mancozeb (ISO); manganese ethylenebis(dithiocarbamate) (polymeric) complex with zinc salt  

Endpoint summary

Description of key information

Mancozeb is only partially orally absorbed but rapidly excreted, predominantly via faeces. It is extensively metabolised (> 95%), with ethylenethiourea (ETU) being the major (18% of the administered dose in urine in rats) metabolite in all species investigated. There is no evidence for accumulation on repeated exposure.

oral absorption rate: 50%

dermal absorption rate: 0.7 %

Key value for chemical safety assessment

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

0.7

Additional information

The following summary of absorption, distribution and excretion in mammals is taken from the Renewal Assessment Report prepared according to the Commission Regulation (EU) N° 1107/2009, prepared for Mancozeb (Volume 1).

The toxicokinetics of mancozeb have been investigated in different species in numerous relatively old studies which were already reviewed during the first approval of mancozeb. In oral studies in laboratory animals, mancozeb is only partially absorbed but rapidly excreted. Rats given single oral doses of 14C-labelled mancozeb at 1.5 or 100 mg/kg bw absorbed about 50% of the dose (calculated by adding the radioactivity present in urine (42%), bile (7%) and tissues (2.5%) – DiDonato &Longacre, 1986). Overall, therefore, an oral absorption value of 50% is established (from rat data) for the derivation of the systemic AOEL and AAOEL. This value was supported by the expert peer-review meeting (no.190). However, it was noted that oral absorption was lower in mice and monkeys and that no information is available in the dog. This is the same value used in the original review. The radioactivity absorption half-lives (t 1/2 absorption) ranged from 0.7 to 1.7 hour and peak concentrations were reached within 3-6 hours, indicating rapid absorption. Radioactivity was eliminated from plasma in a biphasic manner, the half-life for the rapid phase of elimination was 4-6 hours while the half-life for the slow elimination phase was 23-39 hours. Most of the dose was excreted within 24 hours with about half eliminated in the urine and half in the faeces. Mancozeb and/or its metabolites were widely distributed. Less than 4% (mean 2.5%) was found in the tissues after 96 hours, with the thyroid containing the highest residual levels. Most of the 14C dose in faeces was unabsorbed, since only approximately 7% of the dose was found in bile. There is no evidence for accumulation on repeated exposure.

Mancozeb is extensively metabolised (> 95%). Ethylenethiourea (ETU) was the major (18% of the administered dose in urine in rats) metabolite in all species investigated, including humans. The other metabolites identified were ethyleneurea (EU), N-acetylethylenediamine (N-acetyl-EDA), ethylenediamine (EDA), ethylenebisisothiocyanatesulfide (EBIS) and N-formylethylenediamine (N-formyl-EDA), N-acetylglycine, glycine and eventually carbon disulfide. In addition to ETU, EU, EDA and N-acetyl-EDA are considered to be major metabolites (≥ 10% of administered dose) of mancozeb in the rat. The bioconversion of mancozeb to ETU was 6.8% (7%) on a weight basis and 20% on a mole/mole basis (Nelson, 1986); the calculation of 7% was based on an average 18.2% of the administered 14C mancozeb recovered as ETU in urine and bile in the study by Nelson (1986) and the molecular weights of ETU and mancozeb (18.2% x 102 g ETU/mole : 271 g mancozeb/mole = 6.8%). The average bioconversion factor for all the EBDCs was 7.5%. ETU is further broken down to moieties that are incorporated into natural compounds such as oxalic acid, glycine, urea and lactose. Metabolism of ETU in humans, dog, rabbit and mouse appears more efficient than in rats (see section B.6.8.1.1). In monkeys, oral doses of mancozeb were very poorly absorbed, with faeces being the predominant route of excretion (Emmerling, 1978).

The spectrum of metabolites (please refer to the attached document in the Attached background material field) produced was similar in laboratory and farm animals, pointing to two common metabolic pathways which both lead ultimately to the formation of glycine and incorporation of the metabolites into natural products. In the quantitatively predominant pathway, the dithiocarbamate linkages in mancozeb are hydrolysed to produce EDA directly, and EDA is oxidised to glycine, joining the intermediary metabolic pool at this point. The other involves oxidation to EBIS and then to ETU, various derivatives of ETU, and EU before re-joining the main pathway with conversion to EDA, glycine, and incorporation into other products.

An in vitro metabolism study on mancozeb in hepatocytes was conducted to address the new data requirements (Foster, 2015) but problems with the instability of mancozeb in aqueous media meant the original objective of this study could not be fulfilled. The instability of mancozeb in aqueous media strongly indicated that mancozeb is unsuitable for in vitro investigations. The lack of these in vitro investigations is not considered to be a data gap as information on the metabolism of mancozeb in different species, including humans is available from studies in vivo. There are also data in humans exposed to mancozeb (epidemiology and health surveys) showing that ETU is also a major metabolite of mancozeb in humans. These studies show that the metabolism of mancozeb in different species, including humans is qualitatively similar. In addition, such in vitro investigations in hepatocytes or liver microsomes for multiple species, including humans, are available for mancozeb’s main metabolite ETU (see section B.6.8.1.1). These show that the metabolism of ETU in different species (including humans) is qualitatively similar, although quantitative differences in the rate of metabolism across species exist. A new in vitro metabolism study in rat hepatocytes (Vosbeck-Wehling, 2018) has been submitted by Agria during the peer-review process. This study shows that the majority of the transformation products of mancozeb were due to unspecific degradation of the test item in the incubation medium. Similar profiles were observed for all control incubations with the test item in medium as well as medium plus inactivated hepatocytes, indicating that most of the unspecific degradation has already occurred during dissolution of the test item. Three major metabolites were identified: ETU, EBIS and a glutathione adduct linked to an imidazolidinyl-2-one moiety (R1). Overall, this study by Agria confirmed the rapid degradation of mancozeb both in the presence and absence of hepatocytes already seen in the Foster (2015) study submitted by the MTF. The RMS also notes that given the absence of investigations in human hepatocytes, no rat-human comparison is possible. At the expert peer-review meeting 190, it was agreed that qualitatively the in vivo metabolism of mancozeb in different species, including humans is similar. Although a quantitative comparison is not available, the instability of mancozeb prevents the performance of a valid in vitro comparative metabolism study. Therefore, it was concluded that such study is not necessary.