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Administrative data

Description of key information

No data on repeated dose toxicity of sodium dibutyldithiocarmate (SDBC) are available. However, a reliable 90-day study is available for a structural analogue of SDBC, sodium dimethyldithiocarbamate (SDBMC), in which a NOAEL of 10 mg/kg bw/day (calculated for pure (anhydrous) substance) was established, based on haemolytic effects manifested as an increase in mean corpuscular haemoglobin and mean corpuscular volume in both sexes, and signs of bone marrow hyperplasia in females. Applying a correction factor for the difference in molecular weight, this leads to a NOAEL of 16 mg/kg bw/day for isolated (anhydrous) SDBC. Taking into account that SDBC is solely manufactured and marketed as ca. 47% aqueous solution, this corresponds to NOAEL of 34 mg/kg bw/day for the substance as manufactured. The value for the pure substance shall be used for DNEL derivation. 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
16 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Additional information

No data on repeated dose toxicity of sodium dibutyldithiocarbamate (SDBC) are available for assessment. However, Article 13 of REACH 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.

A reliable GLP-compliant 90 -day study, performed according to OECD Guideline 408, is available for a structural analogue of SDBC, sodium dimethyl dithiocarbamate (SDMC). The two substances are structural homologues of each other, differing only in the length of alkyl substituents at the amine function of the dithiocarbamate moieties (butyl vs. methyl). As SDMC is a smaller molecule than SDBC, it is expected that its absorption from the gut shall occur at least as fast, if not faster. Therefore it is considered acceptable to derive the data on repeated dose toxicity of SDBC by read-across from SDMC.

In the 90-day study, groups of 10 male and 10 female rats were daily administered the test substance in water by gavage at dose levels of 10, 50 and 250 mg/kg bw/day (corresponding to 24.4, 122 and 610 mg/kg bw/day for the substance as manufactured, i.e. 41% solution). Animals were observed for clinical signs and signs of functional/behavioral toxicity, and gross pathological, histopathological, haematological and clinical chemistry examinations were performed at terminal sacrifice. A clear haemolytic effect was identified for animals of both sexes treated with 50 and 250 mg/kg/day, characterized by a statistically significant reduction in erythrocyte count in animals treated with 250 mg/kg bw/day together with an increase in mean corpuscular haemoglobin (MCH) and mean corpuscular volume (MCV) in animals treated with 50 mg/kg bw/day. Males treated with 250 mg/kg bw/day also showed a slight increase in mean corpuscular haemoglobin concentration (MCHC). Lower severities of adipose infiltration of the bone marrow indicative of marrow hyperplasia were seen for female rats dosed at 250 mg/kg/day and 50 mg/kg/day. Increases in relative kidney, liver and spleen weight were evident in both sexes treated with 250 mg/kg/day compared with controls. Increased haemosiderin deposition in spleen was observed in females dosed with 50 mg/kg bw/day, while increased haemosiderin deposition in kidneys was observed in males at the same dose level. Males dosed with 250 mg/kg bw/day also showed increased follicular cell hypertrophy in thyroid gland and hyperplasia of the transitional epithelium of urinary bladder. Based on the results of the study, the NOAEL for repeated dose toxicity for pure (anhydrous) SDMC was established at 10 mg/kg bw/day. Using this NOAEL as a point of departure and applying a correction for molecular weight, the NOAEL of 10 x (227.37/143.21) = 16 mg/kg bw/day is obtained for pure (anhydrous) SDBC. As SDBC is manufactured as ca. 47% solution, this corresponds to the value of 34 mg/kg bw/day for the substance as manufactured. Applying the correction for molecular weight, the LOAEL of 50 x (227.37/143.21) = 79.4 mg/kg bw/day and of 168.9 mg/kg bw/day have been calculated for the pure substance and its 47% solution, respectively.


Repeated dose toxicity: via oral route - systemic effects (target organ) cardiovascular / hematological: bone marrow; cardiovascular / hematological: other

Justification for classification or non-classification

Based on the calculated NOAEL of 16 mg/kg bw/day and a LOAEL of 79.4 mg/kg bw/day for anhydrous SDBC, established based on the read-across of the results of 90 -day oral toxicity study from a structural analogue sodium dimethyldithiocarbamate (SDMC), associated with haemolytic effects and indirect evidence of bone marrow hyperplasia, sodium dibutyldithiocarbamate (SDBC) in its anhydrous form should be classified as Specific Target Organ Toxicity - Repeated Exposure Cat. 2, H373 (may cause damage to cardiovascular/hematological organs, including bone marrow, through prolonged or repeated exposure) according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008. As the observed LOAEL of 79.4 mg/kg bw/day exceeds the limit for classification of 50 mg/kg bw/day established by EU Directive 67/548/EEC, classification according to EU Directive 67/548/EEC is not warranted for sodium dibutyldithiocarbamate.

However, the substance is solely manufactured and marketed as ca. 47% aqueous solution. For the substance as manufactured, a NOAEL of 34 mg/kg bw/day and a LOAEL of 168.9 mg/kg bw/day have been calculated. As the observed LOAEL is above the cut-off limits of 100 and 50 mg/kg bw/day, established by EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 and EU Directive 67/548/EEC, respectively, classification of the substance as manufactured (as ca. 47% aqueous solution) for repeated dose toxicity is not warranted.