National Toxicology Program

Phenothiazine
CAS NO. 92-84-2

TOXICOLOGICAL DATA SUMMARY

In a human study to evaluate the efficacy of phenothiazine as a urinary antiseptic, oral administration of up to 42900 mg (215 mmol) did not result in adverse dermal reactions. However, oral administration of phenothiazine (750 mg [3.6 mmol]) did sensitize 2 volunteers to a subsequent sunlamp exposure. Skin irritation and discoloration of the hair and fingernails have been reported in workers exposed to phenothiazine. Oral administration of 425 mg/kg phenothiazine (2.13 mmol/kg) for 5 days to a child was lethal. Overdose and accidental exposure to phenothiazine have caused hemolytic anemia, toxic hepatitis, skin photosensitization, and intense pruritus, but not central nervous system depression.

Due to its low water solubility, the rate of absorption of phenothiazine from the gastrointestinal tract is dependent on particle size; the micronized is absorbed rapidly. Phenothiazine is also absorbed through the skin. In large therapeutic doses, phenothiazine is absorbed into the bloodstream and distributed throughout the tissues and also crosses the blood-brain barrier. Transplacental transfer of phenothiazine to the fetus is limited during the early stages of gestation (species not specified), but phenothiazine passes more freely during later stages. In mammals, phenothiazine is excreted in the urine mainly in the conjugated form as phenothiazine-N-glucuronide and leucophenothiazone sulfate. It may take several days or even weeks for near total elimination to occur. The urinary half-life of orally administered phenothiazine ranges from 12 to 18 hours in the horse, 11 to 17 hours in sheep, and is approximately 11 hours in humans.

Phenothiazine is moderately toxic in mammals (oral LD₅₀ 500 to 5000 mg/kg; 2-20 mmol/kg). Acute dermal exposure to phenothiazine caused skin irritation in guinea pigs and rabbits in some studies but not others, while ocular irritation in rabbits was not reported. No adverse effects were observed in rats exposed by inhalation to 200 mg/L (200000 mg/m³; 24500 ppm) phenothiazine for 1 hour. Short-term dermal exposure to phenothiazine caused damage to skin in rabbits, while short-term oral administration to rats, hamsters, rabbits, and dogs caused damage to spleen, liver, kidneys, and/or bone marrow. Phenothiazine significantly enhanced liver regeneration in rats given a partial hepatectomy and a diet containing phenothiazine for 7 days starting 3 days after surgery. Two of four chicks fed phenothiazine in the diet for 30 weeks died before the tenth week.

In an in vitro reproductive/teratological study, phenothiazine caused a significant decrease in the number of myotubes in Drosophila embryonic cells. In vivo, phenothiazine caused an increase in resorptions in pregnant rats treated in the diet for 22 days. However, phenothiazine administered by gavage to pregnant albino mice and pregnant albino rats during gestation days 6-15 was neither fetotoxic nor teratogenic. In hens, there was no significant reduction in egg production when phenothiazine was administered in the diet for 29 weeks.

The incidence of lung tumors was not increased in A/J mice administered phenothiazine i.p. for 4 days (50 mg/kg/day in corn oil; 0.25 mmol/kg/day) and observed for 16 weeks. Neither was the tumor incidence increased in major tissues (not specified) of C57BL/6 C3H/Anf and C57BL/6 AKR hybrid strain mice administered phenothiazine orally from 7 days of age until 18 months of age. Phenothiazine (0.1 mg/kg; 0.5 mol/kg) was administered by gavage from age 7-28 days, and then in the diet (0.20 ppm; 1 mol/kg feed) at age 29 days to 18 months. Fischer rats fed phenothiazine for 20 weeks and terminated 40 weeks later did not exhibit any bladder tumors. However, when co-administered with N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT), phenothiazine significantly enhanced the incidence of carcinoma of the bladder as compared to rats fed FANFT alone.

Phenothiazine decreased the incidence of intestinal and urinary bladder tumors in rats by about 60% when it was administered in the diet with bracken fern for 1 year. In mice bearing Ehrlich tumors, phenothiazine administered i.p. for 10 days decreased tumor weight by 73% after 30 days. In a similar study, however, i.p. injection of phenothiazine for 7 or 10 days to mice bearing Ehrlich tumors had no anticarcinogenic activity.

Phenothiazine was found to be negative for mutagenicity in Salmonella typhimurium and Escherichia coli with or without metabolic activation but positive in mouse lymphoma cells in the absence of metabolic activation only. In vitro, phenothiazine enhanced the induction of DNA damage in human colon adenocarcinoma cells by methotrexate and fluorodeoxyuridine. Also, phenothiazine was found to exhibit antigenotoxic activity, as demonstrated by its ability to reduce, in the presence of metabolic activation, the mutagenic activity of benzo[a]pyrene in S. typhimurium reverse mutation assays and the number of adducts induced by aflatoxin B1 in calf thymus DNA.

There was no difference in the incidence of toxicosis in lambs administered phenothiazine anthelmintic powder in combination with the insecticide Ciovap® and lambs administered Ciovap® alone and phenothiazine did not potentiate the toxic effects of the organophosphorus insecticides malathion, coumaphos, trichlorfon, ronnel (fenchlorphos), crotoxyphos/dichlorvos, crotoxyphos, or crufomate in Hereford and Angus steer and heifer calves. Clinical and pathological signs of toxicity did not differ between rats administered a single dose of a 5:1 mixture containing phenothiazine and Sevin® by gavage and rats administered a single dose of Sevin® alone.