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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.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

Diss Factsheets

Administrative data

Description of key information

see study records

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
3.33 mg/kg bw/day
Study duration:

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Dose descriptor:
226 mg/kg bw/day
Study duration:

Additional information

One subchronic gavage study on rats has been performed with SDDC. The study results can be adopted for for KDDC since only the cation is different (potassium instead iof siodium). The study has identified the bone marrow as target organ for SDDC with subsequent effects on spleen, kidneys and liver. In addition, less specific effects like hypertrophy or hyperplasia of stomach, urinary bladder, duodenum and thyroids were noted.

Repeated dose studies with ziram have been conducted in dogs, rabbits and rats.

In rats ziram decreased body weight gain, food intake and food efficiency. Dogs presented a subdued behaviour and/or unsteady gait, with slight alterations in body weight and food efficiency, increase in liver weight, they vomited and had diarrhoea. In the rat, T4 serum level after four weeks showed a dose related reduction, T3 and TSH were not significantly affected. Moreover, minor, but consistent, changes in biochemical parameters were observed (total protein, albumin, Ca2+, RBC, urea nitrogen, creatinine and MCHC). In the rat, the target organs were liver and kidneys, as shown by the presence of degenerative alterations. Dogs showed an increased liver weight.

In the subchronic experiment (90 day study), the non-glandular stomach was the target organ with minimal epithelial hyperplasia in rats. No effects indicative of neurotoxicity were apparent when FOB tests were performed in the rat. In dogs, the target organs were liver and spleen, with at the start increased pigmentation of Kupffer cells and/or macrophages with Perls’ positive material, possibly reflecting increased iron metabolism and turnover. A slight lowering of red cell indices, acute inflammatory cell infiltration in the lungs, decreases in heart weight, likely related to convulsions were also observed.

In a 21-day percutaneous test, ziram affected the liver in rabbits. This effect occurred at 300 mg/kg bw/d. No dermal reactions were observed.

The similarity of SDDC and ziram with regard to their toxicological properties can be established by comparison of the outcome of the subchronic oral study in rats with SDDC and the subchronic oral study with dogs and the chronic oral study with rats with ziram. The studies are not strictly comparable because SDDC was dosed by gavage whereas ziram was administered via food.

The principal effects caused by both substances are identical. Haemolysis indicated by a decrease in red blood cells and haemoglobin and by an increase in the mean corpuscular volume and mean corpuscular haemoglobin concentration is accompanied by subsequent effects on spleen, kidneys and liver. Among these effects areincreased pigmentation of Kupffer cells, haemosiderosis and extramedullary haematopoiesis.

The quantitative difference between the LOAELs/NOAELs found in the studies might arise from a difference in bioavailability associated with the different application techniques. Bioavailability from the food matrix used in the ziram studies might be lower or delayed compared to SDDC which was applied undiluted.

The subchronic NOAEL for KDDC is 22.5 mg/kg bw/day based on the gavage study with SDDC. From the 13-week feeding study with ziram, a NOAEL for KDDC of less than 16.7 mg/kg bw/day for rats and 9.2 mg/kg bw/day for dogs is estimated.

Both chronic studies in dogs and rats provide NOAELs equivalent to 3.33 mg/kg bw/day and less than 5.2 mg KDDC/kg bw/day, respectively.

No systemic effects were seen in the 21-day toxicity study with ziram using the dermal route of administration in rabbits. The subacute dermal NOAEL for ziram is equivalent to 208 mg/kg bw/day for KDDC.


Range-finding studies for dietary administration were performed for short periods of exposure in mice and in dogs for 28 days. The studies were used to set dose levels for the subsequent 90-day studies.

Rats and dogs received thiram in their diet either for a 90-day period or for 52 weeks. In both species, oral administration of thiram produced changes in the liver, increase in liver weight, blood cholesterol and decrease of plasma proteins, decreases in food consumption and body weight gain, local irritation to the non-glandular stomach, and macrocytic anaemia. The NOEL and NOAEL are lower for the dog than for the rat. The lowest NOAEL is 0.84 mg/kg bw/day (1 year dog study).

The chronic NOAEL based on a combined chronic/carcinogenicity study in rats (for study records see 7.7). Taking in account the results of the first year and the interim sacrifices, mainly changes in bodyweight, food/water consumption and haematology, the NOAEL was set at 1.5 mg/kg bw/d.

In rabbits, signs of systemic toxicity (liver effects) after dermal exposure to 1000 mg/kg bw/d thiram for 21 days were seen. Thus, the NOAEL for systemic toxicity is established at 300 mg/kg bw/d. Local skin reactions such as erythema with or without oedema and acanthosis were seen at all dose levels. The NOEL local was set lower than 100 mg/kg bw/d.

In one rat test, published in the open literature, a slight dysfunction of the testes following thiram, 25 mg/kg bw/d over 90 days, is suggested.

These effects on liver and liver enzyme parameters were shown to be completely reversible with full recovery observable, which was agreed upon in the evaluation by the RMS Belgium. In light of the reversibility of effects on liver and liver enzymes, in the absence of other severe systemic effects and in view of the occurrence of effects in an individual animal only (see thiram one-year study), a classification with R48/22 is not considered to be appropriate. Effects mediated by local contact at the site of first contact will be mitigated by consideration of suitable protective equipment and are not within the scope of the R48. Such effects are rather addressed by R phrases applicable for local effects (i.e. R34/35-R38/37/38).

Classification for repeated-dose toxicity: none.

Derivation of relevant NOAEL:

Long-term studies have not been conducted with KDDC, but with the closely related substances, ziram and thiram.

The dog appears to be the most sensitive species for ziram toxicity. A one-year study with ziram (Smith et al., 1993) revealed effects on body and prostate weight as well as histopathological findings in liver and spleen. The long-term LOAEL and NOAEL are equivalent to 13.8 and 3.3 mg technical a.s./kg bw/day, respectively.

Likewise, the most sensitive short-term NOAEL was also found in a dog study. The critical effects in a 90-day feeding study in dogs with ziram (McLean et al., 1992) were focal necrosis and Kupffer cell pigmentation in the liver. The short-term LOAEL and NOAEL are equivalent to 25.3 and 8.5 mg technical a.s./kg bw/day, respectively.

Justification for classification or non-classification

see discussion