50-53-3

Hazard

Toxic by ingestion.

Contact allergens

This phenothiazine with sedative properties is used in human medicine and induced contact dermatitis in nurses or those working in the pharmaceutical industry. It is also used in veterinary medicine to avoid mortality of pigs during transportation. It is a sensitizer and a photosensitizer.

Synthesis

Chlorpromazine, 2-chloro-10-(3-dimethylaminopropyl)phenothiazine, is synthesized in an analogous manner, except by alkylation of 2-chlorophenothiazine with 3-dimethylaminopropylchloride.

Environmental Fate

Acute and chronic toxicity due to chlorpromazine generally manifests as an extension of normal pharmacological activity. The precise mechanism of action of chlorpromazine, and other phenothiazines, is unknown; however, it is thought to primarily involve antagonism of dopaminergic (D2) neurotransmission at synaptic sites and blockade of postsynaptic dopamine receptor sites at the subcortical levels of the reticular formation, limbic system, and hypothalamus. This activity contributes to chlorpromazine’s extrapyramidal reactions. Chlorpromazine also has strong central and peripheral activity directed against adrenergic receptors and weak activity against serotonergic, histaminic (H1), and muscarinic receptors. Chlorpromazine has slight ganglionic blocking action. Chlorpromazine is known to depress vasomotor reflexes medicated by the hypothalamus and/or brain stem; inhibit release of growth hormone; antagonize secretion of prolactin release-inhibiting hormone; and reduce secretion of corticotropin-regulatory hormone. Chlorpromazine also has direct effects on cardiac myocytes; it can induce early after-depolarizations, block depolarizing sodium channels, and cause significant prolongation of the QTc interval. Chlorpromazine may be irritating to eyes, mucous membranes, and skin. Contact and inhalation should be avoided.

Metabolic pathway

The in vivo photodegradation of chlorpromazine in rat skin exposed to UV-A results in the formation of promazine and 2-hydroxypromazine in irradiated rats, but not in the skin of rats kept in the dark. Chlorpromazine sulfoxide is a major metabolite of chlorpromazine, found in smaller quantity in the skin of irradiated rats compared with those kept in the dark. Chlorpromazine sulfoxide is not a photoproduct of chlorpromazine under the experimental conditions.

Toxicity evaluation

Chlorpromazine exists as both a vapor and particulate at ambient atmospheric conditions. Chlorpromazine vapor is degraded by photochemically produced hydroxyl radicals with an estimated half-life of 1.6 h. Chlorpromazine particulate is removed by wet or dry deposition. Chlorpromazine is likely to be immobile in soil (Koc 9900, pKa 9.3) and to adsorb to sediment if released into water. It is not expected to volatilize from soil or water. There is high potential for bioconcentration.

Definition

ChEBI: A substituted phenothiazine in which the ring nitrogen at position 10 is attached to C-3 of an N,N-dimethylpropanamine moiety.

Brand name

Thorazine (GlaxoSmithKline).