Registration Dossier

Toxicological information

Direct observations: clinical cases, poisoning incidents and other

Administrative data

Endpoint:
direct observations: clinical cases, poisoning incidents and other
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented. No data on GLP.

Data source

Reference
Reference Type:
publication
Title:
Controlled Clinical Evaluations of Chlorine Dioxide, Chlorite and Chlorate in Man
Author:
Lubbers JR, Chauan S, Bianchine JR
Year:
1982
Bibliographic source:
Environmental Health Perspectives, Vol. 46, pp 57-62.

Materials and methods

Study type:
study with volunteers
Endpoint addressed:
repeated dose toxicity: oral
Principles of method if other than guideline:
To assess the relative safety of chronically administered chlorine water disinfectants in man, a controlled study was undertaken. The clinical evaluation was conducted in the three phases common to investigational drug studies. Phase I, a rising does tolerance investigation, examined the acute effects of progressively increasing single doses of chlorine disinfectants to normal healthy adult male volunteers. Phase II considered the impact on normal subjects of daily ingestion of sodium chlorite at a concentration of 5 mg/L for twelve consecutive weeks. Persons with a low level of glucose-6-phosphate dehydrogenase may be expected to be especially susceptible to oxidative stress; therefore, in Phase III, sodium chlorite at a concentration of 5 mg/L was administered daily for twelve consecutive weeks to a small group of potentially at-risk glucose-6-phosphate dehydrogenase-deficient subjects. Physiological impact was assessed by evaluation of a battery of qualitative and quantitative tests. The three phases of this controlled double-blind clinical evaluation of sodium chlorite in human male volunteer subjects were completed uneventfully.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Sodium chlorite, chlorite

Method

Type of population:
general
Subjects:
- For Phase I and for Phase II, normal healthy adult male volunteers were selected. Subjects were 21 to 35 years of age, and weighed within ± 10 % ofnormal body weight for their frame and stature. A history of disease or any medical or surgical condition which might interfere with the absorption, excretion, or metabolism of substances by the body precluded inclusion. Normal methemoglobin levels, thyroid function, and glutathione levels were mandatory.For Phase I: 10 volunteers in the treated group and 10 in the control group.For phase II: 10 volunteers in the treated group and 10 in the control group.- For Phase III, volunteers were defined as glucose- 6-phosphate dehydrogenase (G-6-PD)-deficient on the basis of a hemoglobin G-6-PD level of less than 5.0 IU/GM hemoglobin in the pre-study screening. Phase III subjects were normal in all other respects. For phase III: 3 volunteers in the treated group.
Ethical approval:
confirmed, but no further information available
Route of exposure:
oral
Reason of exposure:
intentional
Exposure assessment:
estimated
Details on exposure:
In general, freshly prepared stock solutions of sodium chlorite were assayed by the colorimetric techniques of Palin, then diluted with organic-free demineralized deionized water to appropriate concentrations.- Phase I: The study involved a series of six sequences of three days each. Treatment concentrations were increased for each treatment (0.01, 0.1, 0.5, 1.0, 1.8 and 2.4 mg/L). On the first day of each three day treatment sequence, each volunteer ingested 1000 mL of the water in two portions. The second 500 mL portion aliquot was administered 4 hr after the first. Each 500 mL portion was consumed within 15 min. Only two doses of disinfectant were administered on the first day of each treatment sequence. No disinfectant was administered on the second and third day of each sequence. The control group received untreated water. - Phase II: The concentration of sodium chlorite ingested was 5 mg/L. The control group received untreated water. Each subject received 500 mL daily for 12 weeks.- Phase III: The concentration of sodium chlorite ingested was 5 mg/L. The control group received untreated water. Each subject received 500 mL daily for 12 weeks.
Examinations:
- Phase I: A clinical evaluation of the collection of blood and urine samples for determination of pretreatment baseline laboratory values preceded the first treatment. The second and third day of each sequence serve as followup observation days. The second day of the treatment sequence consisted of a physical examination and collection of blood and urine sampIes for determination of posttreatment laboratory values. On the third day, each volunteer was given a physical examination to determine residual effects of treatment with the water disinfectants and byproducts.Taste evaluations were obtained at each dose level. Study participants were asked to rate the treated water as very unpleasant, slightly unpleasant, not pleasant, pleasant, or tasteless.- Phase II: Physicals, collection of blood and urine samples for laboratory assays, and taste evaluations were conducted on a weekly basis during the treatment period and for 8 weeks following cessation of treatment.- Phase III: Physicals, collection of blood and urine samples for laboratory assays, and taste evaluations were conducted on a weekly basis during the treatment period and for 8 weeks following cessation of treatment.

Results and discussion

Clinical signs:
The careful clinical evaluation of every subject in Phases I, II, and III failed to reveal any clinically important impact upon the medical well-being of any subject as a result of sodium chlorite ingestion.The subjective evaluations of palatability indicated that few subjects found the test substances to have an objectionable taste at levels up to 24 mg/L.
Results of examinations:
Hemoglobin electrophoresis results indicated that, in Phase II, a small number of subjects yielded abnormal hemoglobin distributions but these individuals were found to be randomly distributed in both the treatment groups and in the control group.Examination of electrocardiograms revealed no abnormalities.The compiled vital signs were examined for evidence of consistent response to treatment. No such evidence was found.There were no obvious undesirable clinical sequellae noted by any of the participating subjects or by the observing medical team. In several cases, statistically significant trends in certain biochemical or physiological parameters were associated with treatment; however, none of these trends was judged to have physiological consequence. One cannot rule out the possibility that, over a longer treatment period, these trends might indeed achieve proportions of clinical importance. However, by the absence of detrimental physiological responses within the limits of the study, the relative safety of oral ingestion of sodium chlorite was demonstrated.

Any other information on results incl. tables

There were no obvious undesirable clinical sequellae noted by any of the participating subjects or by the observing medical team. In several cases, statistically significant trends in certain biochemical or physiological parameters were associated with treatment; however, none of these trends was judged to have physiological consequence. One cannot rule out the possibility that, over a longer treatment period, these trends might indeed achieve proportions of clinical importance. However, by the absence of detrimental physiological responses within the limits of the study, the relative safety of oral ingestion of sodium chlorite was demonstrated.

Applicant's summary and conclusion

Conclusions:
There were no obvious undesirable clinical sequellae noted by any of the participating subjects or by the observing medical team. In several cases, statistically significant trends in certain biochemical or physiological parameters were associated with treatment; however, none of these trends was judged to have physiological consequence. One cannot rule out the possibility that, over a longer treatment period, these trends might indeed achieve proportions of clinical importance. However, by the absence of detrimental physiological responses within the limits of the study, the relative safety of oral ingestion of sodium chlorite was demonstrated.
Executive summary:

To assess the relative safety of chronically administered chlorine water disinfectants in man, a controlled study was undertaken. The clinical evaluation was conducted in the three phases common to investigational drug studies. Phase I, a rising does tolerance investigation, examined the acute effects of progressively increasing single doses of chlorine disinfectants to normal healthy adult male volunteers. Phase II considered the impact on normal subjects of daily ingestion of sodium chlorite at a concentration of 5 mg/L for twelve consecutive weeks. Persons with a low level of glucose-6-phosphate dehydrogenase may be expected to be especially susceptible to oxidative stress; therefore, in Phase III, sodium chlorite at a concentration of 5 mg/L was administered daily for twelve consecutive weeks to a small group of potentially at-risk glucose-6-phosphate dehydrogenase-deficient subjects. Physiological impact was assessed by evaluation of a battery of qualitative and quantitative tests. The three phases of this controlled double-blind clinical evaluation of sodium chlorite in human male volunteer subjects were completed uneventfully.

There were no obvious undesirable clinical sequellae noted by any of the participating subjects or by the observing medical team. In several cases, statistically significant trends in certain biochemical or physiological parameters were associated with treatment; however, none of these trends was judged to have physiological consequence. One cannot rule out the possibility that, over a longer treatment period, these trends might indeed achieve proportions of clinical importance. However, by the absence of detrimental physiological responses within the limits of the study, the relative safety of oral ingestion of sodium chlorite was demonstrated.