Nickel bis(dibutyldithiocarbamate)

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

0.1

Absorption rate - inhalation (%):

100

Additional information

Toxicokinetics

 

Physico-chemical properties

The substance is a solid with a molecular weight of 467.453 g/mol. An experimental Log P value could not be determined as the substance does not dissolve in water or in octanol. Hence, the log P value was estimated using a QSAR model, resulting in a value of 5.44. The substance has a predicted vapour pressure of 0.0807 Pa at 20°C. The water solubility was determined to be 0.0893 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. Four experimental studies on toxicity following oral administration are available. Acute toxicity was assessed following a single oral exposure of 5 g/kg bw in rats (HRC, 1986a). No mortality was observed, but treatment-related findings included piloerection and bodyweight losses. In a supporting study rats were exposed to a single dose of 1, 2.5 or 5 g/kg bw (TNO, 1978a). No mortality nor toxic symptoms were observed. In another supporting study, rats were exposed to a single dose of 5 g/kg bw (Sumimoto Chemical Co., Ltd. 1977). No mortality was observed, but few hours after exposure, rats showed sluggishness and signs of ataxia. Following repeated oral exposure of rats showed changes in haematological parameters, clinical chemistry, organ weights and histopathology (Triskelion B.V., 2019). Together, these findings indicate systemic absorption of the test substance following oral exposure. 

 

Respiratory absorption

The predicted low vapour pressure (0.0807 Pa) and high boiling point (521.96°C, data generated with a QSAR method) indicate that the availability of the substance for inhalation as a vapour is limited. Indeed, in theexperimental inhalation study with the substance, in which rats were exposed (whole body) for 4 hours (HRC, 1986), no mortality or treatment-related effects were observed in this study. The dose in this study was limited by the highest possible generated concentration of an aerosol of the test substance.

The substance is a fine powder and the experimentally determined particle size distribution (D90 of 10.9 µm, D50 of 6 µm) is favourable towards absorption via the respiratory tract. The high calculated Log P (5.44) and the poor water solubility suggest limited absorption by passive diffusion, but favour absorption by micellular solubilisation. Moreover, substances absorbed via the GI are likely to be absorbed when inhaled. Therefore, systemic absorption of the test substance following inhalation exposure cannot be excluded

 

Dermal absorption

Based on the water solubility of0.0893mg/L 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 (HRC 1986). Clinical signs includeddiarrhoea, bodyweight loss and a poor weight gain. 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 467.453 g/mol and a calculated log P value of 5.44. The molecular weight falls within 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 Zinc bis(dimethyldithiocarbamate) (ZDMC, CAS 137-30-4) is deemed more appropriate.  

 

Dermal penetration of ZDMC 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 were applied to 0.64 cm²of 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/cm²skin. 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. The amount applied in the high dose experiment is approximately in the range of 1-5 mg/cm²skin, recommended values for solid substances in the OECD TG 428.

 

The approximate dermal absorption of the target substance can be estimated 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 substance 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, 2009), which equals 6 µL per cm² per 8 hours. The target substance is virtually insoluble in water (ca. 0.0893 mg/L = 0.0000893 µg/µL). Since 6 µL of water can maximally penetrate 1 cm² of skin per 8 hours, 6 x 0.0000893= 0.000536 µg of the target substance may penetrate 1 cm² of skin per 8 hours.

In an in vitro skin absorption experiment (according to OECD TG 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 determined according to OECD TG 428 using 5 mg/cm² as 8-hour exposure condition, a skin penetration of (0.000536/5000 =) 1.07E-05 % would be observed maximally.

Therefore a value of 0.1 % dermal absorption, as determined in the in vitro dermal absorption study with ZDMC, is considered an absolute worst case. Since 0.1 % is more than 9,000-fold higher than the dermal absorption expected based on water solubility of the test item (1.07E-5 %), 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 a conservative value and an absolute worst case based on the available information for the analogue ZDMC.

 

Distribution

The substance is a hydrophobic solid with a molecular weight of 467.453 g/mol, which does not favour passive diffusion through aqueous channels and pores. The repeated dose toxicity test in rat, performed according to OECD 422, showed changes in the heart, skeletal muscles, liver, alveoli, adrenal glands and parathymic lymph nodes, indicating that test substance is distributed throughout the body. The calculated log P value of 5.44 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 upon incubation with rat liver S9 mix, hydroxylation of the butyl groups would occur.

In vivo (rat) metabolic clearance of the substance is predicted to occur by oxidation of the butyl group and N-dealkylation, both reactions that can be catalysed by cytochrome P450 enzymes.  

 

In vivo metabolism has been described for the structurally related compound 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 be catabolised to the cysteine conjugate via the cysteinyl-glycine conjugate, which then would cyclize losing H₂S to form 2-dimethylamine-thiazolidine carboxylic acid. Faeces contained tetramethylthiuramdisulfide.

 

Excretion

The substance is a hydrophobic solid with a molecular weight of 467.453 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.

 

In vivo excretion has been described for the structurally related compound 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 of [¹⁴C]-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 5.44 precludes accumulation in the alveolar region of the lung. It does suggest 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.