Бензиловый спирт синонимы

Abstract

Benzyl alcohol (CASRN: 100-51-6) is a clear, colorless liquid at room temperature that has gained broad use in commerce due to a wide range of advantageous properties including comparatively moderate toxicity, high polarity, solubility in water and other solvents, low vapor pressure, and faint pleasant aromatic scent. While its major commercial uses are in fragrances and in industrial processes as solvent and textile dye assistant, benzyl alcohol enjoys many other uses. It is an ingredient commonly found in consumer and healthcare products, and arises as a natural product in plants, fruits, tea, and wines. The principal routes of occupational exposure to benzyl alcohol are via inhalation and dermal contact where benzyl alcohol is produced or used. The general population may be exposed to this compound via dermal contact with consumer products, and to a lesser extent via inhalation of ambient air, ingestion of food, and drinking water. Its toxicity became notable when it was associated with the deaths of preterm infants. Chronic cancer studies have proven negative, as have the majority of genotoxicity studies. In humans, exposure to benzyl alcohol can produce irritation, allergic contact dermatitis, and central nervous system depression leading to convulsion, paralysis, and respiratory failure. Low concentrations of benzyl alcohol are used as a bacteriostatic agent in intravenous preparations. In healthy individuals, it is rapidly oxidized to benzoic acid in the liver, and then it is excreted as hippuric acid (glycine conjugate). Only one state (Florida, USA) has set minimum contamination level goal as 2100 μg l⁻¹ in drinking water. Orally administered LD₅₀ doses for this compound range from 1360 to 1580 mg per kg body weight and 1230–3120 mg per kg bodyweight for mice and rats respectively. The main treatment for benzyl alcohol toxicity is discontinuation of the exposure and supportive care. Hemodialysis may enhance the elimination of benzyl alcohol and its metabolites and may also be useful to help correct severe metabolic acidosis.

General information

Benzyl alcohol is commonly used as a preservative in multidose injectable pharmaceutical formulations. For this purpose, concentrations in the range of 0.5–2.0% are used and the whole amount of benzyl alcohol injected is generally very well tolerated. Concentrations of 0.9% are used in Bacteriostatic Sodium Chlorine (USP), which is often used in the management of critically ill patients to flush intravascular catheters after the addition of medications or the withdrawal of blood, and in Sterile Bacteriostatic Water for injection (USP), used to dilute or reconstitute medications for intravenous use. The content of benzyl alcohol in a lot of injectable pharmaceutical formulations needs to be considered carefully. The view still taken in many countries that the additives and excipients in medicines are trade secrets must be deplored. The duty to declare them is only imposed in some countries.

The toxic effects of benzyl alcohol include respiratory vasodilatation, hypertension, convulsions, and paralysis.

Treatment of Choice

Benzyl Alcohol

Benzyl Alcohol 5% (Ulesfia Lotion).

Benzyl alcohol lotion is approved by the US Food and Drug Administration (FDA) for children 6 months and older and may be the treatment of choice. The quantity applied must be sufficient to saturate the hair completely for 10 minutes. FDA phase 3 drug trials comparing the product to vehicle placebo for two 10-minute applications showed it to be safe and effective (P < 0.001).³ Toxicity has been reported with intravenous exposure to benzyl alcohol in neonates and low birth weight infants. The “gasping syndrome” (characterized by central nervous system depression, metabolic acidosis, and gasping respirations) has been associated with benzyl alcohol dosages of >99 mg/kg/day. The product label indicates that benzyl alcohol was quantified in a single plasma sample in 4 out of 19 subjects (21%) after topical application, including 3 subjects in the 6 months to 3 years age group at 0.5 hour after treatment. The level ranged from 1.97 to 2.99 µg/mL—levels unlikely to produce toxicity. With topical use, benzyl alcohol can induce histamine release and produce scalp itching and eye irritation.

Nervous System

Benzyl alcohol is an aqueous soluble preservative widely used in injectable pharmaceutical preparations as well as in cosmetic products. Although toxic in neonates and infants, it is generally recognized as safe by the FDA at concentrations up to 5% in adults. The effect of benzyl alcohol present as preservative in bacteriostatic normal saline has recently come under investigation when administered via intraarticular injection. Patients who undergo MRI-based arthrography for standard clinical indications are commonly administered a contrast agent like gadolinium diluted in bacteriostatic saline. Clifford et al. recently performed a clinical study to prospectively evaluate the effect of benzyl alcohol present in saline, on post-procedural pain in patients following direct shoulder arthrography [13c].

In this study 138 patients underwent MR arthrography. Using the Wong-Baker Faces Pain Scale, patients were asked to report their shoulder pain level before and after the procedure and also followed up for 2 days after the procedure. A control group of 62 patients received preservative-free saline solution as contrast agent diluent while a test group of 62 patients received saline containing 0.9% benzyl alcohol. The patients were randomized for this study and the effect of preservative vs. control on pain level was estimated with multiple regression.

The observed pain scale scores were significantly higher (0.79 units, P = 0.0382) with benzyl alcohol preservative compared with control (saline). In both study groups, the pain scale scores decreased slightly after the procedure, increased by roughly 1 unit over baseline for the test group and 0.3 unit over baseline for the control group by 6 hours after the procedure, were 0.50 unit over baseline for the test group and 0.12 unit over baseline for the control group at 24 hours, then fell to be slightly greater than baseline at 48 hours with benzyl alcohol and slightly less than baseline without benzyl alcohol. These trends over time were highly significant (P < 0.0001).

This report provides evidence of significantly increased patient discomfort when using normal saline preserved with benzyl alcohol as a diluent. This new study is consistent with similar findings reported in the literature [14c, 15c]. Therefore it warrants further investigation and caution while choosing the appropriate diluent for systemic administration of drugs or diagnostic agents.

Benzyl alcohol

Observational studies Neonatal exposure to benzyl alcohol and propylene glycol, pharmaceutical excipients present in parenteral medications, has been studied retrospectively in a neonatal and pediatric intensive unit in a tertiary care university hospital [8^c]. In 170 randomly selected episodes of exposure to parenteral medications containing benzyl alcohol (n = 88) or propylene glycol (n = 82), there were a wide range of cumulative doses of the excipients. The median cumulative dose was 4.5 mg/kg/day for benzyl alcohol and 205mg/kg/day for propylene glycol. Those who received medications by continuous infusion received significantly higher doses of excipients than those who received medications intermittently. In this subset of patients, median cumulative doses were about 21 and 180 times the acceptable daily intake of benzyl alcohol and propylene glycol respectively and exceeded the doses above which toxicity has been reported in infants. There was no significant correlation between the duration of administration and cumulative excipient exposure. The authors emphasized that critically ill neonates, especially those who received medications by continuous infusion, are at risk of exposure to benzyl alcohol and propylene glycol at potentially toxic doses during routine administration.

Important Notes

Observational studies

Exposures to the potentially harmful pharmaceutical excipients benzyl alcohol and propylene glycol present in parenteral medications routinely administered in neonatal and pediatric intensive care units have been examined in 170 episodes of exposure to parenteral medications [62^C]. Patients who received medications by continuous infusion received significantly higher doses of the excipient than those who received medications intermittently. In this subset of patients, the median cumulative doses of the excipients were about 21 and 180 times the acceptable daily intakes of benzyl alcohol and propylene glycol respectively, and exceeded the doses above which adverse reactions have been reported in infants. There was no significant correlation between the duration of medication administration and cumulative excipient exposure. The authors concluded that critically ill neonates, especially those receiving medication by continuous infusion, are at risk of being exposed to benzyl alcohol and propylene glycol at potentially toxic doses during routine medication administration.

1.4 Solubility characteristics, partition coefficient, and ionization constant

The solubility of candesartan cilexetil in benzyl alcohol is 205 mg/mL, and its solubility in water is less than 5 × 10^− 5 mg/mL [7]. The partition coefficient of candesartan cilexetil at pH 1.1, 6.9, and 8.9 exceeds 1000 [7,8].

The pK_a of candesartan cilexetil is 6.0 [8]. In addition, Cagigal et al.[9] determined the pK_a value with graphical method (consisting of the inflexion point, first derivative, second derivative, and curve-fitting methods) and a numerical method (using the LETAGROP SPEFO software package). The pK_a values were found to be 6.3 (inflexion point, first derivative, second derivative), 5.9 (curve-fitting method), and 6.0 (LETAGROP SPEFO).