Phenothiazine

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
- Two healthy adult male volunteers
- Single oral administration of 6mg [35S]-phenothiazine per kg body weight
- RESULT: Excretion via faeces (2/3) and urine (1/3); identified metabolites were in agreement with other species, urinary half life (biphasic) was estimated to be 6-16hrs; complete recovery of radioactivity was achieved over the study period of five days

Additional information

During the literature research on phenothiazine one review was found (The MAK Collection for Occupational Health and Safety, Volume 46, 2009) summarising key elements of absorption, distribution, metabolism and excretion (ADME scheme) of phenothiazine. Resorption of phenothiazine from the gastrointestinal tract after oral application is fast, as can be demonstrated by rapid excretion via urine. However, due to the low water solubility, resorption is dependent on particle size, preparation (e.g. vehicle), and is usually not quantitative. In the study reported as part of the IUCLID5 dossier, [³⁵S]-phenothiazine was orally administered at a dose of 6 mg/kg body weight to two healthy volunteers (Mitchell et al., 2002). 32 % of administered radioactivity was found in the urine collected over a period of 5 d (with 25.7 – 27.2 % being excreted within 24 hrs), while 68 % of radioactivity was found in the faeces. Previous studies (cited within The MAK Collection for Occupational Health and Safety, Volume 46, 2009) estimated the rate of resorption for man to be around 50 % (single dose, orally administered ca. 43 mg/kg body weight). Rabbits, guinea pigs, hamster, rats and mice were estimated to have a resorption rate of 18 -44 % after oral application (study cited within The MAK Collection for Occupational Health and Safety, Volume 46, 2009).

No quantitative information on dermal absorption is available. However, there is one study from DeEds et al. (DeEds et al., 1940, cited within The MAK Collection for Occupational Health and Safety, Volume 46, 2009), where a 2 % alcoholic solution was directly applied on the skin of the forearms of three volunteers. No signs of irritation or phototoxic reactions were found after immediate UV-radiation. Orally administered phenothiazine as well as its metabolite 7-OH-3H-phenothiazine-3-one resulted in a higher sensitivity against UV radiation. Because UV radiation took place immediately after dermal application the absence of recognisable reactions is no proof of lack of dermal resorption. Possibly, there was not enough time for metabolism to form the photo-reactive metabolites.

In two other studies cited within the MAK report, a phenothiazine-saturated aqueous solution was applied to the hands and forearms. According to these studies, less than 0.0002 mg of phenothiazine were absorbed (The MAK Collection for Occupational Health and Safety, Volume 46, 2009).

Via blood stream phenothiazine reaches all organs where it binds to proteins (Mitchell et al., 1982, cited in The MAK Collection for Occupational Health and Safety, Volume 46, 2009). Other studies found that 11 mg [³⁵S]-phenothiazine per kg body weight orally administered to Wistar rats were found in fat tissue (0.56 mg/kg fresh weight), liver (0.32 mg/kg fresh weight) and kidneys (0.15 mg/kg fresh weight). 48 hrs p.a. still 0.5 mg/kg fresh weight were found in the fat tissue, while 0.036 µg/mL were found in blood plasma (studies cited in The MAK Collection for Occupational Health and Safety, Volume 46, 2009). Four metabolism studies used [¹⁴C]-phenothiazine, orally administered at a dose of 1.5 mg/kg body weight. The highest amount of [¹⁴C] was found in the liver, while some [¹⁴C]-labelled substances were found to be excreted via urine. It was also noted that the highest concentrations of [¹⁴C] were found 2 hrs p.a. in liver, blood, plasma, and cells (studies cited in The MAK Collection for Occupational Health and Safety, Volume 46, 2009).

Tadros and Wahab investigated phenothiazine after intravenous injection found that it was taken up by the brain, especially by the brain stem, depending on the species after different periods of time. Cerebrospinal fluid was not investigated (Tadros and Wahab, 1962, cited within The MAK Collection for Occupational Health and Safety, Volume 46, 2009).

Excretion after resorption is independent from the examined species mainly via urine and to a much lesser extent via bile. Renal excretion is following biphasic kinetics, with the larger part being excreted within a few hours after resorption. Complete excretion takes place over a period of 1 -2 days, possibly due to redistribution or reabsorption after biliary excretion (enterohepatic circulation). Half life is estimated to be 6 hrs and 16 hrs. Excretion via exhalation does not play a role for phenothiazine (several studies cited within The MAK Collection for Occupational Health and Safety, Volume 46, 2009).

After absorption phenothiazine is metabolised by oxidation of the ring-system and conjugation of the nitrogen. However, the tricyclic ring-system is maintained. In man the main metabolites found in urine (following oral application) are conjugates of phenothiazine, probably phenothiazine-N-glucorinide, phenothiazine-3-one and traces of phenothiazine-5-oxide, while only not conjugated phenothiazine was found in faeces. Faeces of experimental animals contained traces of 3H-phenothiazine-3-one, 7OH-3H-phenothiazine-3-one and phenothiazine-5-oxide. Metabolism is mainly facilitated by cytochrome P450 isoenzymes and not by flavinmonooxygenase isoenzymes. Differences between species are negligible. However, in rabbits, rats, and mice one additional metabolite, the glucorinide of 7-OH-3H-phenothiazine-3-one, was identified in urine (Mitchell et al., 2002 and 1982, cited within The MAK Collection for Occupational Health and Safety, 2009).

Discussion on bioaccumulation potential result:

Aim of the present study was not to evaluate a possible bioaccumulation potential of phenothiazine but to determine the routes of excretion and metabolism in man. Since this study was conducted with human volunteers, no histopathological information on affected organs is available. However, as a result of this study, all radioactivity could be recovered by either faeces or urine. This is of course is not a proof of a lack of bioaccumulative potential, but is some evidence that after single exposure only negligible amounts of phenothiazine remained in the body of the volunteers if at all. The authors point out in their publication that persistence observed in some animals as measured be trace amount in their urine may be related to the relatively large doses which these animals received. The effective formation of a slow moving bolus within the gut and the slight but constant absorption from this reservoir mimics a multiple or continuous dosing situation which would persist for many days following the original oral administration. Most of the administered phenothiazine is excreted via faeces in form of phenothiazine (or as phenothiazine sulphoxide being reduced to phenothiazine). Urinary excretion accounts for about one third of the administered phenothiazine. About 90% of urinary excreted phenothiazine consist of conjugated phenothiazine, the remaining 10% do consist of phenothiazone, phenothiazine sulphoxide, or thionol. This pattern is observed in other species as well, however some conjugates found in animals seem to be absent in man.