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Toxicological information

Repeated dose toxicity: oral

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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:
OECD Guideline 452 (Chronic Toxicity Studies)
Deviations:
yes
Remarks:
no blood chemistry and histopathology
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
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 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

open allclose all
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.
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.