National Toxicology Program

National Toxicology Program
http://ntp.niehs.nih.gov/go/8170

Executive Summary Methylene Blue: Table of Contents

NATIONAL TOXICOLOGY PROGRAM

EXECUTIVE SUMMARY OF SAFETY AND TOXICITY INFORMATION

METHYLENE BLUE

CAS Number 61-73-4/7220-79-3

November 30, 1990

Submitted to:

NATIONAL TOXICOLOGY PROGRAM

Submitted by:

Arthur D. Little, Inc.



Executive Committee Draft Report


TABLE OF CONTENTS

  1. NOMINATION HISTORY AND REVIEW

  2. CHEMICAL AND PHYSICAL DATA

  3. PRODUCTION/USE

  4. EXPOSURE/REGULATORY STATUS

  5. TOXICOLOGICAL EFFECTS

  6. STRUCTURE ACTIVITY RELATIONSHIPS

  7. REFERENCES

APPENDIX I, ON-LINE DATA BASES SEARCHED

APPENDIX II, SAFETY INFORMATION


OVERVIEW1

Nomination History: Methylene blue was nominated for carcinogenicity testing by the National Cancer Institute (NCI) in 1989. The nomination was based on the numerous uses of this compound and the potential for high exposure in animals and humans.In addition, the NCI noted the lack of long-term toxicity data,including epidemiological studies on methylene blue, as well as the inadequate animal data on this compound.

Chemical and Physical Properties: Methylene blue isa dark green powder or crystalline solid. This odorless compound decomposes at 100°-110° C. Methylene blue is incompatible with strong oxidizing and reducing agents.

Production/Uses/Exposure: Methylene blue is used therapeutically in the treatment of methemoglobinemia and cyanide poisoning. Other medicinal uses of methylene blue include the management of chronic urolithiasis and treatment of cutaneous viral infections as well as the treatment of manic-depressive psychosis. As a dye/stain,methylene blue is used in surgical and medical marking and as an indicator dye, a bacteriologic stain, a food colorant (see note) and adye for cotton and wool. Data from the National Occupational Exposure Survey (NOES) indicate that 69,563 workers, including 42,026 female employees were potentially exposed to methylene blue between 1981and 1983. No data were found on environmental exposure to methyleneblue. In addition, there is no OSHA permissible exposure limit, ACGIH-recommended threshold limit value or NIOSH-recommended exposure limit for methylene blue.

Toxicological Effects:

Human: Acute exposure to methylene blue has been found to cause increased heart rate, cyanosis, vomiting, shock, Heinzbody formation, jaundice, quadriplegia and tissue necrosis in humans. In addition, corneal and conjunctival injury has been reported following acute exposure to this compound. Intravenous administration of methylene blue has been found to cause bluish discoloration of the urine and stool. Numerous case reports were found in the literature describing the effects of methylene blue on the newborn, following the injection of this compound into the amniotic fluid before delivery. At birth, many of the infants reportedly had deep blue stained skin and voided blue urine. Other symptoms including respiratory distress, hyperbilirubinemia, methemoglobinemia,Heinz body formation and increased heart rate occurred after birth.No data were found on the prechronic effects of methylene blue in humans. Chronic application of methylene blue-containing eyedrops has been found to result in staining of the bulbar and palpebralconjunctiva, the lid margins and slight staining of the cornealepithilium. No other data were found on the chronic/carcinogenic effects of methylene blue in humans. Methylene blue has been found to cause an elevation in follicle stimulating hormone and estradiol in fallopian tube secretions, and uterine and peritoneal fluids in vitro. In addition, methylene blue was found to significantly inhibit sperm motility in vitro in samples prepared from human semen. No other studies were found on the reproductive effects of methylene blue in humans.

Animal: Numerous reports were found in the literature describing the association between methylene blue and the formation of Heinz bodies in animals. Intraperitoneal administration of methylene blue has been found to induce Heinz body formation in cats, dogs, mice and rabbits. In cats, methylene blue was observed to cause bluish stained skin, anemia, discolored urine, dyspnea,depression, respiratory stimulation and increased blood pressure.In addition, methylene blue has been found to cause corneal and conjunctival injury in rabbits. No data were available on the prechronic, effects of methylene blue in animals. Administration of this compound at a concentration of 4% in the diet for 2 years was not found to induce tumor formation. Methylene blue has been found to inhibit the ability of mouse embryos to grow and cleave in vitro. This compound also caused an increase in implantations and resorptions in litters born to rats fed diet containing methyleneblue.

Genetic Toxicology: Methylene blue has been found to be mutagenic to Micrococcus aureus. In addition, methyleneblue was mutagenic to Salmonella typhimurium in the presence and absence of metabolic activation. This compound was mutagenicto Escherichia coli in the microsuspension and DNA-cellbinding assays. There are conflicting reports concerning the mutagenicity of methylene blue in Bacillus subtilis. One author reported that methylene blue was mutagenic to B. subtilis in the rec-assay. However, methylene blue was non-mutagenic to this bacteria in another study. Several reports were found concerning mutation induction via irradiation with visible light, in the presence of methylene blue. Photodynamic mutagenesis in the presence of methylene blue has been induced in bacteriophage SerratiaphageX, Escherichia coli and Salmonella typhimurium.Methylene blue was non-mutagenic to Chinese hamsters, in vivo.In addition, this compound was non-mutagenic in cultured Chinesehamster ovary cells and lung fibroblasts. Methylene blue did not induce mutagenic effects in Drosophila melanogaster.

Structure Activity Relationships: No information was found on structure activity relationships for methylene blue.


  1. NOMINATION HISTORY AND REVIEW

    1. Nomination History
    2. Chemical Evaluation Committee Review
    3. Board of Scientific Counselors Review
    4. Executive Committee Review

    1. Chemical Identifiers

      Structure

      METHYLENE BLUE

  2. CHEMICAL AND PHYSICAL DATA
    1. Source: National Cancer Institute [NCI, 1989, a, b]

    2. Date: March, 1989

    3. Recommendations: Carcinogenicity

    4. Priority: High

    5. Rationale/Remarks:

      • Numerous uses: treatment of manic-depressive illness and nitrate poisoning, anti-tumorigenic activity, in vivo detection of bladder tumors

      • Potential for high exposure in humans

      • No FDA long-term studies on methylene blue

      • Lack of epidemiological studies

      • Available animal studies inadequate by current standards

      • Numerous short-term tests with varying results

    1. Date of Review: September 12, 1990

    2. Recommendation:

      • Carcinogenicity

      • Reproductive and teratogenicity studies

      • Determine whether the chemical crosses the blood/brain barrier

    3. Priority: High

    4. NTP Chemical Selection Principle(s): 3, 4, 6

    5. Rationale/Remarks:

      • Widespread uses

      • Some medical and veterinary applications of the chemical have not been approved by FDA

      • Potential for exposure

      • Lack of carcinogenicity data

    1. Date of Review: October 15, 1990

    2. Recommendations:

      • Carcinogenicity

      • Reproductive Studies

    3. Priority:

      • High for carcinogenicity

      • Moderate for reproductive studies

    4. Rationale/Remarks:

      • Widely used compound

      • Potential for exposure

      • Lack of carcinogenicity data

      • Previous neurotoxicity studies are sufficient

    1. Date of Review:

    2. Decision:

CAS No. 61-73-4 (anhydrous)
7220-79-3 (trihydrate)
RTECS No. SO5600000M
Molecular formula: C16H18H3SCl (anhydrous) Molecular weight: 319.85
C16H18H3SCl.3H2O (trihydrate) 373.90

  • Synonyms and Trade Names

    Synonyms: Phenothiazine-5-ium, 3,7-bis(dimethylamino)-,chloride (9CI); C.I. Basic Blue 9 (8CI); methylthionine chloride;methylthioninium chloride; tetramethylthionine chloride; swissblue; aizen methylene blue; C.I. 52015
    Trade Names:Desmoid piller, Desmoidpillen, Methylene Blue,Panatone, Urolene Blue, Vitableu

  • Chemical and Physical Properties

    Property:Value or Status:
    Description: Dark green powder or crystals [Weast, 1988]with bronze luster [Budavari, 1989]/ Odorless [Budavari, 1989]
    Melting Point: Decomposes at 100°-110° C [Kirk-Othmer,1978]
    Boiling Point: No data was found
    Density/Specific Gravity: No data was found
    Refractive Index: No data was found
    Solubility in Water: Water (1 gram in 25 ml of water [Budavari, 1989]);crystallizes with 3 and 5 mols of water [Budavari, 1989]
    Solubility in other Solvents: Chloroform, alcohol [Weast, 1988] (1 gramin 65 ml alcohol) [Budavari, 1989], glycerol,glacial acetic acid, 0.5% soluble in acetone [Kirk-Othmer, 1978]
    Log Octanol/Water Partition Coefficient: No data was found
    Reactive Chemical Hazards:
    • Incompatible with caustic alkali,dichromates, alkali iodides, reducing agents [Budavari, 1989]
    • Incompatible with strong oxidizing agents [Lenga, 1988]
    • Decomposition products include toxic fumes of carbon monoxide,nitrogen oxides, sulfur oxides, and hydrogen chloride gas [Lenga,1988; Sax, 1989]
    Flammability Hazards: No data was found (non-combustible under normal conditions)

       
  •  
     
    NTP is located at the National Institute of Environmental Health Sciences, part of the National Institutes of Health.