Registration Dossier

Toxicological information

Direct observations: clinical cases, poisoning incidents and other

Currently viewing:

Administrative data

Endpoint:
direct observations: clinical cases, poisoning incidents and other
Type of information:
experimental study
Adequacy of study:
key study
Study period:
November 20, 1967 to February 18, 1968
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
The human toxicology on dimethyl sulfoxide
Author:
Brobyn RD
Year:
1975
Bibliographic source:
Ann. N.-Y. Acad. Sci., 243, 497-506
Reference Type:
publication
Title:
The Human Toxicology Of Dimethyl Sulfoxide
Author:
Brobyn RD
Year:
2007
Bibliographic source:
Available at http://www.dmso.org/articles/information/pbrobyn.html
Reference Type:
publication
Title:
Eye effects of DMSO Report of negative effects
Author:
Hull FW, Wood DC, and Brobyn RD
Year:
1969
Bibliographic source:
Northwest Med., 86, 39-41

Materials and methods

Study type:
study with volunteers
Endpoint addressed:
repeated dose toxicity: dermal
Principles of method if other than guideline:
Male volunteer subjects, ages 21-55, were treated with DMSO, applied as an 80% gel, to the skin in a single daily dose of 1 g/kg body weight. DMSO was applied daily for 90 days. A control group, not exposed to DMSO, were studied in a similar manner. All patients were subject to clinical, ophthalmological, hematological and biochemical examinations.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Test compound: Dimethylsulfoxyde
Source: no data
Batch : no data
Purity : spectrograde DMSO

Method

Type of population:
general
Subjects:
- Number of subjects exposed (group C): 54, 40 completed the 90-day study
- Number of subjects in the control group (group D): 26
- Sex: male
- Age: 21-55 years
- Race: no data
- Demographic information: no data
- Known diseases: no preexisting ophthalmologic, pulmonary, cardiac, hepatic, renal, or hematologic diseases
- Other:
Ethical approval:
other: the study was conducted at the State Prison Hospital at Vacaville, California
Route of exposure:
dermal
Reason of exposure:
intentional
Details on exposure:
Group C was to receive 80% DMSO gel at 1 g/kg. Group D would serve as controls and receive no medications.
Examinations:
Physical, ophthalmological, and laboratory examinations were performed prior to the start of the study. All subjects who received DMSO started medication on November 20, 1967, and they finished on February 18, 1968 if the full 90-day course was completed.
Blood and urine samples were obtained from all subjects at l, 2, 4, 6, 8, and 13 weeks (2/20/68). All subjects received a physical examination at the end of the study (2/22/68).
Ophthalmological examinations were conducted weekly up to the twelfth week, and at the fourth, sixth, ninth, twelfth, and eighteenth month of the study.

Physical examinations consisted of determinations of blood pressure, pulse, temperature, and respiratory rate, examination of the neck and thyroid, lungs, heart, liver, kidney, spleen, abdomen, genitourinary system, rectum, and extremities, and an E.N.T. and neurological examination.

Ophthalmological examinations included slit lamp examinations, ophthalmoscopy, and tests of refraction, tonometry, and tangent field. (The results of these examinations are available on individual report forms for each subject.)

Laboratory examinations included hematology (rbc, wbc, differential count, hemoglobin, hematocrit, morphology, color and saturation indices platelets, and reticulocyte count): urinalysis; blood chemistries (creatinine, glucose, [fasting], BUN, cholesterol, thymol turbidity, total protein, prothrombin, albumin, globulin, A/G ratio, uric acid, alkaline phosphatase, SGOT, SGPT, PBI, PSP, creatinine clearance, bilirubin, BSP, calcium, magnesium, phosphorus, sodium, potassium, chloride, CO" ICD, CPK, urinary hydroxyproline).

In addition, Groups C, and D, received cerebrospinal fluid and bone-marrow examinations, and other special examinations.

Results and discussion

Results of examinations:
DMSO appears to be safe for human administration, and in particular, the lens changes that occur in certain mammalian species do not occur in man under this very high prolonged treatment regimen. Some side clinical effects have been observed, but were not considered as adverse. Under these experimental conditions, the NOAEL was 1000 mg/kg/d.

Any other information on results incl. tables

Clincal signs:

The skin reaction and breath odor were anticipated and did occur. Numerous other side effects occurred in both the DMSO-treated and control groups. The comparison of the DMSO-treated and control groups suggests that the true side effects of massive doses of DMSO include some sedation and occasional insomnia and nausea. A small amount of dizziness and diarrhea also occurred in the DMSO-treated group.

Laboratory Examinations:

. Haematology

With the exception of eosinophilia, no significant abnormalities were observed in the large battery of blood chemistries, peripheral blood and urine analyses, or various special procedures. Thus, it is evidence that administration even of massive 1.0 g/kg doses of DMSO daily for as long as 90 days produced no significant toxicity, so far as can be determined by both routine and special laboratory studies.

A transient eosinophilia during the first few weeks of DMSO application occurred in 23 (51%) of the 45 DMSO-treated subjects. Although a similar eosinophilia was noted in 8 (31%) of the 26 control subjects, it is thought that the higher incidence in the DMSO group denotes a true drug effect. It is suggested that this effect is produced by the cutaneous histamine-releasing property of DMSO.

An occasional large lymphocyte with mottled blue cytoplasm and coarse chromatin was observed for 5 days or more in the peripheral blood of 20 (44%) of the 45 subjects who received DMSO, and also, 11 (42%) of the 26 control subjects. Thus it is unlikely that DMSO is responsible for this altered cell morphology.

There was no evidence of gross blood loss or anemia in the DMSO-treated subjects. A modest decrease in hematocrit, hemoglobin and/or the red blood cell count occurred in two subjects. The MCV, color index, and volume index increased in three other subjects.

There were no significant abnormalities in the BUN or urinalyses. A decrease of 15-min PSP excretion was observed in 1 of 8 DMSO-treated subjects.

. Blood chemistry

Serum SGOT levels increased (to between 40 and 100 IU/ml) in 3 DMSO-treated subjects. The levels returned to normal while DMSO therapy was continued, in all except one subject. This subject exhibited an SGOT of 78IU/ml, and an SGPT of 60 IU/ml, at the conclusion of therapy; however, other parameters of the liver functions were normal. It was not possible to obtain further follow-up on this subject. It is noteworthy that 5 of the 26 control subjects exhibited elevated transaminase levels at some time during the study. These abnormalities may relate to the observation that 6% of the sampled population of the prison had elevated transaminase levels.

One subject exhibited increasing concentrations of serum alkaline phosphatase with continuing DMSO treatment; however, all of his other liver function parameters remained normal.

Unaccountably, BSP retention tests were abnormal in 1 of 8 DMSO-treated subjects and 3 of 5 control subjects.

Although fasting blood glucose levels were sometimes slightly above or below normal limits in a number of the DMSO-treated and control subjects, there was no consistent abnormal trend. A slight hyperglycemia was more frequent in the control group, whereas the incidence of slight hypoglycemia was similar in the two group Glucose tolerance tests were normal in 6 of 8 DMSO-treated subjects so evaluated. The tests were inconclusive in the other 2 subjects. (One of 5 glucose tolerance test conducted among the control subjects was also inconclusive.)

An increased prothrombin time was noted in one DMSO-treated subject. Inasmuch as prothrombin times were determined for all DMSO-treated subjects, it seems unlikely that this one instance was drug-related.

- Cerebrospinal fluid:

Although some alterations in cerebrospinal fluid protein were observed in the DMSO-treated subjects, there were similar findings in the control group. There were no alterations in the CSF glucose values for either group. It appears that DMSO has no significant effect on the cerebrospinal fluid.

- Bone marrow:

Repeat bone-marrow examinations were carried out on 7 DMSO-treated subjects and 4 control subjects. There were no significant abnormalities.

Urinalyse:

An attempt to measure urinary hydroxyproline levels in subjects was not successful. The results were quite inconsistent and were cast out on the assay method. Similar laboratory difficulties were encountered in the assessment of urinary hormone assays.

Special Procedures:

Pulmonary function studies, as stated previously, were conducted on all subjects, because this was one of the main areas of suspected toxicity. These were done before treatment and after 2, 4, 6, 8, and 13 weeks. There were no significant changes, although 4 DMSO-treated subjects exhibited slight alterations in the force vital capacity, forced expatory volume, and pulmonary resistance. Among the control subjects, 2 exhibited the same type of changes. There was no evidence of bronchospasm. DMSO treatment had no effect whatsoever on the serial electrocardiograms obtained on the subjects. Serial EEG tracings were obtained on all the subjects in C2 and D2. They were completely normal. Photostimulation and hyperventilation produced no EEG changes. We can conclude that dermal administration of DMSO at l g/kg daily has no effects on the central nervous system.

Ophthalmologic Exams:

Slit lamp examinations, ophthalmoscopy, and refraction, tonometry, and visual field tests were done throughout the study as previously described. No abnormalities were noted in any of the treated or control subjects. This appears to be one of the most significant statements that we can make. There appears to be no ocular toxicity from DMSO after 3 months' treatment at this quite high dose.

Applicant's summary and conclusion

Conclusions:
Thus according to this very extensive toxicology study of DMSO conducted at 3 to 30 times the usual treatment dose in humans (1000 mg/kg bw/d), for 3 months. DMSO appears to be a very safe drug for human administration, and in particular, the lens changes that occur in certain mammalian species do not occur in man under this very high prolonged treatment regimen. After considerable work in evaluating thousands of cases that were treated in 1964 and 1965, and after this special toxicology study, the author feel that unequivocally DMSO is quite safe and produced no adverse effects with the exception of some side effects like sedation, insomnia, nausea, dizziness, or diarrhea.
Executive summary:

The toxicity of DMSO was assessed in human volunteers after repeated dermal application. Male volunteer subjects, ages 21-55, were treated with DMSO, applied as an 80% gel, to the skin in a single daily dose of 1 g/kg body weight. DMSO was applied daily for 90 days. A control group, not exposed to DMSO, were studied in a similar manner. Physical, ophthalmological, and laboratory examinations were performed prior to the start of the study. Blood and urine samples were obtained from all subjects at l, 2, 4, 6, 8, and 13 weeks. All subjects received a physical examination at the end of the study. Ophthalmological examinations were conducted weekly up to the twelfth week, and at the fourth, sixth, ninth, twelfth, and eighteenth month of the study.  

A transient eosinophilia during the first few weeks of DMSO application occurred in 23 (51%) of the 45 DMSO-treated subjects. Although a similar eosinophilia was noted in 8 (31%) of the 26 control subjects, it is thought that the higher incidence in the DMSO group denotes a true drug effect. It is suggested that this effect is produced by the cutaneous histamine-releasing property of DMSO. With the exception of eosinophilia, no significant abnormalities were observed in the large battery of blood chemistries, peripheral blood and urine analyses, or various special procedures. Thus, it is evidence that administration even of massive 1.0 g/kg doses of DMSO daily for as long as 90 days produced no significant toxicity, so far as can be determined by both routine and special laboratory studies. An occasional large lymphocyte with mottled blue cytoplasm and coarse chromatin was observed for 5 days or more in the peripheral blood of 20 (44%) of the 45 subjects who received DMSO, and also, 11 (42%) of the 26 control subjects. Thus it is unlikely that DMSO is responsible for this altered cell morphology. There was no evidence of gross blood loss or anaemia in the DMSO-treated subjects. A modest decrease in haematocrit, haemoglobin and/or the red blood cell count occurred in two subjects. The MCV, colour index, and volume index increased in three other subjects. There were no significant abnormalities in the BUN or urinalyses. A decrease of 15-min PSP excretion was observed in 1 of 8 DMSO-treated subjects. Serum SGOT levels increased (to between 40 and 100 IU/ml) in 3 DMSO-treated subjects. The levels returned to normal while DMSO therapy was continued, in all except one subject. This subject exhibited an SGOT of 78IU/ml, and an SGPT of 60 IU/ml, at the conclusion of therapy; however, other parameters of the liver functions were normal. It was not possible to obtain further follow-up on this subject. It is noteworthy that 5 of the 26 control subjects exhibited elevated transaminase levels at some time during the study. These abnormalities may relate to the observation that 6% of the sampled population of the prison had elevated transaminase levels. One subject exhibited increasing concentrations of serum alkaline phosphatase with continuing DMSO treatment; however, all of his other liver function parameters remained normal. Unaccountably, BSP retention tests were abnormal in 1 of 8 DMSO-treated subjects and 3 of 5 control subjects. Although fasting blood glucose levels were sometimes slightly above or below normal limits in a number of the DMSO-treated and control subjects, there was no consistent abnormal trend. A slight hyperglycemia was more frequent in the control group, whereas the incidence of slight hypoglycemia was similar in the two group Glucose tolerance tests were normal in 6 of 8 DMSO-treated subjects so evaluated. The tests were inconclusive in the other 2 subjects. (One of 5 glucose tolerance test conducted among the control subjects was also inconclusive.) An increased prothrombin time was noted in one DMSO-treated subject. Inasmuch as prothrombin times were determined for all DMSO-treated subjects, it seems unlikely that this one instance was drug-related. Although some alterations in cerebrospinal fluid protein were observed in the DMSO-treated subjects, there were similar findings in the control group. There were no alterations in the CSF glucose values for either group. It appears that DMSO has no significant effect on the cerebrospinal fluid. Repeat bone marrow examinations were carried out on 7 DMSO-treated subjects and 4 control subjects. There were no significant abnormalities. An attempt to measure urinary hydroxyproline levels in subjects was not successful. The results were quite inconsistent and were cast out on the assay method. Similar laboratory difficulties were encountered in the assessment of urinary hormone assays. Pulmonary function studies, as stated previously, were conducted on all subjects, because this was one of the main areas of suspected toxicity. These were done before treatment and after 2, 4, 6, 8, and 13 weeks. There were no significant changes, although 4 DMSO-treated subjects exhibited slight alterations in the force vital capacity, forced expiratory volume, and pulmonary resistance. Among the control subjects, 2 exhibited the same type of changes. There was no evidence of bronchospasm. DMSO treatment had no effect whatsoever on the serial electrocardiograms obtained on the subjects. Serial EEG tracings were obtained on all the subjects in C2 and D2. They were completely normal. Photostimulation and hyperventilation produced no EEG changes. We can conclude that dermal administration of DMSO at l g/kg daily has no effects on the central nervous system. No abnormalities were noted in any of the treated or control subjects. This appears to be one of the most significant statements that we can make. There appears to be no ocular toxicity from DMSO after 3 months' treatment at this quite high dose. The skin reaction and breath odour were anticipated and did occur. Numerous other side effects occurred in both the DMSO-treated and control groups. The comparison of the DMSO-treated and control groups suggests that the true side effects of massive doses of DMSO include some sedation and occasional insomnia and nausea. A small amount of dizziness and diarrhoea also occurred in the DMSO-treated group.

A very extensive toxicology study of DMSO was conducted at the dose level of 1000 mg/kg bw/d for 3 months. DMSO appears to be safe for human administration, and in particular, the lens changes that occur in certain mammalian species do not occur in man under this very high prolonged treatment regimen. Some side clinical effects have been observed, but were not considered as adverse. Under these experimental conditions, the NOAEL was 1000 mg/kg/d.