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EC number: 238-778-0
CAS number: 14726-36-4
In vitro percutaneous absorption study in human skin (mean of 4-6 values)
Distribution of Radioactivity (% Applied Dose)
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
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.
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.
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 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).
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
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.
of the available data for ZBEC
on the available results, a comparable toxicokinetic behavior is
expected for ZBEC.
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.
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.
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.
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.
is virtually insoluble in water (ca. 1 mg/l (= 10-3µg/µl).
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.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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