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Description of key information

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
50
Absorption rate - dermal (%):
10
Absorption rate - inhalation (%):
100

Additional information

Toxicokinetics

Physical chemical properties

The substance is a solid with a molecular weight of 365.97 g/mol. The substance is almost insoluble in water (1.06 mg/L at 20 °C and pH 5.9-6.4) and is not dissolvable in octanol, hence the experimental Log P value cannot be determined. A log P value of 3.11 was calculated using a QSAR model. 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 relatively low molecular weight and calculated Log P value are favourable for oral absorption. However, a solid needs to be dissolved first to be absorbed, and the substance is highly hydrophobic. Following a single oral exposure of the test substance in rats, adverse effects were only seen at doses of 650 mg/kg bw and higher and included , irregular respiration, dyspnoea, diarrhoea, incontinence of urine, decrease of motor ataxia (Sumimoto 1977). As the substance is a known skin, eye and respiratory tract irritant it cannot be excluded that these effects arise from local effects rather than systemic effects. Nevertheless, within 1-7 days following administration mortality occurred at doses of 1000 mg/kg bw and higher, confirming absorption following oral administration. Following repeated oral exposure of rats adverse findings were noted in haematology and clinical chemistry. Moreover, mortality was observed following exposure to 125 or 250 mg/kg bw/day (Triskelion 2017). These findings indicate systemic absorption of the test substance. However, it should be noted that in both studies the test substance was dissolved in corn oil before administration, which facilitates emulsification and digestion.

Respiratory absorption

The substance is a powder and therefore available for inhalation. Despite the low water solubility, the calculated Log P (3.11) and the experimentally determined particle size distribution (99% in the range 10-100 µm) are favourable towards absorption via the respiratory tract. Moreover, substances absorbed via the GI are likely to be absorbed when inhaled.

Dermal absorption

The substance is a hydrophobic solid with a molecular weight of 365.97 g/mol and a calculated log P value of 3.11. Although these physico-chemical characteristics fall within the range mentioned in chapter R.7.c to select a default value of 100% skin absorption, it should be noted that theses ranges are especially applicable for organic molecules, while the substance is an organometallic. Dermal absorption is favourable for uptake at a molecular weight of < 100 g/mol. Based on the water solubility of 1.06 mg/L and the molecular weight dermal absorption in the stratum corneum is likely to be low.

In a dermal acute toxicity test in rabbits, occlusive exposure to 2000 mg/kg bw test substance did not result in adverse symptoms or mortality (Pharmacology Research, Inc). The skin irritating properties of the substance may lead to cell membrane damage and consequently favour dermal absorption. Furthermore, the substance is a known skin sensitizer, which indicates systemic bioavailability.

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. 1 mg/L, equals 0.001 µg/µL).

Since 6 µL of water can maximally penetrate 1 cm² of skin per 8 hours, 6 x 0.001= 0.006 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 (0.006/5000 =) 1.2E-06 % would be observed maximally.

Therefore the lower limit value of 10 % dermal absorption, as suggested in the ECHA Guidance on information requirements and chemical safety assessment – Chapter 7c: Endpoint specific guidance (Version 3.0 June 2017), is considered an absolute worst case. Since 10% is an approximately 8000000-fold higher value based on the dermal absorption expected based on water solubility alone, 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. 

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, 10% is considered to be an absolute worst case.

Distribution

The substance is a hydrophobic solid with a molecular weight of 365.97 g/mol, which does not favour passive diffusion through aqueous channels and pores. However, as the molecular weight is below 500 passive diffusion across cell membranes is expected. The calculated log P value of 3.11 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. The metabolism is expected to occur via a hydrolysis of the parent compound into the respective acid. Predicted metabolites include acetic acid, acetaldehyde, diethylamine and carbon disulphide. Metabolites may also be formed by dealkylation of the parent compound or thy hydrolysed parent compound. 

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. These metabolic routes are in agreement with the metabolic routes that are predicted using the QSAR toolbox for the test substance.

Excretion

The substance is a hydrophobic solid with a molecular weight of 365.97 g/mol. Characteristics favouring urinary excretion include good water solubility and a low molecular weight (below 300 in the rat. Urinary excretion is therefore not expected for the substance itself but is likely for the metabolites. The predicted carbon disulphide metabolite is volatile, and is therefore expected to be excreted as such. 

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. These results of the structurally related ZDMC are in agreement with the expected routes of excretion of the substance itself.

Accumulation

Although the substance is poorly water soluble, the calculated Log P of 3.11 precludes accumulation in the alveolar region of the lung. Since the Log P value is below 4, accumulation in the adipose tissue and stratum corneum is also not expected.