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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

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Administrative data

Link to relevant study record(s)

Description of key information

Key value for chemical safety assessment

Additional information

An ADME study with KDDC is not available. ADME data on ziram is representative for KDDC as well.

Ziram is completely metabolised, i.e., the parent compound was not detectable in any of the analysed matrices. The main metabolic fate of ziram is exhalation of volatile metabolites (CS2,, CO2). These metabolites are formed non-enzymatically as soon as DDC is protonated. All other metabolites detected in excreta are formed predictably via DDC.

KDDC in aqueous solution are in equilibrium with the protonated form of DDC, due to the weak acidity of free DDC. Upon oral uptake, stomach acid will greatly facilitate protonation of DDC which then disintegrates forming the volatiles CS2and dimethylamine. Since the metabolic pathways of KDDC and ziram will converge directly after ingestion (via DDC), it can be surmised that the difference in molecular weight between ziram and KDDC does not affect the metabolism downstream from DDC formation.

Summary of ziram metabolism

Absorption:

As suggested by Tmax, absorption of ziram is slow and slows down with increased dose. Ziram binds at a slower rate (Tmax,blood> Tmax, plasma) but more intensively to blood than plasma constituents (Cmax,blood> Cmax, plasma). T1/2 elimin blood is longer than in plasma leading to a 10 times higher AUC in blood than in plasma.

Increasing the dose by a factor of 10 is associated with a more than 10 times increase in AUC, a 10 times increase in Cmax, while Tmaxand T1/2 elimare increased but not proportional to the dose, suggesting that, by increasing the dose, absorption is slower but more important/or that elimination is retarded. Slight differences are apparent between male and female rats suggesting that ziram reaches more important concentrations in females than in males.

Overall, T1/2 elimis higher than 24 h suggesting that accumulation may occur after repeated exposure.

Bile represents only a very minor route of excretion.

Based on the results of exhaled volatiles as well as urinary excretion, absorption is estimated to reach 59% within 72 h after a single low dose exposure. Absorption increases up to 81.2% after repeated low dose exposure.

In the monograph, it was concluded that the oral absorbed dose reached 58-61% after low dose and a correction factor of 50% was applied. Therefore, based on the new data, no further correction is necessary.

Distribution:

Distribution and uptake of radioactivity by tissues was rapid, with all tissues being exposed within 2 h after dosing . Maximum concentrations of radioactivity were achieved in most tissues at 8h post-dose administration in the low dose group and at 24 h in the high dose group. Maximum concentrations of radioactivity were not proportional with respect to dose level.

High levels of radioactivity were absorbed in the carcass within 2 h but these levels fell rapidly with time. The highest levels of radioactivity were detected in the organs of metabolism and excretion and after 168 h there were only low levels of radioactivity in all tissues. High levels were also detected in highly vascularised tissues resulting probably from the strong binding capacity of CS2to cross-link proteins (such as spectrin in erythrocytes).

 

Metabolism:

Approximately 52-65% of the administered dose was metabolised from which 43-59% were identified.

The most important fraction of ziram was metabolised into volatile compounds excreted in air. These volatile metabolites collectively accounted for ca 51% of the administered dose and consisted of CS2, COS and CO2. Increasing the dose slightly enhances formation of these metabolites.

In urine, independently of the dose, 3 main metabolites were detected, metabolites 4, 6 and 8. Two minor urinary metabolites were identified: dimethylamine-thiazolidine carboxylic acid (M1) and S-glucuronide (5) of dimethyldithiocarbamic acid. In faeces, low levels of thiram were detected.

Ziram is rapidly reduced to dithiocarbamic acid with loss of the metal ion. Traces of thiram were detected in faeces (0.08 – 0.18%). Dimethylthiocarbamic acid is further decomposed to dimethylamine and CS2or conjugated:

-         Decomposition of dimethyldithiocarbamate to CS2is the principal route. CS2is oxidised to CO2 and (by the mixed function oxidase system). Degradation of ziram via this route seems to increase with the dose. Total radioactivity excreted via air represents 42 to 65% of the dose. As suggested in the open literature (Graham et al., 1995) CS2interacts directly with amines, sulfhydryls and hydroxyl functions by nucleophilic addition (not shown). Reaction of CS2with cysteinyl sulfhydryls of cysteine or glutathione yields trithiocarbamates, which can cyclize to form thiazolidine-2-thione-4- carboxylic acid (TTCA; U1). Urine samples were analysed for the detection of TTCA but the analysis was not successful due to technical problems. However, the standard of thiazolidine-2-thione-4- carboxylic acid eluted with a retention time of 14.2 min and radioactivity from a urine sample in this region accounted for 0.02% of administered dose. So, if thiazolidine-2-thione-4- carboxylic acid (U1) was present, it would not have exceeded this percentage.

-         Dimethyldithiocarbamic acid is conjugated with glucuronic acid and glutathione giving rise to urinary metabolites. These conjugation routes are minor pathways as identified glucuronides represent 1.5 – 5.4% of the dose excreted in urine. Conjugation of dimethyldithiocarbamic acid or ziram directly with GSH would be catabolized to the cysteine conjugate via the cysteinyl-glycine conjugate which then cyclise, loses H2S to form 2-dimethylamine-thiazolidine carboxylic acid or M-1 (0.45 – 1.3% in urine).

 

Excretion:

Following oral administration, the majority of radioactivity was excreted as volatiles (CS2, CO2) in expired air (36 – 50%) within 24 h, reaching 42 to 60% of the dose within 168 h. Excretion via urine and faeces reaches 16% and 3% respectively. Increasing the dose 10 times decreased slightly urinary excretion but increased exhalation via CS2. After repeated exposure, urinary excretion was slightly increased (21%) as well as CS2exhalation (42 – 50%). Overall, within 168 h, 64 to 85% of the administered dose was excreted.

The overall recovery in these experiments was lower than would normally be expected due to difficulty in trapping the high levels of volatiles.