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Nomination Summary for Hydrochlorothiazide (N21407)

Nominated Substances: Hydrochlorothiazide

Nomination Date: 03/19/2014

Nominator: Private Individual

Rationale: Diuretics are widely used by many individuals in order to extend and improve the quality of life through the control of hypertension. A significant percentage of the US population uses hydrochlorothiazide and related compounds for controlling hypertension and other disorders. There is sufficient evidence to raise concern that hydrochlorothiazide is epidemiologically associated with cancers of the skin. There is also sufficient evidence that hydrochlorothiazide is a photosensitizer and would be activated by the UV A in sunlight. Unfortunately, there have been no studies conducted to test directly the hypothesis that UV A irradiation of hydrochlorothiazide will result in skin cancer in animals as a validation of the human epidemiology studies. Studies on the toxicity and carcinogenicity of hydrochlorothiazide have been conducted by the NTP; however, they were conducted without consideration of sunlight as a co-carcinogen. At the recent IARC Working Group meeting, there was much discussion that additional studies need to be conducted to test the carcinogenic potential of hydrochlorothiazide in the presence of UV light. Thus, studies in animals that mimic human exposure to hydrochlorothiazide and sunlight to test the hypothesis that oral hydrochlorothiazide administration with sunlight co-exposure will result in an increased incidence of skin cancer are recommended. These and additional studies would aid health care providers in understanding how to minimize risk to the patient that is receiving hydrochlorothiazide and other thiazides for the treatment of hypertension. For instance, pharmacokinetic studies in the animals should be conducted to compare the distribution and residence-time for hydrochlorothiazide in animal skin versus human skin. Considering that humans take thiazides once or twice daily over prolonged periods of time, and the compounds have rapid serum half lives, these pharmacokinetic studies could then be used to test the hypothesis that sunlight exposure at minimum serum concentrations (e.g., prior to hydrochlorothiazide dosing) would result in a decreased risk skin cancer as compared to the cancer incidence following exposure during the peak hydrochlorothiazide concentration in the skin. This could lead to recommendations that patients take the hydrochlorothiazide at times that would minimize serum and skin levels of the drug during peak sunlight exposure. It is expected that investigation of the pharmacokinetics and mechanism of action could lead to additional suggestions for intervention in the photosensitization of hydrochlorothiazide.

NTP Principles: not specified

Agents and Status

The following information relates to the specific agent and may include history from earlier or later nominations for this same agent.

CASRN: 58-93-5

Agent Name: Hydrochlorothiazide