Mitchener M (1971): Toxic effects of trace elements on the reproduction of mice and rats. Arch Environ Health 23: 102—106; Schroeder HA, Mitchener M (1972): Selenium and tellurium in mice. Effects on growth, survival, and tumors. Arch Environ Health 24, 66--71}.

Also the MAK value covers all relevant systemic toxicological endpoints (acute toxicity, toxicity after repeated dosing, for reproduction, genotoxicity and carcinogenicity).

For the dermal route the low absoption of 0.1 % has to be taken into account, that means, that the dermal DNEL is set to 7 mg/kg per day.

The registrant(s) noticed the ongoing discussion about effects on diabetes caused by Selenium (see for MAK Commision, 2010:http://onlinelibrary.wiley.com/book/10.1002/3527600418), but due to data from ref. (7) should Selenium have a protective effect against diabetes and there may exist a certain risk that a lowered uptake of Selenium may cause adverse effects on human health.

In particular studies from North America (which caused the suspicion of diabetogenic effects) may overestimate the assumed toxicity of Selenium, because (citation)

“…the American and Canadian subjects in this study had higher baseline plasma selenium levels than comparable European subjects. This reflects the fact that the American continent has high levels of selenium in soil and rock, and hence the American population in general has higher dietary intakes of selenium than those in Europe. Serum or plasma selenium levels in European populations without selenium supplementation are in the range of 50-90 ng/mL (Rayman, 2002). In the UK, measurements on approximately 1000 subjects, from the National Diet and Nutrition Surveys of the elderly and of adults and children, showed mean plasma selenium levels of 71 ng/mL (in 1994-5) and 68 ng/mL (in 1997) respectively (Gregory et al., 2000; Bates et al., 2002). These levels may be compared with the mean initial plasma levels of selenium (135 ng/mL) of participants in SELECT, and in the US NPC trial, in which mean initial plasma levels of selenium were 113 ng/mL.”{cited fromref. (2), p.23}.

Therefore the overall conclusion is drawn that to date the well defined MAK value of 0.05 mg/m³should be defined the DNEL for the workplace for Selenium and its inorganic compounds.

It is interesting to note that the TLV in the UK for workplace exposure from Selenium and its compounds (except for Hyrogen selenide) for an 8 hour shift is 0.1 mg/m³{see ref. (8)}.

Final comments:

There is little benefit to be gained from DNELs which define human exposure which is lower than what is thought to be the minimum intake for Selenium necessary to assure for the physiological concentrations in mammalian cells.

For some European regions health relevant Selenium deficiency would occur without the application of Selenium fertilisers or Selenium enriched animal food. Definition of unrealistically low DNELs could therefore establish a potential threat to human health.

The ratio of the DNELs for the general population and for workers is only 1:1.6 (4.3 versus 7 µg/kg bw per day), while the ECHA guidance document R.18 recommends a ratio of 1:2.

This fact indicates for an adequate protection of workers.

References:

(1) Blumeet al.: Scheffer/Schachtschabel, Lehrbuch der Bodenkunde, Heidelberg, 2010

(2) European Food Safety Authority (EFSA):SCIENTIFIC OPINION: L-selenomethionine as a source of selenium added for nutritional purposes to food supplements, Scientific Opinion of the Panel on Food Additives and Nutrient Sources added to Food. (Question No EFSA-Q-2005-103, EFSA-Q-2006-195, EFSA-Q-2006-196, EFSA-Q-2006-304), Adopted on 14 May 2009,The EFSA Journal(2009) 1082, 1-39

available at:

http://www.efsa.europa.eu/en/scdocs/doc/ans_ej1082_L-Selenomethionine_op_en.pdf

(3) Scientific Committee on Food (SCF): Opinion of the Scientific Committee on Food on the Tolerable Upper Intake Level of Selenium (expressed on 19 October 2000):SCF/CS/NUT/UPPLEV/25 Final

available at:http://ec.europa.eu/food/fs/sc/scf/out80g_en.pdf

(4) Yang G, Gu L, Zhou R, Yin S (1989) Studies of human maximal and minimal safe intake and requirement of selenium.In: Wendel A (Hrsg) Selenium in biology and medicine, Springer-Verlag, Berlin, 223—228

(5) Schrauzer GN, 2003: The nutritional significance, metabolism and toxicology of selenomethionine. Adv. Food Nutr. Res. 47, 73-112.

(6) German MAK Commission: Toxikologisch-arbeitsmedizinische Begründungen von MAK-Werten “Selen und seine anorganischen Verbindungen”, Freising-Weihenstephan, Germany 1999 - 2010, available at:http://onlinelibrary.wiley.com/book/10.1002/3527600418

(7) Akbaraly TN et al (2010): Plasma selenium and risk of dysglycemia in an elderly French population: results from the prospective Epidemiology of Vascular Ageing Study. Nutrition & Metabolism 2010, 7:21

available at:http://www.nutritionandmetabolism.com/content/7/1/21

(8) Health and Safety Executive: EH40/2005 Workplace exposure limits, Merseyside, UK, 2011 available at:www.hse.gov.uk/

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.015 mg/m³

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.3 mg/kg bw/day

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.3 µg/kg bw/day

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Rationale for and derivation of DNELs (Derived No Effect Level) for Selenium and its inorganic compounds

Basic approach:

Derivation of DNELs normally starts from the effect data (like the NOAEL: No Observed Adverse Effect Level) gained from appropriate studies with experimental animals and is theoretically calculated for the human situation by application of “standard” assessment (uncertainty) factors to realistically take into account for inter- and intraspecies differences and variability respectively.

In those cases where adequate human data exists, in particular when certain toxicological endpoints may have been observed only in humans but not in experimental animals such human data should be used instead of the animal data as is the case for Selenium and its inorganic compounds, where abundant human data exist and where critical human endpoints have never been observed in the experimental animal.

Further, official toxicological evaluations of those potential health hazards by national and/or international scientific bodies should be followed after having being reviewed critically.

Therefore the human data base will be used for the rationale for and the derivation of DNELs also because Selenium is unique as it is an essential micronutrient for mammalian cells.

Rationale for DNELs:

The rationale for the direct use of human DNELs (for the general population and also for workers) is as follows:

Selenium is an essential element for animals and humans, which is needed for the proper function of a number of enzymes and proteins, like for example for glutathione peroxidases, thioredoxin reductase and deiodase and also binding and transport proteins.

Its “therapeutic” window is narrow, such that Selenium deficiency can cause severe adverse health effects, but also overdosing may lead to the clinical manifestation of Selenosis.

Due to its essentiality human dietary intake of Selenium (from foodstuff and drinking water) is necessary (and also “unavoidable”) and has been documented and reviewed with regard to any potential health concerns which may derive from that fact (see below for derivation of DNEL).

Nutritional supplemental Selenium and Selenium added fertilisers are even required in areas with low Selenium concentrations in the soil. Soil which contains 0.02 to 2 mg Selenium/kg is the most important Selenium source for humans (and animals). Since also the amount of Selenium in plants depends on the concentration in soil, diseases of grazing animals have been observed where such levels were low enough {see ref. (1)}.

Due to the facts of essentiality, the “unavoidable” human uptake, the need for nutritional supplementation (in some cases) and the relatively narrow “therapeutic” window accompanied with reliably human effect data national and international scientific bodies have thoroughly evaluated the benefits of Selenium for human health as well as its possible adverse effects.

Therefore in the following for the derivation of DNELs the general population (consumers) and for workers two reviews (besides further supporting documents) will be used mainly, because they are considered to be most relevant due to the facts that they were rather recently published and that they directly address the physiologically necessary oral intake of Selenium (organic and inorganic) for the general population and the due to the exposure of humans (workers) at the workplace respectively:

· European Food Authority (EFSA):SCIENTIFIC OPINION: L-selenomethionine as a source of selenium added for nutritional purposes to food supplements

Scientific Opinion of the Panel on Food Additives and Nutrient Sources added to Food

Adopted on 14 May 2009,The EFSA Journal(2009) 1082, 1-39

available at:

http://www.efsa.europa.eu/en/scdocs/doc/ans_ej1082_L-Selenomethionine_op_en.pdf

· German MAK Commission: Toxikologisch-arbeitsmedizinische Begründungen von MAK-Werten “Selen und seine anorganischen Verbindungen”, 1999, 2001 and 2010

available at:http://onlinelibrary.wiley.com/book/10.1002/3527600418

Derivation of DNELs:

In the following a short outline is presented for the derivation of the DNELs for the general population and for workers respectively making use of the above mentioned reviews.

Please note that all DNELs (UL) mentioned below are referring to Selenium; the respective DNELs for the substance to be registered takes into account the Selenium moiety based on the respective molecular weight.

For general population:

EFSA and its panel stated, that (citation) “the toxicity of L-selenomethionine is comparable with other forms of selenium” {see ref. (2), p. 2}. This is particularly proven by the facts that bioavailability of L-Selenomethionine is higher than for inorganic Selenium compounds, that the biological half-live is also longer for L-Selenomethionine and that all Selenium moieties after systemic uptake are reduced to the Selenid anion (Se^2-) which represents the “starting point” for its mode of action an further metabolic fate.

From this follows, that the assessment as laid down by the EFSA panel for L-selenomethionine as a nutritional supplement is also valid for the inorganic Selenium compounds to be registered and the EFSA panel`s derivation of a Tolerable Upper Intake Level (UL) can be used accordingly without any further modification and therefore represents the human DNEL for the oral route.

The EFSApanel also confirms the UL, whichwas set by the Scientific Committee on Food (SCF) for inorganic Selenium compounds, to be 300 µg Selenium per person per day (equivalent to 4.3 µg per kg bodyweight (bw) per day for a person of 70 kg) {see ref. (3)}.

The starting point here was a NOAEL from (epidemiological) human studies of 850 µg per person per day or 12 µg/kg bw per day for clinical selenosis. This figure was published by Yanget al.{see ref. (4)}.and was derived from observations on Chinese subjects living in seleniferous areas. It results from an increasing effect on prothombine time by higher Selenium levels. The SCF applied an additional assessment factor of 3, because the NOAEL was derived from data for a lifetime uptake for all subgroups of a population. This approach is in line with ECHA recommendations.

It has to emphasized, that the study of Yang et. al. is not under dispute with respect to its reliability and represents a common denominator of the reviewd papers.

Further assessment factors for inter- or intraspecies variability or for time scaling are not required for such epidemiological data.

This human NOAEL is far below the most relevant NOAEL for inorganic Selenium compounds of 0.12 mg/kg bw per day from animal studies by far, which was identified by the EFSA panel from a 90-day study on dogs {see ref. (2) p.17, referring to ref. (5)}.

The EFSA panel considers, that overall (citation)„the toxicity of L-selenomethionine is comparable to other forms of selenium, in terms of equivalent amounts of bioavailable selenium. As with other selenium compounds, the results of toxicological studies with L-selenomethionine in animals are indicative of a steep dose-response curve, with a threshold for onset of toxicity in the range of 100–400 μg selenium/kg bw/day, dependent on the species.“{cited from ref. (2), p. 25}

This statement includes all relevant systemic toxicological endpoints (acute toxicity, toxicity after repeated dosing, for reproduction, genotoxicity and carcinogenicity) without restriction.

The derived human NOAEL (equivalent to the DNEL) seems to cover the general population for all routes of exposure; it is 300 µg Selenium per person per day or 4.3 µg/kg bw per day which represents the UL of the EFSA panel and the SCF.

Basically this UL was very recently fully acknowledged by the Office of Dietary Supplements of the US National Institutes of Health (available at:http://ods.od.nih.gov/factsheets/Selenium-HealthProfessional/).

Similarly in a document from the World Health Organization (WHO) for drinking water quality {see ref. (6)} the human NOAEL for Selenium uptake was stated to be 4 µg/kg bw per day.

Finally the US Environmental Protection Agency has defined a Reference Dose (RfD) for Selenium to be 5 µg/kg bw per day (avalaible at:http://www.epa.gov/iris/subst/0472.htm).

The derived DNEL of 300 µg Selenium per person per day or 4.3 µg/kg bw per day will therrfore be used for the oral and dermal route.

The corresponding DNEL for inhalation expressed as concentration in the air is calculated by:

Daily respiratory volume = 20 m³according to ECHA guidance R.8 for 24 hours of exposure.

DNEL = 300 µg per person per day,

DNEL_inh= 0.3 mg/20 m³= 0.015 mg/m³or 15 µg/m³