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Key value for chemical safety assessment

Effects on fertility

Additional information
Short description of key information:
No data on reproductive toxicity of sodium dibutyldithiocarbamate (SDBC) are available. However, in accordance with Column 2 of Annex VIII, the study does not need to be conducted,as two reliable developmental toxicity studies, one with rats and one with rabbits, are available for a structural analogue of SDBC, zinc bis(dimethyldithiocarbamate) (ZDMC), indicating that the substance is not a developmental toxicant.

Effects on developmental toxicity

Description of key information
No data on developmental toxicity are available for sodium dibutyldithiocarbamate (SDBC). However, GLP-compliant guideline studies with rats and rabbits are available for its structural analogue zinc bis(dimethyldithiocarbamate) (ZDMC). Based on the results of these studies, a NOAEL for maternal toxicity (corrected for molecular weight and calculated for pure (anhydrous) substance) was set at ~ 5 mg/kg bw/day, based on increased water and decreased food consumption in the rat study and reduced body weight and decreased food intake in the rabbit study. Taking into account that SDBC is solely manufactured and marketed by the registrant as ca. 47% aqueous solution, this corresponds to 11 mg/kg bw/day for the substance as manufactured. The NOAELs for developmental toxicity, recalculated for the pure substance, were set at 5.9  mg/kg bw/day in the rat study, based on the marginal increase in the number of fetuses with visceral abnormalities, and 11 mg/kg bw/day in the rabbit study, based on slightly increased post-implantation loss and reduced litter weight, foetal weight and crown/rump length. Taking into account that SDBC is solely and marketed manufactured as ca. 47% aqueous solution, this corresponds to 11 and 24 mg/kg bw/day of substance as manufactured, respectively.
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
5 mg/kg bw/day
Additional information

No information on developmental toxicity of sodium dibutyldithiocarbamate (SDBC) is available. However, Article 13 of the REACH legislation states that, in case no appropriate animal studies are available for assessment, information should be generated whenever possible by means other than vertebrate animal tests, i.e. applying alternative methods such as in vitro tests, QSARs, grouping and read-across.

Data on developmental toxicity are available on the zinc-containing structural analogue of SDBC, zinc (bisdimethyldithiocarbamate) (ZDMC). The latter substance is a zinc salt of a homological dialkylcarbamodithioic acid, namely dimethyldithiocarbamic acid, which differs only in the length of alkylic substituents in the dithiocarbamate moiety (butyl vs. methyl). Based on the structures of the substances, it is expected that their toxicological behavior shall be governed by the toxicological profiles of the respective Na+and Zn2+cations and dithiocarbamate anions. It can also be expected that, based on structural similarity, dimethyl- and dibuthyldithiocarbamate anions shall be metabolized via similar pathways, as it is not expected that the difference in the carbon chain length of alkyl substituents at the amine function of dithiocarbamate moieties shall have a profound difference on the substances reactivity.

Human toxicological profiles of sodium and zinc cations are well known. Sodium is an essential constituent and one of the most abundant ions in all humans, as well as in all animal species. It is known to be non-genotoxicin vivo(see for example OECD SIDS of sodium carbonate,, 2002). Effects on fertility and development of Zn2+cation were assessed in the European Union Risk Assessment Report on zinc (2008, rapporteur The Netherlands). The report concluded that neither fertility nor developmental toxicity are considered end-points of concern for humans. Adverse effects on fertility and foetal development were shown to occur in experimental animals at dose levels of 200 mg Zn2+/kg bw/day, however, based on the available data it is impossible to conclude whether these adverse effects are directly related to zinc, or whether they are the result of disturbances in other physiological functions. Therefore the effects on developmental and reproductive toxicity of SDBC and ZDMC are expected to be governed primarily by the dithiocarbamate moieties and thus it is considered acceptable to derive the data on toxicokinetic behavior of SDBC by read-across from ZDMC.

Two GLP-compliant guideline developmental toxicity studies, one with rats and one with rabbits, are available for ZDMC. In the rat study (Huntingdon Research Centre Ltd, 1990) the test substance was administered by gavage in 1% methylcellulose to groups of pregnant female Sprague-Dawley rats at nominal dose levels of 1, 4, 16, 64 mg/kg bw/day at days 6-15 of gestation, followed by the sacrifice at day 20. Animals were observed for clinical signs, body weight changes, food and water consumption. Uterine contents were examined for the number of corpora lutea, number and distribution of dead and live fetuses, number of late and early resorptions, individual foetal weights and fetal abnormalities. Soft tissue and skeletal examinations were performed on the half of fetuses from each litter.

A dose-related increased water and decreased food consumptions were evident in the dose groups of 16 and 64 mg/kg bw/day. The dams in these groups also showed a slight bodyweight loss at the initiation of treatment. At termination at 16 mg/kg bw/day paralleled control whereas at 64 mg/kg bw/day parity with controls was not reached. There was no difference in mean pre-implantation loss and implantation rate. Also no adverse changes were noted at necropsy.

Mean foetal weight was at 64 mg/kg bw/day lower than the controls. Incidence of foetuses with visceral anomalies was marginally higher and not dosage-related at 16 and 64 mg/kg bw/day, but 5/20 and 5/16 animals in these groups showed a thinning of the diaphragm. That was thought unlikely to be treatment-related as no foetus showed diaphragmatic hernia. Based on the results of the study, a NOAEL for maternal toxicity was set at 4 mg/kg bw/day, based on increased water and decreased food consumption, while a NOAEL for developmental toxicity was set at 4 mg/kg bw/day, based on the marginal increase in the number of fetuses with visceral abnormalities. As these fetal effects were observed at dose levels which elicited maternal toxicity, and no clear dose-response was obvious, classification of the substance as a developmental toxicant is considered to be not warranted.

In the rabbit study (Hazleton Laboratories Europe Ltd., 1986), 16 female rabbits were exposed to 3, 7.5 and 15 mg/kg bw/day test substance, using 1% methylcellulose as a vehicle, during days 7 -19 of gestation and sacrificed on day 28. Signs of maternal toxicity (reduced body weight gain and food intake) were observed at the dose levels of 7.5 mg/kg bw/day and above, resulting in a NOAELmaternalof 3 mg/kg bw/day. Adverse effects on development, manifested as slightly increased post-implantation loss and reduced litter weight, foetal weight and crown/rump length, were observed at the highest dose level of 15 mg/kg bw/day, resulting in a NOAELdevelopment= 7.5 mg/kg bw/day.

As can be seen, the NOAELs for maternal toxicity obtained in the rat and rabbit study, differ only marginally. Applying the correction for molecular weight andtaking into account that ZDMC contains two dithiocarbamate anions while SDBC contains one, the NOAELmaternalof ~5 mg/kg bw/day is set for pure SDBC (3 x 2 x (227/306) = 4.45 mg/kg bw/day based on the rabbit study and 4 x 2 x (227/306) = 5.9 mg/kg bw/day based on the rat study). Taking into account that SDBC is solely manufactured and marketed by the registrant as a ca. 47% aqueous solution, this corresponds to the NOAEL of 11 mg/kg bw/day for the substance as manufactured. For developmental toxicity, a NOAEL of 5.9 mg/kg bw/day is obtained based on the rat study and 11 mg/kg bw/day based on the rabbit study. Taking into account that SDBC is solely manufactured and marketed as ca. 47% aqueous solution, this corresponds to NOAELs of 11 mg/kg bw/day and 24 mg/kg bw for substance as manufactured.

The lowest of the observed NOAELs, calculated for pure substance (5 mg/kg bw/day), shall be taken forward as a point of departure for DNEL derivation.

Justification for classification or non-classification

Based on the read-across with a structural analogue of sodium dibutyldithiocarbamate (SDBC), zinc bis(dimethyldithiocarbamate) (ZDMC), and taking into account that fetal effects were observed at dose levels which elicited maternal toxicity, and no clear dose-response was obvious, classification of SDBC for developmental toxicity is not warranted in accordance with EU Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.