N,N'-dimethyldiphenylthiuram disulphide

Endpoint summary

Description of key information

No specific study on toxicokinetic, metabolism and distribution available

Additional information

The following remarks on the toxicokinetics of N,N’-dimethyldiphenylthiuram disulfide are based on the studies described within the REACH process. Experimental toxicokinetic studies are not available and have not been performed. The criteria outlined in the “Guidance on information requirements and chemical safety assessment Chapter R.7c: “Endpoint specific guidance” will be applied throughout this statement.

N,N’-Dimethyldiphenylthiuram disulfide is described as a white to grey organic solid (powder, M.P.: 160-210 °C under normal ambient condition). Its molecular weight is 364 g. The vapour pressure of N,N-Dimethyldiphenylthiuram disulphide is estimated by QSAR considerations and the given value ranges between 0.000000097 and 0.00000037 Pa at 25°C. The water solubility of the test material is less than 0.2 mg/l at 20 °C. The partition coefficient (log Pow) of N,N-Dimethyldiphenylthiuram disulphid was determined to be 4.7 at 25°C.

From these data it can be concluded that vapour exposure is unlikely route of exposure.

ABSORPTION

Despite the molecular weight below 500 g but regarding log Pow > 4 and the extreme low water solubility it can be assumed that the absorption via oral, dermal and inhalation might be poor. This is confirmed by the following studies:

For industrial use, granulometric measurements yielded a median diameter of 31.0 μm with the main fraction of 94.9 % distributing in the range of 10 -100 μm, thus leading to the assumption that alveolic barrier cannot be passed. Furthermore, in an acute inhalation study of an inhalable (MMAD = 4.1 µm) solid aerosol of N,N-Dimethyldiphenyl-thiuram disulphide with rats no animal died and no signs of systemic or local toxicity in rats up to the maximum attainable concentration (5064 mg/m³) were observed (Pauluhn 2012 , Report No AT06412 of 20.04.2012).

No acute dermal toxicity study is available, but in acute skin and eye irritation studies in rabbits (Mihail 1977, Report No. T8051309, 16.01.1977) no systemic intolerance is reported. Furthermore, no sensitizing effect has been identified in the Local Lymph Node Assay (Vohr 2012, Report No. AT 06397, 16.03.2012).

With respect to oral application single administration of 5000 mg/kg bw did not cause death nor any signs of intoxication, thus, confirming the assumption of poor absorption also for acute oral application (Löser 1976, Report No.T3035258, 15.06.1976). However, from the available results in the subacute study it can be concluded that absorption is likely. In the respective 28-day gavage study with rats (0, 100, 300 and 1000 mg/kg bw/day given as suspension in Solutol 15 HS/Ethanol /water = 4 : 1 : 5, Wirnitzer 2012, draft report) N,N’-Dimethyldiphenylthiuram disulphide caused significant hemolytic anemia from 100 mg/kg bw/day (LOAEL) onwards increasing in severity with the dose accompanied by histopathological effects in spleen and kidney but not in the liver, discolored feces at mid and high dose rats (both sexes) and reduced body weight development in high dosed rats. Dose-related increasing significant reticulocytosis can be interpreted as adaptive process. These findings lead to the assumption that in the acidic environment of the stomach (pH = 1.0-1.5) the molecule may undergo, at least partially, hydrolysis which lead to different physico-chemical characteristics regarding absorption through the mucosa of the stomach as shown by clear hematotoxicity. In vitro, however, at pH = 6 (aequous environment), the expected hydrolysis product “N-Methylaniline” could not be detected

DISTRIBUTION

Referring to distribution there is no specific investigation available. But, the lipophilicity of the substance (log Pow>4) gives evidence that the substance is likely to distribute into the cells and the observed histopathological adverse effects in kidney and spleen in the 28-day gavage study with rats rats (0, 100, 300 and 1000 mg/kg bw/day given as suspension in Solutol 15 HS / Ethanol / water = 4 : 1 : 5, Wirnitzer 2012, draft report) seem to confirm this assumption.

METABOLISM

Referring to metabolism, there is no specific investigation available. Also, the results of the above discussed 28-day gavage study does not provide any information on metabolization of N,N’-Dimethyldiphenylthiuram disulphide . From negative results of the in-vitro genotoxicity tests, especially in the presence of metabolic activation systems (Ames test, , Herbold 2001, Report No. PH30729. 13.02.2001; HPRT test, Wollny 2012, Harlan CCR 1434100, 14.05. 2012 and the Micronucleus test-in-vitro for chromosome aberrations (Sutter 2012, Draft Report No. A57983),.it can be assumed, that DNA-reactive metabolites of N,N’-Dimethyldiphenylthiuram disulphide will most probabely not be generated in mammals in the course of hepatic biotransformation.

EXCRETION

Referring to excretion there is no specific investigation available. The low water solubility of the test material which is less than 0.2 mg/l at 20 °C, in conjunction with the finding of discolored feces at mid and high dose rats, this may be a hint that the main excretion route is via feces and not via urine.