Tetrakis(diethyldithiocarbamato-S,S')tellurium

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

dermal absorption in vitro / ex vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

See attached read across justification

Reason / purpose for cross-reference:

read-across source

Key result

Time point:

6 h

Dose:

6.4 mg/cm²

Parameter:

percentage

Absorption:

0.1 %

Remarks on result:

other: Result read-across source CAS No. 137-30-4

Time point:

6 h

Dose:

0.016 mg/cm²

Parameter:

percentage

Absorption:

2.2 %

Remarks on result:

other: Result read-across source CAS No. 137-30-4

Description of key information

In an OECD TG 428 study according to CLP, dermal absorption of was determined to be 0.1%.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

0.1

Absorption rate - inhalation (%):

100

Additional information

Physical chemical properties

The substance is a solid with a molecular weight of 728.755 g/mol. An experimental Log P value could not be determined as a result of technical difficulties. Hence, the log P value was estimated using a QSAR model, resulting in a value of 4.389. The substance has a vapour pressure of 2.28E-7 Pa (at 20°C) . The water solubility was determined to be 0.634 mg/L (at 20°C). These physico-chemical properties of the substance will enable qualitative judgements of the toxicokinetic behaviour (Guidance on information requirements and chemical safety assessment Chapter R.7.c: Endpoint specific guidance, R.7.12 Guidance on Toxicokinetics).

 

Absorption

GI absorption

The molecular weight of the substance is relatively high but not unfavourable for absorption. As is evident from the calculated log P (>4) and the low water solubility (<1 mg/L), the substance is highly hydrophobic, which limits absorption by passive diffusion. However, the high lipophilicity of the substance is favourable for micellular solubilisation. Three experimental studies on toxicity following oral administration are available. Acute toxicity was assessed following a single oral exposure of the 5 g/kg bw in rats (Huntingdon Research Centre Ltd., 1986). No mortality was observed, but treatment-related findings included piloerection, soft faeces and bodyweight losses. In a supporting study rats were exposed to a single dose of the substance (TNO, 1978). Mortality was observed from 4.2 g/kg bw and higher. Treatment-related observations included sluggishness, humpback behaviour, severe diarrhoea, soiled fur, emaciation and encrustations around eyes. Following repeated oral exposure of rats no clinical signs or mortality were noted (Triskelion B.V., 2017). Significant treatment-related decreased body weight changes and food consumption was observed. The a treatment-related increase in mean landing footsplay and of time pattern of activity of males was observed. Additionally, treatment related effects were observed on relative organ weight in the liver, brain, and kidneys. Together, these findings indicate systemic absorption of the test substance.

 

Respiratory absorption

The substance is a fine powder and the experimentally determined particle size distribution (D90 of 15.9 µm, D50 of 7.7 µm) are favourable towards absorption via the respiratory tract. Despite the high calculated Log P (4.389), which is unfavourable for absorption by passive diffusion, the poor water solubility favours absorption by micellular solubilisation. Moreover, substances absorbed via the GI are likely to be absorbed when inhaled. One experimental inhalation study with the substance is available, in which rats were exposed (whole body) for 4 hours (Huntingdon Research Centre Ltd., 1986). No mortality was observed in this study. Small losses of bodyweight or a reduction in the rate of weight gain were observed. However, the dose in this study was limited by the highest possible generated concentration of an aerosol of the test substance.

 

Dermal absorption

Based on the water solubility of 0.634 mg/L and the molecular weight dermal absorption in the stratum corneum is likely to be low. Congruently, in an acute toxicity study in which rabbits were dermally exposed for 24 hours, the LD50 was determined to be greater than 2 g/kg bw (Huntingdon Research Centre Ltd., 1986). Clinical signs included abnormal gait, piloerection, poor food consumption and mucoid discharge from the anus. These signs indicate systemic availability, however it should be noted that animals were exposed under occlusive conditions.

 

The substance is a hydrophobic solid with a molecular weight of 728.755 g/mol and a calculated log P value of 4.389. These physicochemical characteristics fall outside the range mentioned in chapter R.7.c to select a default value of 100% skin absorption. However, it should be noted that thesesranges are especially applicable for organic molecules, while the substance is an organometallic.Therefore, for dermal absorption a read-across strategy to its structural analogue Ziram is deemed more appropriate.

 

Dermal penetration of Ziram was studied in vitro in a GLP-compliant guideline study, using human cadaver skin. 6.4 μL of two test substance preparations with nominal concentrations of 1.55 and 643 mg/mL was applied to 0.64 cm2 of human skin for 6 hours under occlusive conditions (4-6 diffusion cells per experiment). The total applied amounts of the test substance corresponded to 0.016 and 6.4 mg/cm2 skin. The total recovery of radioactivity in two experiments was 91.75% and 94.12%, respectively. 87.82% and 93.95% were recovered upon the skin swab after 6 hours exposure in the low-dose and high-dose experiments, respectively, while 0.39% and 0.2% penetrated through skin into the receptor fluid and 1.84% and 0.04% were recovered in stratum corneum. The total percentage of absorption through skin was thus determined to correspond to 2.23% and 0.1% in low-dose and high-dose experiments, respectively. It should be added that the amount applied in the high dose experiment is approximately in the range of 1-5 mg/cm2 skin, recommended by OECD Guideline 428 for solid substances.

 

The approximate dermal absorption of the substance can also be calculated based on its (water) solubility. Solid substances will only penetrate the skin in (aqueous) solution. Therefore, skin absorption can only occur through the water that penetrates the skin and the maximum skin absorption is defined by the maximum water solubility of the salts and the maximum amount of water that can penetrate the skin.

The maximum amount of water that can penetrate the skin is determined to be 17 µL per 1 cm² per 24 hours (Ten Berge, W. A simple dermal absorption model: derivation and application. Chemosphere.2009 Jun; 75(11):1440-5), which equals 6 µL per cm² per 8 hours.

The substance is virtually insoluble in water (ca. 0.634 mg/L, equals 0.000634 µg/µL).

Since 6 µL of water can maximally penetrate 1 cm² of skin per 8 hours, 6 x 0.000634 = 0.003804 µg of hydrolysed salt may penetrate 1 cm² of skin per 8 hours. In an in vitro skin absorption experiment (according to OECD guideline 428), the application should mimic human exposure, normally 1-5 mg/cm² (1000-5000 µg/cm²).

Thus, in case the skin penetration of the test substance would be experimentally be determined according to OECD guideline 428 using 5 mg/cm² as exposure condition, a skin penetration of (0.003804/5000 =) 7.6E-07 % would be observed maximally.

The value of 0.1 % dermal absorption, as determined in thein vitrodermal absorption study with Ziram, is considered an absolute worst case, since 0.1 % is an approximately 130000-fold higher value based on the dermal absorption expected based on water solubility alone. Therefore, it is considered that confounding factors of the route to route extrapolation (e.g. the absence of a first-pass effect in dermal absorption) are sufficiently covered.

 

Conclusion absorption

Since it is likely that the substance will be absorbed via the inhalation and oral route, and in the absence of substance-specific absorption data, the default absorption values from the REACH guidance (Chapter 8, R.8.4.2) are used for DNEL derivation, namely: 100% for inhalation and 50% for oral absorption. For dermal absorption, 0.1% is considered to be an absolute worst case based on the available information.

 

Distribution

The substance is a hydrophobic solid with a molecular weight of 728.755 g/mol, which does not favour passive diffusion through aqueous channels and pores. The behaviour observations in the repeated dose study with the substance (i.e. treatment-related increase in mean landing footsplay and of time pattern of activity) suggest that the substance reaches the CNS (Triskelion B.V., 2017). The calculated log P value of 4.389 suggests increased intracellular concentrations, particularly in fatty tissues.

 

Metabolism

In vivo data regarding metabolism is not available for the substance. Using the QSAR toolbox, it was predicted that in vivo (rat) the substance is mainly cleared by hydrolysis and oxidative metabolism. Predicted metabolites include acetic acid and acetaldehyde.

 

In vivo metabolism has been described for the structurally related compound ziram (ZDMC). The principal route of metabolism for ZDMC was hydrolysis to form carbon disulphide and carbonyl sulphide and the formation of carbon dioxide. These volatile metabolites comprised the majority of the excreted dose (ca. 51%). Urine contained 2-dimethylamine-thiazolidine carboxylic acid and the S-glucuronide of dimethyldithiocarbamic acid. The latter compound is presumably formed by glutathione conjugation of either the dimethyldithiocarbamic acid or ZDMC directly. The glutathione conjugate would then be catabolised to the cysteine conjugate via the cysteinyl-glycine conjugate, which then cyclised, loosing H2S, to form 2-dimethylamine-thiazolidine carboxylic acid. Faeces contained tetramethylthiuramdisulfide.

 

Excretion

The substance is a hydrophobic solid with a molecular weight of 728.755 g/mol.Characteristics favouring urinary excretion include good water solubility and a low molecular weight (below 300 in the rat. Urinary excretion is therefore note expected for the substance itself but is likely for the metabolites.

 

In vivo excretion has been described for the structurally related compound ziram (ZDMC).The tissue retention and excretion of radioactivity was determined after single and multiple oral doses of (14C)-ZDMC at nominal dose levels of 15 and 150 mg/kg bw. In addition, for one excretion balance study non-radiolabelled ZDMC was administered daily for 14 days and twenty-four hours after receiving the last dose, a single dose of (14C)-ZDMC was administered. In the low dose group, 63.27 and 64.41% of total dose was recovered over 168 hours in males and females, respectively, from which 3.068 and 3.238% were recovered in faeces. In the high dose group, the recovery over 168 hours was 75.88 and 76.46% in males and females, respectively, out of which 4.574 and 2.844% were recovered in faeces. In the repeated administration group, the recovery was 74.09 and 84.93% in males and females, respectively, with 3.112 and 4.145 % recovered in faeces. In the biliary excretion study, following a single administration of14C-ZDMC to 2 male animals at nominal dose levels of 50 and 100 mg/kg bw, 2.2% and 1.9% was excreted in bile, 16.9% and 9.6% in urine and 17 and 3.1% in faeces, respectively. The majority (ca. 51%) of the administered dose was excreted as volatile metabolites CS2, COS or CO2. The remaining dose was excreted in urine (ca. 10.9-20.8%) and faeces (ca. 4%), with virtually none via bile. Excretion was rapid and essentially complete within 24 hours.

 

Accumulation

Although the substance is poorly water soluble, the calculated log P of 4.389 precludes accumulation in the alveolar region of the lung.It does suggests increased intracellular concentrations, particularly in fatty tissues, and accumulation of the substance in the stratum corneum, from which it can be cleared when the stratum corneum is sloughed off.