Dimethyl sulfoxide

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

Pharmacokinetics and distribution of [35S]methylsulfonylmethane following oral administration to rats

Author:

Magnuson BA, Appleton J and Ames GB

Year:

2007

Bibliographic source:

J Agric Food Chem., 55(3):1033-8

Materials and methods

Objective of study:

distribution

excretion

toxicokinetics

Principles of method if other than guideline:

Investigation of the pharmacokinetics, distribution, and excretion of [35S]MSM in rats

Test material

Test material information

Constituent 1

Reference substance name:

Dimethyl sulphone

EC Number:

200-665-9

EC Name:

Dimethyl sulphone

Cas Number:

67-71-0

Molecular formula:

C2H6O2S

IUPAC Name:

dimethyl sulfone

Constituent 2

Reference substance name:

Methylsulfonylmethane

IUPAC Name:

Methylsulfonylmethane

Details on test material:

The Methylsulfonylmethane (MSM) used in this study was OptiMSM distilled microprill provided by Cardinal Nutrition, Inc. (Vancouver, WA). Labeled [35S]MSM was prepared by Perkin-Elmer Life Sciences (Boston, MA) as an aqueous solution (5 mCi/mL, 500 mCi/mmol).

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Taconic Farms (Germantown, NY)
- Age at reception: 7-8 weeks old
- Fasting period before study: overnight and for approximately 4 h postdose
- Housing:
- Diet: Harlan Teklad Certified Rodent Diet 8728C, ad libitum
- Water: ad libitum
- Acclimation period: >1 week

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Duration and frequency of treatment / exposure:

Single

Doses / concentrations

Remarks:

Doses / Concentrations:
500 mg/kg and 50 µCi/rat

Details on dosing and sampling:

Five rats were designated group 1 (blood group), and three rats were designated group 2 (urine and feces group). Samples of blood were collected at 0, 15, and 30 min and 1, 2, 4, 8, 12, 24, and 48 h from group 1. Tissues were collected from group 1 and 2 animals after 48 and 120 h, respectively. Urine and feces were collected during the following time intervals: -24 to 0 (prestudy initiation), 0-24, 24-48, 48-72, 72-96, and 96-120 h after dosing.

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, feces, blood, liver, heart, kidneys, spleen, brain, testes, eyes, scapular skin (shaved), and knee joints (bone and cartilage)s, cage washes
- Time and frequency of sampling: see Table 1

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: as above
- Time and frequency of sampling: see Table 1
- From how many animals: see Table 1
- Method type(s) for identification: Liquid scintillation counting
- Limits of detection and quantification: no data
TREATMENT FOR CLEAVAGE OF CONJUGATES (if applicable):

Statistics:

Mean and standard deviation calculations were performed using Excel Office XP (Microsoft, Redmond, WA). Pharmacokinetic analysis of the total
35S blood concentration-time data was calculated by noncompartmental analyses using WinNonlin, version 4.1. (Pharsight Corp., Mountain View, CA).

Results and discussion

Main ADME results

Main ADME results 1

Type:

excretion

Results:

Urine (0-120h): 85.8 ± 4.8 % of the dose

Main ADME results 2

Type:

excretion

Results:

Feces (0-120h): 3.0 ± 3.0 %

Main ADME results 3

Type:

excretion

Results:

Total (0-120h): 88.9 ± 5.1 %

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:

Blood Concentrations of MSM.
Oral administration of [35S]-MSM to rats resulted in the rapid appearance of substantial blood concentrations of 35S at the first time point of 15 min postdose and quantifiable concentrations at all time points up to 48 h (Figure 1). Radiolabel concentrations remained close to peak levels for 8 h following dose administration (mean blood levels were >80% of the maximal concentration level from 0.5 to 8 h postdose). The peak mean blood concentration of 618 µg equiv/mL was achieved at 2 h following MSM administration. Significant blood concentrations of radioactivity (>70 times the quantifiable level of 0.816 µg equiv/mL) persisted through the 48 h time point. Examination of the blood
concentrations versus time analysis from individual rats revealed that the blood concentration profile was very consistent from rat to rat (data not shown).

Distribution of Radioactivity.
Total radioactivity appeared to be widely distributed throughout the body, and measurable levels of total 35S were found in all tissues analyzed at 48 h postdose (Table 3).
The highest levels of radiolabel were found in kidney, testes, and eye. These values were comparable ((15%) to the blood concentration (63.7 µg equiv/g) found at the 48 h time point. Radioactivity levels in the skin (51.8 µg equiv/g) and bone (35.2 µg equiv/g) were lower than the (15% range. No quantifiable levels of radioactivity (values greater than twice ranging from 0.76 to 2.43 µg equiv/g depending on the tissue) were found in any of the tissues analyzed at the 120 h time point, suggesting that all radioactivity was eliminated by 120 h.

Details on excretion:

Excretion in Urine and Feces.
Following a single admin- istration of [35S]MSM, the majority of the radioactivity (85.8%) was excreted in the urine (Table 4). Only a relatively minor amount of the radioactive dose (3.03%) was excreted in the feces. The majority of the radioactivity (58.7%) was excreted within the first 24 h, with 79.0% excreted by 48 h on the basis of radioactivity in urine and feces. Less than 1% of the radioactivity was found in the cage wash (Table 4).

Toxicokinetic parameters

Toxicokinetic parameters 1

Toxicokinetic parameters:

Cmax: 622 ± 37 µg equiv/mL

Toxicokinetic parameters 2

Toxicokinetic parameters:

Tmax: 2.1 ± 1.2 h

Toxicokinetic parameters 3

Toxicokinetic parameters:

other: AUC(0-48): 14052 ± 835 h µg equiv/mL

Toxicokinetic parameters 4

Toxicokinetic parameters:

other: AUC0-inf: 15124 h µg equiv/mL

Toxicokinetic parameters 5

Toxicokinetic parameters:

other: kel: 0.0575 ± 0.0069 1/h

Toxicokinetic parameters 6

Toxicokinetic parameters:

half-life 1st: 12.2 ± 1.4 h

Metabolite characterisation studies

Metabolites identified:

no

Any other information on results incl. tables

Table 3.Tissue Concentrations of Radioactivity and Tissue/Blood Ratios following [35S]MSM Administration to Rats

		concentration^a(µg equiv/g)		tissue/blood ratio
tissue	N	48 h	120 h	48 h	120 h
blood^b	3	63.7 ± 12.3	N/A	N/A	N/A
liver	3	54.7 ±11.4	BLQ	0.856	N/A
heart	3	59.4 ±11.7	BLQ	0.932	N/A
kidney	3	71.1 ±15.7	BLQ	1.11	N/A
spleen	3	58.2 ±14.4	BLQ	0.909	N/A
testes	3	69.4 ±16.2	BLQ	1.08	N/A
brain	3	58.7 ±11.8	BLQ	0.921	N/A
eye	3	66.7 ±12.9	BLQ	1.05	N/A
skin	3	51.8 ±13.7	BLQ	0.807	N/A
bone	3	35.2 ±0.9	BLQ	0.563	N/A

^aValues are expressed as means ±SD. BLQ, below the limit of quantification; N, number; N/A, not applicable.^bThis mean blood concentration uses only the same three animals utilized for tissue analysis.

 

Table 4.Mean Individual and Cumulative Urine, Feces, and Urine +Feces Percent of [35S]MSM Dose Recovered in Rats^a

 

		urine (% of dose)		feces (% of dose)		urine + feces (% of dose)
time (h)	N	individual	cumulative	individual	cumulative	Individual	cumulative
-24 to 0	3	BLQ	BLQ	BLQ	BLQ	BLQ	BLQ
0-24	3	57.1 ±6.2	57.1 ±6.2	1.6 ±0.5	1.6 ±0.5	58.7 ±6.7	58.7 ±6.7
24-48	3	19.2 ±3.9	76.3 ±3.8	1.1 ±0.4	2.7 ±0.4	20.3 ±4.4	79.0 ±4.1
48-72	3	4.3 ±1.3	80.7 ±2.6	0.2 ±0.0	2.9 ±0.3	4.5 ±1.3	83.5 ±2.8
72-96	3	1.2 ±0.3	81.8 ±2.2	0.1 ±0.0	3.0 ±0.3	1.3 ±0.3	84.7 ±2.5
96-120	3	0.3 ±0.1	82.1 ±2.2	0.0 ±0.0	3.0 ±0.3	0.44 ±0.1	85.1 ±2.4
cage wash	2	0.2 ±0.0	82.2 ±2.3	N/A	N/A	0.2 ±0.0	85.2 ±2.5
cage contents	3	3.6 ±3.0	85.8 ±4.8	N/A	N/A	3.6 ±3.0	88.9 ±5.1
total			85.8 ±4.8		3.0 ±0.3		88.9 ±5.1

^aValues are expressed as means ±SD; BLQ, below the limit of quantification; N, number; N/A, not applicable.

 

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
MSM is rapidly absorbed, well distributed throughout the body, and quickly eliminated primarily through the urine. No evidence of accumulation in specific tissues was noted.

Executive summary:

The objective of this study was to evaluate the pharmacokinetic profile and distribution of radiolabeled Methylsulfonylmethane (MSM) in rats. Male Sprague-Dawley rats were administered a single oral dose of [35S]MSM (500 mg/kg), and blood levels of radioactivity were determined at different time points for up to 48 h. Tissue levels of radioactivity at 48 and 120 h and urine and fecal radioactivity levels were measured at different time points for up to 120 h following [35S]MSM administration to rats. Oral [35S]MSM was rapidly and efficiently absorbed with a mean tmax of 2.1 h, Cmax of 622 microg equiv/mL, and AUC0-inf of 15124 h.microg equiv/mL. The t1/2 was 12.2 h. Soft tissue distribution of radioactivity indicated a fairly homogeneous distribution throughout the body with relatively lower concentrations in skin and bone. Approximately 85.8% of the dose was recovered in the urine after 120 h, whereas only 3% was found in the feces. No quantifiable levels of radioactivity were found in any tissues after 120 h, indicating complete elimination of [35S]MSM. The results of this study suggest that [35S]MSM is rapidly absorbed, well distributed, and completely excreted from the body.