Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
11.1 mg/kg bw/day
Additional information

Due to the lack of available data, the potential of disulfiram to affect fertility is assessed using read-across from studies conducted with a surrogate substance, thiram (CAS 137 -26 -8). After correction for molecular weight (factor: 1.23) the NOAELs for thiram are used as NAELs for disulfiram. (For detailed information on the justification of read-across, please refer to the analogue justification document attached in IUCLID section 13).

One GLP-compliant two-generation study was conducted with thiram in rats (, 1991). Animals of all generations were administered 30, 60 or 180 ppm disulfiram in the diet.At the parental level, there were no treatment-related findings concerning mortality, ante mortem observations and reproductive parameters, e. g. copulatory, fertility and gestation indices, mean copulatory interval, mean gestation length as well as sperm morphology and motility. Food consumption and body weight decreased in groups dosed with 60 and 180 ppm, mainly during gestation. With regard to the litters, there were no treatment-related findings concerning the number of stillborn pups, survival indices, necropsy findings or malformations. Under the conditions of this study the NOAEL for reproductive toxicity was greater than 9 mg/kg bw/day. Based on the molecular weight, this refers to a NAEL of 11.1 mg/kg bw/day for disulfiram.

Short description of key information:

Based on the read-across from thiram, a NOAEL of 11.1 is derived by correcting the NOAEL of 9 mg/kg bw/d for thiram with the correction factor of 1.23 for molecular weight.

Effects on developmental toxicity

Description of key information

Based on read-across with thiram, it is expected that disulfiram has no specific effects on pre-natal development in rats or rabbits.

Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
18.5 mg/kg bw/day
Additional information

The developmental toxicity / teratogenicity of disulfiram is assessed using read-across from studies conducted with a surrogate substance, thiram (CAS 137 -26 -8). After correction for molecular weight (factor: 1.23) the NOAELs for thiram are used as NAELs for disulfiram. (For detailed information on the justification of read-across, please refer to the analogue justification document attached in IUCLID section 13).

Prenatal developmental toxicity studies according to OECD or EPA guidelines were performed in rabbits (York, 1992, Tesh, 1988) and rats (Tesh, 1988). In these studies, pregnant rabbits were dosed with up to and including 10 mg thiram /kg bw/d during gestation days 7 to 19. Based on the results of the study performed by, (1992), the foetal NOAEL is considered to be ≥ 10 mg/kg bw/day in rabbits given thiram via oral gavage, with the maternal NOAEL being as well ≥ 10 mg/kg bw/day. In the presence of maternal toxicity, Tesh (1988) reported a developmental NOAEL of 5 mg/kg bw/d. 25 pregnant rats per group were dosed with 7.5, 15 and 30 mg thiram/kg bw/d during gestation days 6 to 15. Based on a high incidence of small foetuses and an associated retardation of foetal development in the high dose group, the NOAEL is considered to be 15 mg/kg bw/day in rat. Based on the molecular weight this refers to a NAEL of 18.5 mg/kg bw/day for disulfiram.

Justification for classification or non-classification

The available data on toxicity to reproduction is conclusive but not sufficient for classification according to the EU Directive 67/548/EEC and the CLP Regulation.