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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2016

Materials and methods

Objective of study:
metabolism
toxicokinetics
Principles of method if other than guideline:
Evaluation the toxicokinetic profiles of Dimethyl sulphide (DMS) following single oral administration (gavage) to male Sprague-Dawley rats.
GLP compliance:
yes (incl. QA statement)

Test material

Constituent 1
Chemical structure
Reference substance name:
Dimethyl sulphide
EC Number:
200-846-2
EC Name:
Dimethyl sulphide
Cas Number:
75-18-3
Molecular formula:
C2H6S
IUPAC Name:
(methylsulfanyl)methane
Details on test material:
Name: Dimethyl sulphide
CAS No.: 75-18-3
Molecular weight: 62.13
Batch No.: C8753
Purity: 99.7%

Name: Dimethyl sulphoxide
CAS No.: 67-68-5
Molecular weight: 78.13
Batch No.: 475832
Purity: 100%
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories Italia, Calco, Italy.
- Age at study initiation: approximately 10 weeks old
- Weight at study initiation: 365 g (range: 341 g to 386 g)
- Fasting period before study: yes
- Housing: by three, in polycarbonate cages with stainless steel lids
- Diet: SSNIFF R/M-H pelleted maintenance diet, ad libitum
- Water: ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 50 ± 20
- Air changes (per hr): approximately 8 to 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Solution in the vehicle.
There was a good agreement between the nominal and actual administered doses, as all deviations were within ± 5%. Specifically, dose-levels of DMS ranged from -1.96 to +2.78% .

VEHICLE
- Justification for use and choice of vehicle (if other than water): solubility
- Concentration in vehicle: 160 mg/mL
- Amount of vehicle (if gavage): 5 mL/kg

HOMOGENEITY AND STABILITY OF TEST MATERIAL:
According to CiToxLAB France/Study No. 43120 VAS describing the preparation procedure for DMS (stability testing) for a range of concentrations of 100 to 200 mg/mL covering the concentration used in this study. The dose formulation was kept in sealed vial just after preparation. Deviation of DMS concentration in the administered dose formulation analyzed was found before and after treatment at 2.2% and -2.5%, respectively, when compared to the nominal value.
Duration and frequency of treatment / exposure:
Single
Doses / concentrations
Dose / conc.:
800 mg/kg bw/day (actual dose received)
Remarks:
(equivalent to ca. 13 mmol/kg bw)
No. of animals per sex per dose / concentration:
9
Control animals:
no
Details on study design:
- Dose selection rationale: The dose-level of 800 mg/kg of DMS are in the range of the NOAELs in repeated dose toxicity studies
Details on dosing and sampling:
PHARMACOKINETIC STUDY
- Tissues and body fluids sampled: plasma
- Time and frequency of sampling: 0.5 h ± 3 min, 2 h ± 6 min, 4 h ± 6 min, 6 h ± 6 min, 9 h ± 20 min, 12 h ± 20 min, 24 h ± 1 h, 36 h ± 1 h and 48 h ± 1 h (nine sampling times). Three animals/group were sampled alternatively at each time-point.

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: plasma
- Time and frequency of sampling: same as above
- From how many animals: 3 per time point
- Method type(s) for identification: GC-MS
- Limits of detection and quantification: 2 µg/mL

TREATMENT FOR CLEAVAGE OF CONJUGATES (if applicable): no
Statistics:
None

Results and discussion

Toxicokinetic / pharmacokinetic studies

Toxicokinetic parametersopen allclose all
Toxicokinetic parameters:
Cmax: 187 µg/mL
Remarks:
DMSO
Toxicokinetic parameters:
Cmax: 82.1 µg/mL
Remarks:
DMSO2
Toxicokinetic parameters:
AUC: 1647 h*µg/mL
Remarks:
DMSO
Toxicokinetic parameters:
AUC: 1855 h/µg/mL
Remarks:
DMSO2

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
dimethyl sulfoxide (DMSO)
dimethyl sulphone (DMSO2)

Any other information on results incl. tables

Toxicokinetics

Nominal sampling times were used to calculate the toxicokinetic parameters as the deviations were minor and remained within the acceptable range.

·                    DMS administration (Figures 1 , Table 1)

After a single oral administration of DMS, DMSO was quantifiable in plasma samples from 0.5 to 12h and DMSO2from 4 to 48h. DMS was detectable up to 6h post-exposure but not quantified. Therefore, the DMS was metabolized first in DMSO then in DMSO2.

A low inter-animal variability was observed on DMSO plasma concentrations, with CV ranging from 1 to 15%. While a moderate inter-animal variability was observed on DMSO2 plasma concentrations, with CV ranging from 4 to 28%.

 

Table 1: Plasma toxicokinetic parameters of DMSO and DMSO2 following single oral administration of DMS at 800 mg/kg (group 1) to male Sprague-Dawley rats

 

Analyte

Tmax

Cmax

AUC0-t

¿z

t1/2

AUC0-8

AUCt-8

Vz/F

Cl/F

RM

(h)

(µg/mL)

(h*µg/mL)

(1/h)

(h)

(h*µg/mL)

(%)

(mL/kg)

(mL/h/kg)

Cmax

AUC0-t

DMSO

6

187

1647

nr

nr

nr

nr

nr

nr

nr

nc

nc

DMSO2

24

83.1

1855

nr

nr

nr

nr

nr

nr

nr

nr: not reported, as¿zcould not be estimated.

nc: not calculated.

 

The Cmaxof DMSO and DMSO2 were reached at 6h and 24h post-administration, respectively. The Cmaxof DMSO was approximately 2.2-fold higher than the Cmaxof DMSO2 but the AUC0-tof DMSO2 was 1.1-fold higher than of DMSO.

Applicant's summary and conclusion

Conclusions:
DMS is oxidised to DMSO and then DMSO to DMSO2. Previous published studies also shown the reduction of DMSO to DMS.
Executive summary:

The toxicokinetic profiles of Dimethyl sulphide (DMS), Dimethyl sulphoxide (DMSO) and Dimethyl sulphone (DMSO2) was evaluated following single oral administrations (gavage) of DMS to male Sprague-Dawley rats. A group of 9 male Sprague-Dawley rats received DMS, at 800 mg/kg by oral (gavage) administration (dose levels are equivalent to ca.13 mmol/kg). The dosing formulations were administered on a single occasion under a constant dosage volume of 5 mL/kg. Blood samples were collected at 0.5h, 2h, 4h, 6h, 9h, 12h, 24h, 36h and 48h after oral administration. Mortality, morbidity and clinical signs were checked once the day during acclimation period and then at each blood sampling occasion. The body weight of each animal was recorded once before the pre-treatment period and on the day of treatment. After their respective last blood sampling time-point, the rats were sacrificed by an intraperitoneal injection of sodium pentobarbital and cervical dislocation. Blood levels of DMSO and DMSO2 were quantified by Gas Chromatography with FID detection (GC-FID).

The DMS concentrations in the dose formulation were within ± 2.5% of the nominal concentration value. The determination of DMS concentration levels in plasma was not validated, no concentration levels and toxicokinetic parameters are determined for DMS.

DMSO was quantifiable in plasma samples from 0.5 to 12h after single oral administration. DMSO2was quantifiable in plasma samples from 4 to 48h. Therefore, the DMS was metabolized first in DMSO then after in DMSO2. After single oral administration of DMS, a low inter-animal variability was observed on DMSO plasma concentrations, while a moderate inter-animal variability was observed on DMSO2 plasma concentrations. The maximum plasma concentrations (Cmax) of DMSO were reached at 6h post-administration of DMS. The maximum plasma concentrations of DMSO2 were reached at 24h post-administration. After single oral administration of DMS, the Cmaxand AUC0-tvalues of DMSO were of 187 ng/mL and 1647 h*ng/mL, respectively. The Cmaxand AUC0-tvalues of DMSO2were of 83.1 ng/mL and 1855 h*ng/mL, respectively. There was no mortality, and no morbidity or clinical signs occurred during the study.

DMS is oxidised to DMSO and then DMSO to DMSO2. Previous published studies also shown the reduction of DMSO to DMS.