Registration Dossier

Administrative data

Link to relevant study record(s)

Referenceopen allclose all

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
Reference:
Composition 0
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. certificate)
Test material information:
Composition 1
Radiolabelling:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals 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
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
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:
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
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
Metabolites identified:
yes
Details on metabolites:
dimethyl sulfoxide (DMSO)
dimethyl sulphone (DMSO2)

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.

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.

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented, meets generally accepted scientific principles, acceptable for assessment.
Reference:
Composition 0
Objective of study:
distribution
GLP compliance:
not specified
Test material information:
Composition 1
Radiolabelling:
no
Species:
mouse
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
No data available
Route of administration:
inhalation: vapour
Vehicle:
unchanged (no vehicle)
Details on exposure:
Mice weighting about 20g were exposed to an atmosphere containing gaseous DMS in a desiccator. Five different concentrations of DMS gas were investigated and 5 mice were used for each group. Liquid DMS was placed in the bottom of the desiccator which was immediately covered with a lid. The underside was warmed to 40°C in a water bath to vapourize the DMS and the gas mixed with air from the atmosphere with a stirring bar. As DMS was vapourized, the lid was raised slightly by the expanded atmosphere, some of which over-flowed from the desiccator. After the overflow had ceased the lid was opened slightly, a mouse was inserted into the atmosphere and the lid was closed immediately. A small amount of the atmosphere was sampled to determine the concentration of DMS in the atmosphere by inserting a micro-syringe through the adhesive vinyl tape closing a small outlet at the side of the desiccator. The behaviour of the mouse after exposure to the atmosphere was observed and the time elapsed until changes in gait and respiratory arrest were also noted. After death had occurred. The atmosphere was sampled again to determine the concentration of DMS in the atmosphere.
Duration and frequency of treatment / exposure:
Single exposure until death
Remarks:
Doses / Concentrations:
6.8, 11.6, 23.6, 34.0 and 50.6%
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
Blood and issue samples were taken, weighed, sealed in class vials and stored at -20°C until quantification of the DMS content was carried out.
Details on distribution in tissues:
DMS was distributed in all tissues of the mice at levels of 0.05-12.9 mg/g with an average of 2.34 mg/g. At a concentration of 6.8 ± 1.3%, DMS was distributed in every tissue almost equally except for the lungs where the concentration was much lower. At concentrations of 11.6 ± 0.5%, 23.6 ± 3.7% and 34.0 ± 3.1 % distribution patterns were almost the same. At a concentration of 30.6 ± 3.6%, DMS was distributed in lung, blood, heart muscle and brain at similar levels to those at 6.8%.
Metabolites identified:
no
Executive summary:

Following single acute exposure of mice to atmospheres of dimethyl sulfide vapors from 6.8% to 50.6% (w/v), dimethyl sulfide was distributed in all tissues almost equally, except for the lungs where the concentration was much lower (Terazawa et al., 1991).

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
data not available
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented, meets generally accepted scientific principles, acceptable for assessment
Reference:
Composition 0
Objective of study:
excretion
metabolism
Qualifier:
no guideline followed
Principles of method if other than guideline:
Metabolism and excretion of DMS after 4 consecutive subcutaneous injections to rabbits
GLP compliance:
no
Test material information:
Composition 1
Radiolabelling:
yes
Remarks:
14C-DMSO and 14C-DMSO2
Species:
rabbit
Strain:
other: New Zealand
Sex:
female
Details on test animals and environmental conditions:
Virgin female New Zealand rabbits of about 2.5 kg body weight were housed in metabolism cages which allowed the separation of urine from feces, although some leaching of the feces by the urine was possible. The rabbits were maintained on an unlimited diet of Purina Rabbit Checkers and tap water. Urine was collected daily and frozen until processed.
Route of administration:
subcutaneous
Vehicle:
other: sesame oil
Details on exposure:
DMS: Non radioactive DMS was diluted with an equal volume of sesame seed oil and 2ml of the mixture was administered s.c. to rabbits on each of four consecutive days, and the urine was collected and analysed for 6 days.
DMSO: Two ml of water containing 50% (w/v) of nonradioactive DMSO was injected subcutaneously into a rabbit on each of 5 consecutive days. On the second day, 14C-DMSO was substituted for the nonradioactive material. The radioactive dose was 2.85 X 10e6 cpm; specific activity was 570 cpm per milligram.
DMSO2: Three ml of a solution of 4 gm of 14C-DMSO2 in 11 ml of water was injeeted subcutaneously into a rabbit on each of 4 consecutive days for a total close of 1.82 X 10e6 cpm.
Duration and frequency of treatment / exposure:
once daily for 4 or 5 days
No. of animals per sex per dose:
one
Control animals:
not specified
Details on dosing and sampling:
Extraction of urine:
The urine was extracted continuously with methylene chloride or chloroform. Under these conditions dimethyl sulfone was quantitatively extracted after 48 hours of extraction, whilst dimethyl sulfoxide was still present in the extract after 12 days.

Determination of metabolites:
The chlorocarbon extracts were evaporated below 30°. The residual material was dissolved in methanol and examined by gas-liquid chromatography (GLC).
Chromatographic conditions: gas chromatograph with flame ionization detector. Column: 6 feet, stainless steel. Packing: 30% butanediol succinate on 45-60 mesh Chromasorb W. Temperature: injection block 130° ; column 115° ; carrier gas was nitrogen (flow rate = 60 mL per minute).
Under these conditions peak height was directly proportional to dimethyl sulfone and dimethyl sulfoxide concentrations.

Radioactive counting.
All assays for radioactivity were carried ont by liquid scintillation spectrometry with appropriate corrections for quenching.
Details on excretion:
DMS : After 4 days of continuous extraction of the urine, 374 mg DMSO (8.6% of the original dose of DMS) and 504 mg dimethylsulphone (DMSO2; 9.8% of the DMS dose) were recovered. The extraction was judged to be complete for DMSO2, but the results of the DMSO experiment (see below) indicate that about half of the DMSO excreted in the urine was not recovered. These results indicated that DMSO and DMSO2 were the principal metabolites of DMS, and suggested that the remainder of the dose was probably expired unchanged.
The expiration of dimethyl sulfide by the rabbit was indicated by the strong odor observed on the animal's breath during the experiment.
Since the feces were not examined, some excretion by this route is possible.
DMSO: The urine from the 14C-DMSO treated rabbit was collected for 6 days, pooled, and filtered under reduced pressure. The volatile material was frozen out at -78° during the filtration and was shown to have no radioactivity. This indicates that little or no DMS was excreted in the urine. The breath of the animal smelled strongly of DMS.
About 50% of the radioactivity was excreted in the urine. No attempt was made to measure the expired radioactivity or to examine the feces.
DMSO2: Urine was collected from a rabbit for about one week before any dose was given. Extraction of the urine with chloroform for 2 days, and examination of the extract by GLC indicated the presence of 41 mg of endogenous DMSO2. The rabbit was then injected subeutaneously with 14C-DMSO2. Urine was collected for 20 days The combined urine from days 6, 9, and 12, was extracted with ehloroform for 3 days. Examination of the extract by GLC showed the presence of DMSO2 with with no trace of DMSO. The breath of the rabbit during the experiment did not smell of DMS. A total of 2446 mg of DMSO2 was found in the extract.
The radioactivity excreted in the urine was all accounted for as DMSO2 and amounted to 76% of the dose. As no DMSO was detected in the urine, it is unlikely that any radioactivity was expired in the breath as DMS; the odor of DMS was not noticed. The fecal material was not examined.
Metabolites identified:
yes
Details on metabolites:
DMSO, DMSO2

Table 1: GLC results in urine from DMS treated rabbit

Days of extracting

mg DMSO *

mg DMSO2 **

0 - 1

87

410

1 - 2

68

78

2 - 3

105

16

3 - 4

114

-

* : dimethyl sulfoxide

** : dimethyl sulfone

Table 2: GLC results in urine from DMSO treated rabbit

Days of extracting

mg DMSO *

mg DMSO2**

0 - 1

230

258

1 - 2

168

98

2 - 6

522

TRACE

6 - 12

156

-

* : dimethyl sulfoxide

** : dimethyl sulfone

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Executive summary:

The subcutaneous injection of either dimethyl sulfide (DMS) or dimethyl sulfoxide (DMSO) leads to the excretion of DMSO and dimethyl snlfone (DMSO2) in the urine of rabbits and to the expiration of a malodorous material (presumably DMS). DMSO2, however, is not reduced to either the sulfoxide or the sulfide but is excreted unchanged. DMSO2 is also found in the urine of untreated rabbits.

Description of key information

Based on the data available on dimethylsulphide (DMS), it is assumed that DMS is extensively absorbed by the oral and inhalation routes. Due to its low boiling point (37°C), dermal absorption is assumed to be very limited due to a rapid volatilization. DMS is metabolised in the rat via S-oxidation to the sulphoxide (DMSO) and to the sulphone (DMSO2). The sulphoxide and sulphone are physiologically stable, and for the most part excreted unchanged.

Absorption

The assessment of the absorption profile of DMS is based on the available toxicological data and the physicochemical properties as suggested by the REACH Guidance Chapter R.7c:

Molecular weight: 62.138 g/mole 

Vapeur pressure: 52.3 kPa @ 20°C

Water solubility: 7280 mg/L at 20°C 

Partition coefficient log Kow = 0.84

Oral

The low molecular weight, high water solubility and moderate log Kow are in favor of a significant absorption of DMS by the oral route. Using a model to predict either high or low fraction absorbed for an orally administered, passively transported substance, the rates of absorption of DMS were 50% for a dose of 1 and 1000 mg (Danish QSAR).

Inhalation

The low molecular weight, high vapor pressure, high water solubility, moderate log Kow and mortality in the acute inhalation toxicity study are in favor of a significant absorption of DMS by inhalation exposure. Therefore, according to the REACH Guidance, a default value of 100% inhalation absorption will be used.

Dermal

DMS is a highly volatile liquid, therefore absorption across the skin is limited by the rate at which the liquid evaporates off the skin surface. The rate of absorption of DMS was estimated using the IH SkinPerm model using a Kp derived from the EPI Dermwin model. For an instantaneous deposition of 1000 mg over 1000 cm² of skin or a deposition over time of 1 mg/cm²/h, DMS is virtually not absorbed after 8 hours. Therefore, according to the REACH Guidance, a default value of 10% skin absorption will be used.

Distribution

Following single acute exposure until death of mice (within about 8 min) to atmospheres of DMS vapors from 6.8% to 50.6% (w/v), dimethyl sulphide was distributed in all tissues almost equally (Text table 1, Terazawa et al., 1991).

Text table 1. Distribution of dimethyl sulfide (DMS) in tissues of mice exposed to an atmosphere containing DMS

DMS (%)

6.8 ± 1.3

11.6 ± 0.5

23.6 ± 3.7

34.0 ± 3.1

50.6 ± 3.6

Lung

0.19 ± 0.21a

2.90 ± 1.57

1.66 ± 0.73

2.12 ± 0.44

0.29 ± 0.32

Blood

0.76 ± 0.16

5.34 ± 0.94

2.30 ± 0.38

4.54 ± 1.91

0.96 ± 0.29

Heart muscle

1.20 ± 0.72

3.96 ± 1.16

4.06 ± 1.36

3.78 ± 0.88

1.42 ± 0.36

Brain

1.16 ± 0.36

9.12 ± 2.77

8.22 ± 3.80

8.00 ± 2.92

0.88 ± 0.32

Liver

1.28 ± 0.74

4.50 ± 1.33

2.10 ± 0.97

2.24 ± 0.50

0.34 ± 0.14

Spleen

0.40 ± 0.18

2.20 ± 0.99

1.20 ± 0.47

1.48 ± 0.50

0.20 ± 0.09

Kidney

1.10 ± 0.34

3.62 ± 0.67

1.60 ± 1.08

1.94 ± 0.55

0.48 ± 0.13

Muscle

0.92 ± 0.55

1.52 ± 0.71

1.06 ± 0.26

2.14 ± 1.05

0.38 ± 0.10

aMean ± S.D. (mg of DMS/g of wet weight) ( n = 5)

Metabolism

Data are availableon the metabolism of DMS. An extensive review of the metabolism of alkylSulphides, Sulphoxides/Sulphones and Sulphonateswas performed by EFSA (2012).

Sulphides are sufficiently lipophilic to be efficiently absorbed from the gastrointestinal (GI) tract. DMSOand DMSO2are excreted in the urine as metabolites of DMS administered subcutaneously to rabbits (Williams et al., 1966).

According to EFSA (2012), once alkyl sulphides enter systemic circulation, they are rapidly oxidised to sulphoxides, and, depending on the structure of the sulphide, may be further oxidised to the sulphone. The products of S-oxidation reactions may react spontaneously with glutathione, and it is likely that they also exhibit reactivity towards nucleophilic sites in cellular macromolecules. The S-reaction is favoured by the presence of a lone reactive pair of electrons on divalent sulphur in monosulphides, as shown by the excretion in the urine of dimethyl sulphoxide and dimethyl sulphone and to the expiration of a malodorous material (presumably dimethyl sulphide) after DMS subcutaneous administration to rabbits (Williams et al., 1966).

Figure

Although S-oxidation generally yields mixtures of sulphone and sulphoxide metabolites, the relative amounts of excretion products are dependent upon the polarity of the sulphide. In rats, polar aliphatic sulphides give rise to higher proportion of the sulphoxide metabolites(Damani, 1987). This is probably due to the water-solubility of the sulphoxides, which presumably limits their partitioning into the catalytic sites on the microsomal monooxygenase systems (P450 and FMO), involved in the S-oxidation reaction(Damani, 1987).The first oxidation from sulphide to sulphoxide is reversible, whereas the sulphone group is stable and is not reduced back to the sulphoxide; this latter irreversibility seems to be related to the substrate specificity of the reductase(Renwick, 1989). The reduction of sulphoxide is mediated by the GI tract microflora as well as by hepatic and extra hepatic mammalian reductase. In many cases the reversible nature of the sulphide/sulphoxide reaction depends on the dynamic metabolising system provided by intestinal flora (1010bacteria/g of gut content). Anaerobic organisms populate the upper intestines and stomach of mice and rats. Their distribution is concentrated in the lower intestines in rabbits and humans, possibly due to lower gastric pH. In all species, reduction predominates in the lower gut, mainly the cecum and colon. Therefore, if gut flora is involved in the metabolism of monosulphide, the sulphur derivatives must either be incompletely absorbed or reach the lower gut as biliary metabolites(Renwick and George, 1989), then entering the enterohepatic circulation.

In many mammalian species, dimethyl sulfoxide (DMSO) is quickly biotransformed from an essentially odourless liquid to a highly volatile smelly metabolite, dimethyl sulphide (DMS). DMSO metabolism to DMS is mediated by sulfoxide reductases, primarily in the liver and kidneys, and then DMS is rapidly reoxidized to DMSO by mixed-function oxidases. Irreversible oxidation of DMSO to dimethyl sulfone (DMSO2) is extensive (Swanson, 1985).

The subcutaneous injection of either dimethyl sulfide (DMS) or dimethyl sulfoxide (DMSO) leads to the excretion of DMSO and dimethyl sulfone (DMSO2) in the urine of rabbits and to the expiration of a malodorous material (presumably DMS). DMSO2, however, is not reduced to either the sulfoxide or the sulfide but is excreted unchanged. DMSO2is also found in the urine of untreated rabbits (Williamset al., 1966).

Toxicokinetic

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 (Sabadie, 2016). 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 DMSO2were 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 DMSO2plasma concentrations. The maximum plasma concentrations (Cmax) of DMSO were reached at 6h post-administration of DMS. The maximum plasma concentrations of DMSO2were reached at 24h post-administration. After single oral administration of DMS, the Cmax and AUC0-tvalues of DMSO were of 187 ng/mL and 1647 h*ng/mL, respectively. The Cmax and 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. 

Figure 1. Concentration-time profile of DMSO and DMSO2in plasma following single oral administration of DMS at 800 mg/kg and DMSO at 1000 mg/kg

 

 

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
50
Absorption rate - dermal (%):
10
Absorption rate - inhalation (%):
100

Additional information