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Endpoint:
basic toxicokinetics in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
Please see for more information the read-across justification in Section 13.
Reason / purpose:
read-across source
Details on absorption:
Absorption was relatively slow with maximum concentrations of radioactivity being reached within 10 h at the low dose level and 24 h at the high dose level.
There was a ca 3 (5) fold increase in the blood elimination half-life compared to plasma for the 150 (15) mg/kg dose. This suggests that radioactivity was binding to the blood cells but was probably saturated between doses of 15 and 150 mg/kg.
Details on distribution in tissues:
Single Oral Administration at the Low Dose Level in Both Sexes (Group G):
All tissues had been exposed to radiolabelled material within 2 h of administration. Levels of radioactivity absorbed into the carcass and tissues were 39/41% (♂/♀) at 2 h, 12/18% at 8 h, 2.7/2.1% at 24 h and 1.1% (both) at 96 h.
There were no sex-differences in concentration of radioactivity except for thyroids.
Greatest concentrations of radioactivity at all time points were found in organs of metabolism and excretion (liver, lung, kidney), vascularised tissues (spleen, thyroid, adrenals), fat, blood and plasma.

Single Oral Administration at the High Dose Level in Both Sexes (Group H):
All tissues had been exposed to radiolabelled material within 2 h of administration. Levels of radioactivity absorbed into the carcass and tissues were 74/76% (♂/♀) at 2 h, 45/54% at 8 h, 6.1/12.5% at 24 h and 1.1/1.3% at 96 h.
There were no sex-differences in concentration of radioactivity.
As in the low dose group the greatest concentrations of radioactivity at all time points were found in organs of metabolism and excretion (liver, lung, kidney), vascularised tissues (spleen, thyroid, adrenals), fat, blood and plasma.
Details on excretion:
Excretion of radioactivity was rapid, the major proportion being excreted as volatiles in expired air within 24 h of administration. Low levels of radioactivity were detected in all tissues at 168 h following dose administration. No accumulation of ziram seems to occur.
Due to difficulty in trapping the high levels of volatiles (ca 70%) the overall recovery in these experiments was lower than would normally be expected.
The excretion balance of multiple oral administrations was comparable to single administration. Repeat dosing was therefore not considered to have any effects on the rates or routes of excretion.
Only a very small amount of the dose was excreted in bile (ca 2.2% and 1.9% at 50 mg/kg and 100 mg/kg respectively).
Metabolites identified:
yes
Details on metabolites:
The principal route of metabolism was hydrolysis to form and exhale CS2, COS and CO2 (ca 51%). The remaining dose was excreted in urine and faeces, with excretion essentially complete within 24 h. Compounds found in urine included 2-dimethylamine-thiazolidine carboxylic acid (M1) and the S-glucuronide of dimethyldithiocarbamic acid and an unknown metabolite of apparent mass 326. Faeces contained thiram.
Endpoint:
dermal absorption in vitro / ex vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
Please see for more information the read-across justification in Section 13.
Reason / purpose:
read-across source
Absorption in different matrices:
Please see Table in Section "Any other information on results incl. tables"
Total recovery:
Please see Table in Section "Any other information on results incl. tables"

Table

In vitro percutaneous absorption study in human skin (mean of 4-6 values)

 

 

Distribution of Radioactivity (% Applied Dose)

Samples

1.55 mg/mL

643 mg/mL

1.        Receptor fluid (0-24 h)

0.38

0.02

2.        Receptor fluid at termination

0.01

nd

3.        Skin

nd

nd

4.        Receptor chamber

nd

nd

5.        Tape (stratum corneum)

1.84

0.04

6.        Total absorbed (1+2+3+4+5)

2.23

0.06

7.        Skin swab (after 6 h)

87.82

93.95

8.        Tape (surface)

1.49

0.11

9.        Donor chamber

0.21

nd

10.     Total non-absorbed (7+8+9)

89.52

94.06

11.     Total recovery (6+10)

91.75

94.12

Description of key information

The toxicokinetic information will be updated when information requested by ECHA (Decision number: CCH-D-2114382075-49-01/F) is complete. The deadline for the submission of this information is 21 June 2021.

Key value for chemical safety assessment

Additional information

No information on toxicokinetic behavior of zinc bis(dibenzyldithiocarbamate) (ZBEC) 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.

Toxicokinetic data are available on the structural analogue of ZBEC, zinc bis(dimethyldithiocarbamate) (ZDMC). The latter substance is a salt of a homological dialkylcarbamodithioic acid, namely dimethyldithiocarbamic acid, which differs only in the substituents at the amine function in the dithiocarbamate moiety (benzyl 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 Zn2+ cation and the respective dithiocarbamate anions. It can also be expected that, based on structural similarity, dimethyl- and dibenzyldithiocarbamate anions shall be metabolized via similar pathways, as it is not expected that the difference in the substituents at the amine function of dithiocarbamate moieties shall have a profound difference on the substances reactivity. Therefore it is considered acceptable to derive the data on the toxicokinetic behavior of ZBEC by read-across from ZDMC.

A GLP-compliant guideline toxicokinetic study is available for ZDMC, in which the radiolabelled substance was administered by gavage in carboxymethyl cellulose to groups of male and female Sprague-Dawley rats. Pharmacokinetics, excretion balance and tissue distribution investigations were performed at nominal dose levels of 15 and 150 mg/kg bw, while biliary excretion experiment was conducted using two animals, one dosed at 50 mg/kg bw and the other at 100 mg/kg bw. For one excretion balance study non-radiolabelled ZDMC was administered daily for 14 days. 24 h after receiving the last dose, a single dose of (14C)-ZDMC was administered.

 

Absorption

Absorption of ZDMC was relatively slow at both 15 and 150 mg/kg bw with maximal plasma concentrations in the low dose group achieved at 6.8 and 10.4 hours (0.859 and 0.804 μg equiv./g in males and females, respectively), and at 24 hours in both sexes in the high dose group (6.548 and 8.373 μg equiv./g in males and females, respectively). The values for maximal plasma concentrations in the high dose group were ca. 10-fold higher than in the low dose group. The increase in absorption was approximately proportional to the dose, indicating that the absorption was not saturated at least up to 150 mg/kg bw. During the absorption phase, concentrations of radioactivity in blood were similar to those in plasma; however, during the elimination phase, in the group dosed with 150 mg/kg bw, concentrations were ca. 3-fold higher in blood compared to those in plasma, indicating that a binding to blood cells may occur.

 

Distribution

The distribution of radioactivity after a single oral dose of (14C)-ZDMC at nominal dose levels of 15 mg/kg bw and 150 mg/kg bw was determined at various time points. Two hours post-administration, in the low-dose group, the highest amounts of the radiolabel were recovered in liver (3.144 and 2.395 μg equiv./g in males and females, respectively), kidneys (2.305 and 1.491 μg equiv./g), fat (2.393 and 2.129 μg equiv./g), spleen (1.209 and 1.126 μg equiv./g) and thyroid (0.373 and 1.106 μg equiv./g), while in the high-dose group, the highest amounts were recovered in liver (17.38 and 13.34 μg equiv./g), fat (10.57 and 10.32 μg equiv./g), kidney (7.486 and 5.986 μg equiv./g), lung (5.792 and 51.09 μg equiv./g), spleen (3.853 and 9.270 μg equiv./g) and thyroid (3.196 and 62.66 μg equiv./g).

 

Metabolism

The principal route of metabolism for ZDMC was hydrolysis to form carbon disulphide and carbonyl sulphide and the formation of carbon dioxide. These volatile metabolites comprised the majority of the excreted dose (ca. 51%). Urine contained 2-dimethylamine-thiazolidine carboxylic acid and the S-glucuronide of dimethyldithiocarbamic acid. The latter compound is presumably formed by glutathione conjugation of either the dimethyldithiocarbamic acid or ZDMC directly. The glutathione conjugate would then be catabolised to the cysteine conjugate via the cysteinyl-glycine conjugate, which then cyclised, loosing H2S, to form 2-dimethylamine-thiazolidine carboxylic acid. Faeces contained tetramethylthiuramdisulfide.

 

Excretion

The tissue retention and excretion of radioactivity was determined after single and multiple oral doses of (14C)-ZDMC at nominal dose levels of 15 and 150 mg/kg bw. In addition, for one excretion balance study non-radiolabelled ZDMC was administered daily for 14 days and twenty-four hours after receiving the last dose, a single dose of (14C)-ZDMC was administered. In the low dose group, 63.27 and 64.41% of total dose was recovered over 168 hours in males and females, respectively, from which 3.068 and 3.238% were recovered in faeces. In the high dose group, the recovery over 168 hours was 75.88 and 76.46% in males and females, respectively, out of which 4.574 and 2.844% were recovered in faeces. In the repeated administration group, the recovery was 74.09 and 84.93% in males and females, respectively, with 3.112 and 4.145 % recovered in faeces. In the biliary excretion study, following a single administration of 14C-ZDMC to 2 male animals at nominal dose levels of 50 and 100 mg/kg bw, 2.2% and 1.9% was excreted in bile, 16.9% and 9.6% in urine and 17 and 3.1% in faeces, respectively. The majority (ca. 51%) of the administetered dose was excreted as volatile metabolites CS2, COS or CO2. The remaining dose was excreted in urine (ca. 10.9-20.8%) and faeces (ca. 4%), with virtually none via bile. Excretion was rapid and essentially complete within 24 hours.

 

Application of the available data for ZBEC

Based on the available results, a comparable toxicokinetic behavior is expected for ZBEC.

Based on the higher molecular weight of ZBEC, it is expected that its absorption from the gut shall not be faster than that of ZDMC. For ZDMC, at least 60% oral absorption was determined based on the available toxicokinetic study. The default value of 50% oral absorption is recommended in the Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment in case route-to-route extrapolation needs to be performed. As the oral absorption of ZBEC is expected not to exceed the oral absorption of ZDMC, and taking into account that the lower oral absorption represents a worst-case approach in case of route-to-route extrapolation (as it represents lower internal dose), using the precautionary principle a value of 50% oral absorption shall be used for DNEL derivation for ZBEC. However, if the read-across is applied and the DNELs are calculated based on the results of the studies with the structural analogue ZDMC, a value of 60% for oral absorption is applied.

 

Dermal absorption

No data on dermal absorption of ZBEC are available. Dermal penetration of its structural analogue ZDMC was studied in vitro in a GLP-compliant guideline study, using human cadaver skin. 6.4 μl of two test susbtance preparations with nominal concentrations of 1.55 and 643 mg/ml was applied to 0.64 cm2 of human skin for 6 hours under occlusive conditions (4 -6 diffusion cells per experiment). The total applied amounts of the test substance corresponded to 0.016 and 6.4 mg/cm2 skin. The total recovery of radioactivity in two experiments was 91.75% and 94.12%, respectively. 87.82% and 93.95% were recovered upon the skin swab after 6 hours exposure in the low-dose and high-dose experiments, respectively, while 0.39% and 0.2% penetrated through skin into the receptor fluid and 1.84% and 0.04% were recovered in stratum corneum. The total percentage of absorption through skin was thus determined to correspond to 2.23% and 0.1% in low-dose and high-dose experiments, respectively. It should be added that the amount applied in the high dose experiment is approximately in the range of 1-5 mg/cm2 skin, recommended by OECD Guideline 428 for solid substances.

The approximate dermal absorption of ZBEC can also be calculated based on its (water) solubility. Solid substances will only penetrate the skin in (aqueous) solution. Therefore, skin absorption can only occur through the water that penetrates the skin and the maximum skin absorption is defined by the maximum water solubility of the salts and the maximum amount of water that can penetrate the skin.

The maximum amount of water that can penetrate the skin is determined to be 17 µl per 1 cm2 per 24 hours (Ten Berge, W. A simple dermal absorption model: derivation and application.Chemosphere.2009 Jun;75(11):1440-5), which equals 6 µl per cm2 per 8 hours.

ZBEC is virtually insoluble in water (ca. 1 mg/l (= 10-3µg/µl).

Since 6 µl of water can maximally penetrate 1 cm2of skin per 8 hours, 6 x 10-3= 0.006 µg of hydrolysed salt may penetrate 1 cm2 of skin per 8 hours. In an in vitro skin absorption experiment (according to OECD guideline 428), the application should mimic human exposure, normally 1-5 mg/cm2 (1000 -5000 µg/cm2). Thus, in case the skin penetration of ZBEC would be experimentally be determined according to OECD guideline 428 using 5 mg/cm2 as exposure condition, a skin penetration of 1.2 × 10-4 % (0.006/5000) would be observed maximally. Therefore a value of 0.1% dermal absorption, observed in the study with ZDMC, is considered to be a worst-case approach and shall be used for DNEL derivation.