Dimethyl sulfoxide

Repeated dose toxicity: oral

Administrative data

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

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:

The toxicity of dimethyl sulphoxide (DMSO) for the dog, pig, rat and rabbit

Author:

Noel PRB, Barnett KC, Davies RE, Jolly DW, Leahy JS, Mawdesley-Thomas LE, Shillam KWG, Squires PF, Street AE, Tucker WC and Worden AN

Year:

1975

Bibliographic source:

Toxicology, 3 (2), 143-69

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 452 (Chronic Toxicity Studies)

Deviations:

yes

Remarks:

no blood chemistry and histopathology

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Dimethyl sulfoxide

EC Number:

200-664-3

EC Name:

Dimethyl sulfoxide

Cas Number:

67-68-5

Molecular formula:

C2H6OS

IUPAC Name:

dimethyl sulfoxide

Details on test material:

Test compound: dimethylsulfoxide
Source: Crown Zellerbach Corporation
Batch number: no data
Purity: Pharmaceutical-grade

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Wilmington, Massachusetts, USA
- Age at study initiation: no data
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: 5 to a cage;
- Diet (e.g. ad libitum): Spillers autoclaved Laboratory Small Animals diet
- Water: ad libitum)
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

IN-LIFE DATES: 1965-1967

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 50%
- Amount of vehicle (if gavage): 2 to 18 mlKg bw/d according to the dose levels

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

18 months (78 weeks)

Frequency of treatment:

5 days/wk

Doses / concentrations

Remarks:

Doses / Concentrations:
1, 3 and 9 ml/kg bw/d (1100 - 3300 - 9900 mg/kg bw/d)
Basis:

No. of animals per sex per dose:

50 males and 50 females

Control animals:

yes, concurrent vehicle

Details on study design:

Post-exposure period: none

Groups of 50 male and 50 female Sprague Dawley rats received oral daily doses, 5 days a week for a total of 18 months (78 weeks), of 1, 3 or 9 ml/kg DMSO (50% aqueous solution), a control group received 9 ml distilled water/kg/day. 

After 52 weeks, 10 males and 10 females from each were sacrificed.  Animals were observed daily, weighed weekly and food intake was calculated at weekly intervals. Ophthalmoscopic examination of the eyes of all animals was made before dosing and then at regular intervals throughout the study. Hematology studies (PCV, haemoglobin, total and differential white cell count and prothrombin index), together with urinalysis and measurement of urine concentration were performed on sample animals from each group after 4, 12, 20, 32, 51, 60 and 72 weeks. 

After 78 weeks remaining animals were sacrificed and their tissues preserved.

Positive control:

Not appropriate

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

WATER CONSUMPTION : No data

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: before dosing and then at regular intervals
- Group examined: all

HAEMATOLOGY: Yes
- Time schedule for collection of blood: 4, 12, 20, 32, 51, 60 and 72 weeks
- Anaesthetic used for blood collection: No data
- Animals fasted: No data

URINALYSIS: Yes
- Time schedule for collection of urine: 4, 12, 20, 32, 51, 60 and 72 weeks
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: No

Statistics:

Numerical results were subjected to statistical analysis, comprising analysis of variance followed by Student's 't' test. The result of the analysis was usually expressed as the least difference that had to exist between test and control group means before a 5% or 1% level of significance was reached

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

but not relevant

Mortality:

mortality observed, treatment-related

Description (incidence):

but not relevant

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

>= 1 ml/kg/day (slight decrease < 10%)

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

effects observed, treatment-related

Description (incidence and severity):

at 9 ml/kg/day

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

at 9 ml/kg/day

Clinical biochemistry findings:

not examined

Urinalysis findings:

not specified

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
Mortalities were few and could not be related to DMSO treatment. Occasional behavioural changes, persisting for about 5 min after dosing, were observed. These consisted of stretching and arching of the back, accompanied by an in-drawing of flanks and abdomen, and were attributed to abdominal discomfort.

BODY WEIGHT AND WEIGHT GAIN-FOOD CONSUMPTION
Bodyweight records indicated a dose-related depression of weight gain in both sexes (<10%), with the exception of males receiving 1 ml/kg (Figures 7 and 8). There was no accompanying reduction of food intake.

OPHTHALMOSCOPIC EXAMINATION
Examination of the eye revealed no changes in the retina or vitreous. No peripheral (equatorial) opacities were seen and there was no difference in incidence of polar opacities between test and control animals. Prominent nuclear annuli were seen in a small number of animals towards the end of the study, as expected, but there was no dose-relationship to suggest any increase resulting from administration of DMSO. The only relevant finding was some degree of change in the refractive index of the nuclear region in 3 rats receiving 9 ml/kg.

HAEMATOLOGY
Laboratory investigations were limited to haematological tests, the only abnormality being a slight reduction of haemoglobin and PCV in male rats receiving 9 ml/kg.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

3 300 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: Slight decreased (<10%) of mean body weight gain at all dose levels and sexes except males at 1100 mg/kg bw/d.

2

Dose descriptor:

LOAEL

Effect level:

9 900 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: Slight decreased Hb and PCV in male at 9900 mg/kg bw/d. Changes in the lens of the eye at 9900 mg/kg bw /d

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The potential toxicity of DMSO was evaluated following repeated oral administration for 78 weeks. Groups of 50 male and 50 female Sprague Dawley rats received oral daily doses, 5 days a week for a total of 18 months (78 weeks), of 1, 3 or 9 ml/kg DMSO (50% aqueous solution), a control group received 9 ml distilled water/kg/day.
After 52 weeks, 10 males and 10 females from each were sacrificed. Animals were observed daily, weighed weekly and food intake was calculated at weekly intervals. Ophthalmoscopic examination of the eyes of all animals was made before dosing and then at regular intervals throughout the study. Haematology studies (PCV, haemoglobin, total and differential white cell count and prothrombin index), together with urinalysis and measurement of urine concentration were performed on sample animals from each group after 4, 12, 20, 32, 51, 60 and 72 weeks.

After 78 weeks remaining animals were sacrificed and their tissues preserved.

Mortalities were few and could not be related to DMSO treatment. Occasional behavioural changes, persisting for about 5 min after dosing, were observed. These consisted of stretching and arching of the back, accompanied by an in-drawing of flanks and abdomen, and were attributed to abdominal discomfort.
Bodyweight records indicated a dose-related depression of weight gain in both sexes, with the exception of males receiving 1 ml/kg (Figures 7 and 8). There was no accompanying reduction of food intake.

Examination of the eye revealed no changes in the retina or vitreous. No peripheral (equatorial) opacities were seen and there was no difference in incidence of polar opacities between test and control animals. Prominent nuclear annuli were seen in a small number of animals towards the end of the study, as expected, but there was no dose-relationship to suggest any increase resulting from administration of DMSO. The only relevant finding was some degree of change in the refractive index of the nuclear region in 3 rats receiving 9 ml/kg.

Laboratory investigations were limited to haematological tests, the only abnormality being a slight reduction of haemoglobin and PCV in male rats receiving 9 ml/kg.

Under the experimental conditions, the No Observed Adverse Effect Level (NOAEL) is 3300 mg/kg/day and the LOAEL is 9900 mg/kg/day for the ophthalmology and haematology effects.

Executive summary:

The potential toxicity of DMSO was evaluated following repeated oral administration for 78 weeks. Groups of 50 male and 50 female Sprague Dawley rats received oral daily doses, 5 days a week for a total of 18 months (78 weeks), of 1, 3 or 9 ml/kg DMSO (50% aqueous solution); a control group received 9 ml distilled water/kg/day.

After 52 weeks, 10 males and 10 females from each group were sacrificed.  Animals were observed daily, weighed weekly and food intake was calculated at weekly intervals. Ophthalmoscopic examination of the eyes of all animals was made before dosing and then at regular intervals throughout the study. Haematology studies (PCV, haemoglobin, total and differential white cell count and prothrombin index), together with urinalysis and measurement of urine concentration were performed on sample animals from each group after 4, 12, 20, 32, 51, 60 and 72 weeks. After 78 weeks remaining animals were sacrificed and their tissues preserved.

Mortalities were few and could not be related to DMSO treatment. Occasional behavioural changes, persisting for about 5 min after dosing, were observed. These consisted of stretching and arching of the back, accompanied by an in-drawing of flanks and abdomen, and were attributed to abdominal discomfort. Bodyweight records indicated a slight dose-related depression of weight gain (<10%) in both sexes, with the exception of males receiving 1 ml/kg. There was no accompanying reduction of food intake. Examination of the eye revealed no changes in the retina or vitreous. No peripheral (equatorial) opacities were seen and there was no difference in incidence of polar opacities between test and control animals. Prominent nuclear annuli were seen in a small number of animals towards the end of the study, as expected, but there was no dose-relationship to suggest any increase resulting from administration of DMSO. The only relevant finding was some degree of change in the refractive index of the nuclear region in 3 rats receiving 9 ml/kg. Laboratory investigations were limited to haematological tests, the only abnormality being a slight reduction of haemoglobin and PCV in male rats receiving 9 ml/kg.

The No Observed Adverse Effect Level (NOAEL) is 3300 mg/kg/day based on the slight depression of the body-weight gain and the LOAEL is 9900 mg/kg/day for the ophthalmology and haematology effects.