Tellurium

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

The repeated (oral) dose studies (OECD 421 – highest dose 600 mg/kg/day) and OECD 408 (+ sperm analysis; highest dose 100 mg/kg/day), did not reveal indications that tellurium dioxide had adverse effects at any of the reproductive organs. 

In the OECD 421 study the NOAEL was 25 mg/ kg /day for the parental and fertility endparamaters.  

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

25 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Effects on developmental toxicity

Additional information

In the following four key studies will be first comprehensively described by their decisive study parameters and from the summarized results basic conclusions will be drawn with regard to the interpretation of elemental Tellurium`s reproductive/developmental potency and derived effect levels thereof (taking also into account the subacute repeated dose toxicity study).

Several studies on toxicity to reproduction are available for elemental Tellurium and Tellurium dioxide as has been shortly outlined in the literature searches attached in Section 12 of the registration dossier.

 

Duckett and coworkers evaluated the pathological mechanisms and morphology of Tellurium induced hydrocephalus in rats at doses of 2500 and 3000 ppm, which are fare above the derived effect levels in the selected key studies.

 

Garroet al.described a dose depending development of hydrocephalus at doses between 500 and 2500 ppm Tellurium in the diet, with special attention on the pathogenesis of hydrocephalus.

 

Agnew and coworkers investigated the precise period of teratogenic susceptibility of the rat embryo by single injections of 13 mg/kg body weight on specific days of gestation.

 

Perez-D´Gregorio evaluated the influence of a decrease in maternal body weight on teratogenic effects in a pair–feed study and showed that teratogenicity is not mediated by alterations in the diet.

 

However, most of the reported studies were not conducted according to an internationally accepted test guideline nor any standard procedures. Furthermore the target of the investigations was outside the scope of the assessment necessary under the REACH Regulation.

 

Despite the mentioned restrictions and the focus put onto (only) four key studies, it can be stated that considering the dose response relationship and the observed effects a consistent picture can be drawn from the available data base.

 

Key Studies for the endpoint reproductive/developmental toxicity

For the determination of equitoxic potency of various Tellurium moieties (in this case elemental Tellurium and Tellurium dioxide) and hence definition of the NOAEL and furtheron derivation of DNELs the relative bioavailability is the most important figure.

 

Bioavailability

All available data hint for a rather poor absorption of elemental Tellurium after oral uptake, i.e. systemic absorption was measured in human studies with elemental Tellurium, but also with tetra- or hexavalent Tellurium salts and is stated with 10 to 25 % of the applied dose [3].

In rats and rabbits absorption after oral exposure was determined with 10 to 40 % of applied dose.

The dermal absorption after application onto the skin is unknown [37] as is the case for human respiratory absorption [5].

For the determination of equitoxic potency of various Tellurium moieties (in this case elemental Tellurium and Tellurium dioxide) and hence definition of the NOAEL and further on derivation of DNELs or hazard classification the relative bioavailability is the most important figure.

For this purpose in vitro studies with elemental Tellurium (Te) and Tellurium dioxide (TeO₂) were conducted [18, 19, 22, 23] to assess their behavior in a physiological environment with regard to any toxicokinetic differences.

Therefore, bioavailability simulating inhalation and oral uptake was measured by the substance`s solubility in artificial alveolar fluid and in artificial saliva and gastrointestinal fluid respectively.

The results indicate that Tellurium dioxide is of approximately three times higher solubility than elemental Tellurium (see following table for measured solubility data).

Table 2: Measured solubility data for Tellurium and Tellurium dioxide

	Tellurium dioxide [mg/L]	Tellurium [mg/L]
Mean solubility in artificial alveolar fluid after 72 hours	799.1 ± 7.3 (Te) 999.4 ± 9.1 (Tellurium dioxide)	238.4 ± 16.1
Factor	3.35 (based on Te)
Mean solubility in artificial gastrointestinal fluid	156.7 ± 13.2 (Te) 196.03 ± 16.5 (Tellurium dioxide)	56.68 ± 1.46
Factor	2.76 (based on Te)

It is a well-accepted fact, that such in vitro studies with inorganic substances may underestimate the in vivo bioavailability, because living cells do possess active transport systems to control for homeostatic reasons the uptake of for example essential elements. Nevertheless the in vitro data do allow for a comparative insight into the bioavailability of different redox species of an element and are therefore suitable for comparing study results with different Tellurium compounds in particular since the element Tellurium is not thought to be essential.

Despite total lack of information, the relative absorption after dermal exposure compared with oral exposure may be estimated by using data from other metals:

The Health Risk Assessment Guidance for Metals (HERAG) proposes for dermal absorption after exposure to dust or other dry metal compounds a default value of 0.1 % [11].

From this it follows that the dermal systemic bioavailability of elemental Tellurium may be estimated to be 10 % of the oral bioavailability (based on 10 % oral uptake) which results in a systemic bioavailability of 1 % of the external dermal dose. This figure clearly exceeds the above mentioned 0.1 % as typical for other metals and can therefore be considered a very conservative approach.

The figure of 1 % of dermal uptake of elemental Tellurium will be used further in the exposure considerations.

 

Tellurium dioxide: Reproductive/developmental toxicity screening test following oral (gavage) administration in Wistar rats

 

Technical description of the study:

• Test substance: Tellurium dioxide


• Method: OECD Guideline 421 (Reproductive/Developmental Toxicity Screening Test)


• Species: male/female rat (Wistar)


• Type of study: screening reproductive/developmental toxicity study


• Route: oral gavage


• Experimental animals: 12 rats per sex/group


• Dosing period for males: 28 days (14 days pre-mating and 14 days mating/post mating)


• Dosing period for females: 14 days pre-mating, up to 14 days mating, through gestation and 4 days post-partum dosing. 


• Dosing for males and females:0, 25, 120 and 600 mg/kg body weight (bw) per day (d) [mg/kg/d]

 

Study results: 

• NOAEL (parenteral generation) for reproductive toxicity to males: 600 mg/kg bw/d (highest dose applied)

There were no effects identified on the male reproductive system.

 

• NOAEL (parenteral generation) for reproductive toxicity to females: 25 mg/kg bw/d.

Effects observed at 120 and 600 mg/kg/d are not considered secondary to systemic toxicity. At 600 mg/kg/d there were adverse effects of treatment on the oestrus cycle, mating ability, fertility and gestation period. Similar but lesser effects were seen at 120 mg/kg/d. Higher intrauterine mortality, post-natal and/or total mortality were recorded at 120 and 600 mg/kg/d.

 

• NOAEL (parenteral generation) for systemic effects: 25 mg/kg bw/d

At 600 mg/kg/d treatment related effects in females included mortality (5/12), clinical signs of decreased activity, hunched back, piloerection and dark feces. In males and females at 120 and 600 mg/kg/d dark feces were observed.

 

Reduced body weight or body weight gain was observed in both sexes at 120 and 600 mg/kg/d; in males the terminal body weights were about 7 % and 14 % lower than control, in females at day 14 body weights were about 5 % and 11 % below controls at 120 and 600 mg/kg/d respectively, although the effect became more pronounced in pregnancy.

 

• NOAEL (F1 generation) for male/female offspring: No NOAEL identified,because pup mortality was also observed in the low dose group at 25 mg/kg/d.

 

Interpretation of study results with respect to toxicity profile of Tellurium dioxide:

No NOAEL could be identifiedwith respect to reproductive/developmental toxicity, because also in the lowest dose group of 25 mg Tellurium dioxide/kg body weight per day severe effects (i.e. dead of pups) were observed.

The adverse effects on the off-spring were also observed without maternal toxicity because the NOAEL for reproductive toxicity to females was 25 mg/kg body weight per day.

 

The study did not show any specific target organ toxicity of Tellurium.

Males were unaffected by administration of Tellurium dioxide with regard to reproductive toxicity.

 

Perez-D’Gregorio et al.: Teratogenicity of Tellurium dioxide: prenatal assessment

 

Technical description of the study:

 ·      Test substance: Tellurium dioxide

·      Species: female rat (Wistar)

·      Type of study: developmental toxicity study

·      Route: multiple maternal subcutaneous injections

·      Experimental animals: 10 dams per group

·      Exposure: females for gestational days 15 to 19

·      Dosing: 0, 10, 100, 500 and 1000 µMol Tellurium/kgas Tellurium dioxide

·      Observations: examination of fetuses on day 20

 

Study results: 

• NOAEL (parenteral generation) for maternal toxicity: 100 µMol/kg bw/d

Toxicity was expressed as weight loss, centrolobular fatty change in the liver and 40 % lethality at the highest dose

 

• NOAEL (F1 generation) for developmental toxicity for male/female off-spring: NOAEL 10 µMol/kg bw/d as Tellurium dioxide

The most prominent effects were observation of hydrocephalus followed by increase in fetal mortality at higher doses.

 

·      At 500 and 1000 µMol/kg bw/d 11 % and 81 % mortality were recorded for day 20 fetuses. 100 % incidence of hydrocephalus was noted at doses of ≥ 100 µMol/kg bw/d with a dose related increase in severity.

 

 

Explanation of dose for route to route extrapolation:

 

·      Factor for route to route extrapolation subcutaneous -> oral: 2 as a very conservative approach

 

·      10 µMol Tellurium dioxide/kg/dareequivalent to 1596.1 µg Tellurium dioxide/kg/d

 

·      Additional application of a factor of 2 for route to route extrapolation gives the following values:

 

-    10 µMol TeO₂/kg/dsubcutaneously =    3.19 mg Te O₂/kg/d orally

-  100 µMol TeO₂/kg/dsubcutaneously =    31.9 mg Te O₂/kg/d orally

-  500 µMol TeO2/kg/d subcutaneously = 159.5 mg Te O₂/kg/d orally

- 1000 µMol TeO2/kg/d subcutaneously =    319 mg Te O₂/kg/d orally

 

Interpretation of study results with respect to toxicity profile of Tellurium dioxide:

From the subcutaneous NOAEL of 10 µMol Tellurium dioxide/kg body weight per day fordevelopmental toxicity of male/female F1 generation an equivalent oral NOAEL of 3.19 mg Tellurium dioxide/kg body weight per day follows with regard to development of hydrocephali.

The adverse effects on the fetuses were also observed without evidence of maternal toxicity.

 

E. M. Johnson et al.: Developmental investigation of Tellurium, study on rats

 

Technical description of the study:

·      Test substance: Tellurium

·      Species: female rat (Sprague-Dawley)

·      Type of study: developmental toxicity study

·      Route: oral feeding study

·      Experimental animals: 32 to 33 dams per group

·      Exposure: females for gestational days 6 to 15

·      Dosing: 0, 30, 300, 3000 and 15000 ppm Tellurium in diet

·      Observations: examinations of 2/3 of fetuses of test groups on day 20; 1/3 of the rats were permitted to deliver naturally and off-spring was observed for 7 days.

 

Study results:

·      The test substance was added to foodstuff, the fact of which may lead to a lower bioavailability because adsorption of Tellurium to foodstuff may be likely.

 

·      Also for the control group one hydrocephalus was reported.

 

• NOAEL (parenteral generation) for maternal toxicity: 30 ppm

Maternal toxicity was evident by decreased feed consumption and decreased body weight gain in groups receiving ≥ 300 ppm Tellurium in the diet.

 

• NOAEL (F1 generation) for male/female off-spring: 300 ppm Tellurium in the diet

Both skeletal and soft tissue malformations, primarily hydrocephali were noted in the off-spring of rats exposed to 3000 and 15000 ppm Tellurium in diet.

 

Explanation of conversion of dose for elemental Tellurium into equivalent dose for Tellurium dioxide:

Conversion of amount of elemental Tellurium in the diet to dose in mg per kg body weight and day has been done by E. M. Johnsonet al. and is reproduced in the following:

 

-      30 ppm Tellurium in the diet =     2.2 mg Te/kg/d

-    300 ppm Tellurium in the diet =   19.6 mg Te/kg/d

-  3000 ppm Tellurium in the diet = 165.6 mg Te/kg/d

- 15000 ppm Tellurium in the diet = 633.4 mg Te/kg/d

 

Test substance: Tellurium

 - Factor for higher bioavailability of TeO₂compared to Te: 3:

- 19.6 mg elemental Te are (biologically) equivalent to 6.53 mg Te in TeO₂due to threefold higher bioavailability of Tellurium dioxide

  - Atomic weight for Te: 127.61 g/Atom; molecular weight for TeO₂: 159.61 g/Mol, i.e. resulting in a conversion factor of 1/1.251 = 0.799: i.e. 6.53 mg Te in TeO₂are equivalent to approximately 8.2 mg TeO₂, therefore:

 

 

-      30 ppm Tellurium in the diet =     2.2 mg Te/kg/d =   0.92 mg TeO₂/kg/d 

-    300 ppm Tellurium in the diet =   19.6 mg Te/kg/d =     8.2 mg TeO₂/kg/d 

-  3000 ppm Tellurium in the diet = 165.6 mg Te/kg/d =   69.1 mg TeO₂/kg/d 

- 15000 ppm Tellurium in the diet = 633.4 mg Te/kg/d = 264.2 mg TeO₂/kg/d 

 

 

Interpretation of study with respect to toxicity profile of Tellurium dioxide:

 

From this study a NOAEL of 8.2 mg/kg/d for Tellurium dioxide can be derived with respect to reproductive/developmental toxicity.

 

The maternal NOAEL for systemic toxicity is 0.92 mg Tellurium dioxide/kg body weight per day but it is to be noted that the observed “toxicity” at the next higher dose of 8.2 mg Tellurium dioxide /kg body weight per day is very unspecific because only decreased feed consumption and decreased body weight gain was observed.

 

In light of the fact that formation of hydrocephalus, i.e. a very severe and specific effect, occurred already at this dose clearly indicates that the observed developmental toxicity is unrelated to the slight onset of unspecific maternal toxicity.

 

E. M. Johnson et al.: Developmental investigation of Tellurium, study on rabbits

 

This study forms part of the publication of E. M. Johnson et al..

 

Since rabbits which have been used instead of rats may be less sensitive compared to the rat (less severe effects were observed), this study is used as a more supporting study for classification purposes, but not for DNEL derivation.

 

Technical description of the study:

·      Test substance: Tellurium

·      Species: female rabbit (New Zeeland white)

·      Type of study. developmental toxicity study

·      Route: oral feeding study

·      Experimental animals:17 dams per group (artificially inseminated)

·      Exposure: females for gestational days 6 to 18

·      Dosing: 0, 125, 175, 1750 and 5250 ppm Tellurium in the diet

·      Observations: on day 29 of presumed gestation, all surviving does were killed.

 

Study results: 

• NOAEL (parenteral generation) for maternal toxicity: 175 ppm Maternal toxicity was evident by decreased feed consumption and decreased body weight gain in groups receiving ≥ 1750 ppm Tellurium in diet.

 

• NOAEL (F1 generation) for male/female off-spring: 300 ppm Rabbit fetuses of the highest dose group had slightly elevated evidence of skeletal delays and nonspecific abnormalities.

 

Interpretation of study results with respect to toxicity profile of Tellurium dioxide:

 

From this study an oral NOAEL on rabbits of 300 ppm equivalent to12 mg Tellurium/kg body weight per daycan be derived with respect to reproductive/developmental toxicity.

Explanation and conversion of dose for elemental Tellurium into equivalent dose for Tellurium dioxide (as outlined for the study with rats) will result in an oral NOAEL on rabbits of 5 mgTellurium dioxide/kg body weight per day.

 

Even though effects in fetuses were less severe than in rat fetuses adverse effects were clearly observed at a dose which did not lead to overt maternal toxicity.

 

 

Summary of observed effects with regard to reproductive/developmental toxicity

 

It should be noted that no study exists which specifically covers reproductive toxicity with regard to sexual function and fertility.  However information can be deduced from the OECD 421 screening study and in the subacute repeated dose toxicity study (OECD 408) described above.   

In the screening study with Tellurium dioxide at 600 mg/kg body weight per day there were adverse effects of treated females on the oestrus cycle, mating ability, fertility and gestation period.  

The 90-day sub-acute repeated dose toxicity study, histological evaluation of the male and female reproductive organs did not reveal any adverse effects and no changes in sperm parameters (motility and concentration) at the highest tested dose of 100mg/kg/day were detected. .

 

The results of above described key studies for reproductive/developmental toxicity have been compiled into the following matrix for overview purposes:

 

Type of study	OECD 421 (Kiss 2013)	Developmental study (Perez-D’Gregorio et al.)	Developmental study (only study with rats) (E. M. Johnson et al.)
Test sub-stance	Tellurium dioxide	Tellurium dioxide	Tellurium
Exposure period for females	14 days pre-mating, up to 14 days mating, through gestation and 4 days post-partum dosing	days 15 to 19 of gestation	days 6 to 15 of gestation
Route	oral gavage	subcutaneous	feeding study
NOAEL maternal reproductive toxicity	25 mg/kg/d	---	---
NOAEL maternal systemic toxicity	25 mg/kg/d	100 µMol/kg/d (equivalent to 31.9 mg Te dioxide/kg/d orally)	30 ppm (equivalent to 0.92 mg Te dioxide/kg/d)*
NOAEL F1	< 25 mg/kg/d (lowest dose applied)	10 µMol/kg/d (equivalent to 3.19 mg Te dioxide/kg/d orally)	300 ppm (equivalent to 8.2 mg Te dioxide/kg/d)*
Major adverse effects in off-spring	increased pup mortality in pups born alive	fetus mortality and hydrocephalus	skeletal and soft tissue malformations, primarily hydrocephali

 

*See respective comments in “Interpretation of study with respect to toxicity profile of elemental Tellurium” of above described study

 

In conclusion according to screening study Tellurium (elemental Tellurium and Tellurium dioxide) does not seem to be an overt toxicant to male rats, neither with regard to generalized systemic toxicity nor with regard to reproduction parameters (slightly reduced body weight or body weight gain at 120; no effect on reproduction parameters at 600 mg Tellurium dioxide/kg body weight per day).

 

For female rats generalized systemic and maternal toxicity has been observed, i.e. again reduced body weight and body weight gain at 120; some deaths at 600 mg Tellurium dioxide/kg body weight per day. The respective NOAELs were identical, 25 mg Tellurium dioxide/kg body weight per day.

 

Pronounced pup mortality with pups born alive was already observed at 25 mg Tellurium dioxide/kg body weight per day which is obviously a non-toxic maternal dose.

 

One developmental study [Perez-D’Gregorio et al.] revealed clear maternal toxicity at 159.5 mg Tellurium dioxide/kg body weight per day; the NOAEL being approximately 31.9 mg Tellurium dioxide/kg body weight per day (considering route to route extrapolation).

At a clearly non-toxic maternal toxic dose Tellurium caused a dramatic increase (i.e. 100 %) of hydrocephali in fetuses, i.e. the NOAEL being 3.19 mg Tellurium dioxide/kg body weight per day (considering route to route extrapolation).

 

A further developmental study with rats [ E. M. Johnson et al.] basically follows the toxicity pattern as outlined before, because maternal toxicity was observed from 300 ppm Tellurium/kg diet (equivalent to 8.2 mg Tellurium dioxide/kg body weight per day). Effects on fetuses (even though only small) were already observed at this dose and drastically increased with increasing doses with regard to the occurrence of hydrocephalus whereas maternal toxicity did not increase respectively.

 

Overall it is to be concluded that Tellurium is capable to specifically cause hydrocephali in fetuses at doses with no or only marginal toxicity to exposed dams.

 

 

Definition of starting point for DNEL derivation

Based on the findings the starting point of a DNEL derivation may be stated by the following key parameters:

 

·      (Lowest) NOAEL_subcutaneous(F1 generation) for developmental toxicity in male/female fetuses: 10 µMol/kg/d (test substance: Tellurium dioxide; developmental toxicity study with rats after subcutaneous application)

 

·      NOAEL_oral(F1 generaton) for developmental toxicity in male/female fetuses: 3.19 mg Tellurium dioxide/kg/d considering a route to route extrapolation (s.c. to oral) by factor of 2)

 

·      Observed effects: increased fetal mortality and occurrence of hydrocephalus at absence of maternal toxicity

 

In conclusion it follows that a potential starting point for the DNEL derivation with regard to developmental toxicity may be well characterized by the oral NOAEL of 3.19 mg Tellurium dioxide/kg body weight per day.

 

 

Read-across rationale for Tellurium dioxide:

Elemental Tellurium and Tellurium dioxide are reduced to Telluride [Te2-] which is further metabolized to the mono- and dimethyl telluride (which are excreted to various degrees (also depended on route of exposure) in exhaled air, sweat, feces and urine) and also to the Trimethyl telluronium cation which is excreted in urine.

Since the physico-chemical behaviour of elemental Tellurium and Tellurium dioxide is the same with regard to their metabolic fate (reduction to the Telluride anion) it is highly likely that both substances will behave very similar with regard to systemic toxicity. Thus, it can be assumed that Tellurium is a suitable analogue substance to Tellurium dioxide.

This assumption is proven by a similar toxicological profile which is demonstrated by the same outcomes in different toxicological studies, as described in the following.

In acute oral toxicity studies in rats for both substances the LD50 value is > 5000 mg/kg body weight. In none of the studies an animal died.

Neither a skin nor an eye irritating property was observed in in vitro studies with both Tellurium and Tellurium dioxide.

Both substances are proven to be skin sensitizers in the Local Lymph Node Assay (LLNA).

Furthermore, negative data from bacterial reverse mutation assays (Ames–Test) for point mutations are available for Tellurium and Tellurium dioxide. For genotoxicity on mammalian cells in vitro only data on Tellurium dioxide are available, however as no indication for a genotoxic potential of neither Tellurium nor Tellurium dioxide can be derived from the presented in vitro studies, it can be concluded that Tellurium and the read across substance Tellurium dioxide do not pose a potential hazard regarding this endpoint. On this basis and in the absence of any in vivo study, no classification for germ cell mutagenicity is proposed.

For developmental toxicity a very similar toxicity pattern is proven by results from the reproduction/developmental screening study with Tellurium dioxide and the developmental toxicity studies with both, source and target substance.

For repeated dose toxicity read across from studies with Tellurium dioxide were performed. Also, data on reproductive effects on fertility are only available for Tellurium dioxide. Due to the high degree of concordance regarding the other endpoints, it can reasonably be assumed that both substances would also show comparable results for these endpoints.

Furthermore, the formation of identical metabolites under physiological conditions (which is described in the following) is crucial for this read-across justification.

Methylated Tellurium is identified as the central metabolite of Tellurium metabolism in mammalian cells. Since all inorganic Tellurium compounds are to be metabolized to methylated Tellurium before they are excreted into the blood stream and transported to the different (from a toxicological point of view) conceivable target organs and compartments all inorganic Tellurium compounds should be comparable with respect to their toxicological properties.

Especially effects on the unborn child as discussed for Tellurium to represent the most critical toxicological endpoint, depends on the Tellurium moiety as distributed by the blood stream.

A qualitative assessment of the hazard profile is therefore consequently not depending on the chemical species of Tellurium. Generally, as Tellurium dioxide is considered to be somewhat more bioavailable than Tellurium, read-across from Tellurium dioxide represents a worst-case approach.

In sum, it is considered justified based on the practically identical metabolic fate, the similarity of physico-chemical properties, the identical toxicological profile for acute, local and systemic endpoints, that results of genotoxicity, repeated dose toxicity and reproductive toxicity, including effects on /via lactation, conducted with the source substance Tellurium dioxide, are likely to predict the properties of the target substance Tellurium. With respect to the somewhat higher bioavailability of Tellurium dioxide, using the studies conducted with Tellurium dioxide and the corresponding classifications, clearly represents a worst-case approach.

Data are therefore considered as adequate to fulfil the information requirements of REACH Annex VIII, 8.4.2/8.4.3 (in vitro cytogenicity study in mammalian cells/in vitro gene mutation study in mammalian cells), Annex VIII/ IX, 8.6.1 and 8.6.2 (repeated dose toxicity) and Annex VIII 8.7.1 (reproduction/developmental toxicity screening) of the target substance Tellurium.

(for further information see justification for read-across of elemental tellurium in section 13 of the dossier)

Justification for classification or non-classification

Justification for classification or non classification:

Tellurium was subject to CLH process in 2019 and 2020. The RAC in its assessment and comparison with the classification criteria concludes that tellurium fulfills the criteria for classifications as

Repr. 1B; H360 Df and Lact; H362, which was included in the 18. ATP to CLP (Regulation 2022/692 of 16 February 2022, Index-No. 052-001-00-0).

See RAC opinion CLH-O-0000006810-77-01/F adopted 11 June 2020 for more information.