Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: Assessment based upon available information.
Adequacy of study:
key study
Study period:
not applicable
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Information selected for the toxicokinetic assessment is primarily study data. Studies were conducted inaccordance with recognised testing guidelines. While some studies not been conducted under GLP certification due to the age of the study and geographical location, all studies were conducted in reputable contract research organisations using specifically bred models that are fully validated for the types of study. All data used for the toxicokinetic assessment is rated at least 2 for relevance and reliability (based upon Klimisch, 1997) and were conducted upon the registered substance, Methylenebis (dibutyldithiocarbamate).

Data source

Reference
Reference Type:
other: Desk study
Title:
Unnamed
Year:
2020
Report Date:
2020

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
All available information on Methylenebis (dibutyldithiocarbamate) has been reviewed and assessed to produce a report on the toxicokinetic properties of the subtsance.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
liquid: viscous

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Oral Route

Absorption is generally correlated with molecular weight, partition coefficient, and water solubility. The highly insoluble nature of the substance in water suggests that oral bioavailability of the substance is limited. The Oasis SAR analysis has also showed that the substance is not bioavailable via the oral route, in accordance with Lipinski’s Rule. SAR analysis using the OECD QSAR Toolbox microbial metabolism simulator indicates that the substance can be metabolized to 25 metabolites, including aliphatic and carboxylic acids and carbonyl compounds; 17 of the 25 predicted metabolites are orally bioavailable based on Lipinski’s Rule. Systemic effects were not observed in acute and short-term range-finding studies in rats, at doses up to 16,000 mg/kg in the acute oral toxicity study and up to 1000 mg/kg/day in the 14-day repeated dose oral range-finding toxicity study. A systemic effect, accumulation of hyaline droplets in the proximal convoluted tubules of the kidney, was observed in males at the 1000 mg/kg/day limit dose in the 90-day repeated dose oral toxicity study in rats. An increased incidence of incompletely ossified sternebrae and partially undescended lobe of thymus in the fetuses were observed at the limit dose, 1000 mg/kg/day, in the prenatal developmental toxicity study in rats. The evidences from the repeated dose toxicity studies suggests that absorption of the substance, likely of its metabolites generated by microbial metabolism within the mammalian gastrointestinal (GI) tract, did occur.

Dermal Route

The highly insoluble nature of the substance in water also suggests that its absorption via the dermal route is limited. The metabolism of the substance in skin is expected to be limited because the uptake of the substance itself into the stratum corneum and the epidermis is likely very low. These assumptions are supported by the absence of observed systemic effects following dermal application of the substance in the acute dermal toxicity study in rabbits at up to 2000 mg/kg. Additionally, the local lymph node assay (LLNA) in mice showed that the substance did not induce cell proliferation in local lymph nodes at test material concentrations of up to 25%, the highest concentration tested.

Inhalation Route

The potential for inhalation toxicity was not studied directly. However, the liquid nature of the substance and its very low vapor pressure (<1.3 x 10-8 Pa at 20°C) indicate that its potential to enter atmospheric air in a respirable form is minimal. Therefore, respiratory absorption under normal use, and based on the life-cycle information for the substance, is expected to be inconsequential.
Details on distribution in tissues:
The hydrophobic and highly insoluble nature of the substance suggest that the substance, upon systemic absorption, may be transported through the circulatory system in association with a carrier molecule such as a lipoprotein or other macromolecules. The lipophilic character and molecular weight of the substance suggest that the majority of the substance will readily traverse cellular barriers and distribute into fatty tissues. The absorption of the substance via the oral and dermal routes is, however, limited. The microbial metabolites of the substance, upon absorption via the GI tract, may be transported through the circulatory system. The increased hydrophilic character of these metabolites suggests that the majority of the absorbed microbial metabolites will excreted through urine, which is supported by the evidence of systemic exposure and accumulation of hyaline droplets in the proximal convoluted tubules of the kidney in the 90-day repeated dose study, but not of cumulative toxicity, as would be manifested by an accumulation of the lipophilic substance or metabolites in tissues.
Details on excretion:
The characteristics of the substance suggest that it may undergo phase I and phase II metabolic transformation. The resulting metabolites are expected to undergo routine renal and/or biliary excretion.

Metabolite characterisation studies

Details on metabolites:
Like most xenobiotics, the substance, upon systemic absorption, is expected to undergo phase I oxidation/reduction and subsequent Phase II conjugation. The SAR analysis using the in vivo rat metabolism simulator, rat liver S9 metabolism simulator, and skin metabolism simulator of the OECD QSAR Toolbox has predicted that the substance may be metabolized upon systemic absorption to the metabolites shown in the attached table.

Acute and repeated dose toxicity testing provided no evidence that the substance was metabolized to toxic metabolites. Data from two bacterial mutagenicity assays, a chromosomal aberration test in cultured peripheral human lymphocytes, and an in vitro mammalian cell gene mutation test with L5178Y mouse lymphoma cells did not show any evidence of genotoxic activity from the substance, either in the absence or in the presence of a rat liver S9 microsomal enzyme system. Furthermore, significant in vitro cytotoxicity of the substance was not observed in the absence or in the presence of a rat liver S9 microsomal enzyme system. This suggests that the metabolites are unlikely to be more toxic than the substance itself.

Any other information on results incl. tables

The ready biodegradability test showed that the substance is not readily biodegradable. The substance did not show any toxicity to aquatic organisms at the limit of solubility in the acute ecotoxicology tests to wastewater microorganisms, algae, daphnia, or fish, or in the chronic toxicity tests using daphnia and fish. The substance is strongly hydrophobic (log Pow= 8.42), and its water solubility is extremely low (0.247 mg/L). The biomagnification factor (BMF) was less than one, well below the BMF of greater than 2,000 for classification as bioaccumulative, based on the bioaccumulation test in fish via dietary exposure according to OECD Guideline 305. Therefore, the substance is not bioaccumulative in aquatic organisms.

Applicant's summary and conclusion

Conclusions:
Based upon the available data, the oral and dermal absorption of the substance, Methylene bis(dibutyldithiocarbamate) (CASRN 10254-57-6), is expected to be limited, but its microbial metabolites generated within mammalian GI tract are expected to be absorbed. Inhalation exposure is not expected under normal use due to the physical nature of the substance (liquid) and its low vapor pressure. The histopathological findings in the repeated dose study indicate that the substance distributes into tissues with no accumulation upon absorption. The SAR analysis indicates that the substance, upon absorption, undergoes phase I oxidation/reduction. No significant cytotoxicity of the substance was observed in the absence or presence of a rat liver S9 microsomal enzyme system in the genotoxicity assays, which suggests that the metabolites may not be more toxic than the substance itself. The substance and its metabolites are expected to undergo routine renal and/or biliary excretion.