Potential impurities in drug substances: Compound-specific toxicology limits for 20 synthetic reagents and by-products, and a class-specific toxicology limit for alkyl bromides.

This paper provides compound-specific toxicology limits for 20 widely used synthetic reagents and common by-products that are potential impurities in drug substances. In addition, a 15 µg/day class-specific limit was developed for monofunctional alkyl bromides, aligning this with the class-specific limit previously defined for monofunctional alkyl chlorides. Both the compound- and class-specific toxicology limits assume a lifetime chronic exposure for the general population (including sensitive subpopulations) by all routes of exposure for pharmaceuticals. Inhalation-specific toxicology limits were also derived for acrolein, formaldehyde, and methyl bromide because of their localized toxicity via that route. Mode of action was an important consideration for a compound-specific toxicology limit. Acceptable intake (AI) calculations for certain mutagenic carcinogens assumed a linear dose-response for tumor induction, and permissible daily exposure (PDE) determination assumed a non-linear dose-response. Several compounds evaluated have been previously incorrectly assumed to be mutagenic, or to be mutagenic carcinogens, but the evidence reported here for such compounds indicates a lack of mutagenicity, and a non-mutagenic mode of action for tumor induction. For non-mutagens with insufficient data to develop a toxicology limit, the ICH Q3A qualification thresholds are recommended. The compound- and class-specific toxicology limits described here may be adjusted for an individual drug substance based on treatment duration, dosing schedule, severity of the disease and therapeutic indication.

[Transition of Psychotropic Drugs in Japanese Pharmacopoeia (JP) (Part 15). Transitions in the Standards and Test Methods of Potassium Bromide in JP I (1886) and JP X VI (2011), and Comparison between the USP and BP].

In mental clinics, bromide agents such as potassium bromide were often once used as therapeutic drugs to treat psychiatric disorders. They were also given as hypnotic, sedative and antiepileptic medicines. However, the appearance of new medicines has resulted in them not being used for these purposes in recent years. Potassium bromide is still continuously listed in today's JP and BP. This suggests that it maintains value as a basic medicine for treating mental disorders in the history of psychotropic medicines. However, regarding the standards and test methods for potassium bromide in the present JP, as a result of a comparison between the USP of the same age, BP and EP, a gap is seen, and this is very regrettable. The exchange of art and scientific information related to medical sciences with foreign countries is becoming more active today. Therefore, scholarly information overseas should be collected and reflected in the standards and test methods for potassium bromide adopted in the JP of Japan. The author believes that the standards and test methods comparable to those at the international level should introduced. On the other hand, potassium bromide was recetnly relisted by USP29 (2006) for the first time in approximately 50 years. Moreover, instrumental analysis was introduced as part of the test methods in BP2013; that is, an epoch-making revision was made in terms of test methods. It is assumed from this that there is a sign of new change regarding the existence of potassium bromide as hypnotic, sedative and antiepileptic medicines, and its utility value. It is believed that the sign of change in view of the utility value and pharmacological evaluation probably arose with the new clinical knowledge that potassium bromide was used to treat a baby seriously ill with myoclony epilepsy, as well as to treat a dog with epilepsy.

Oil production and groundwater quality in the Edwards-Trinity Plateau Aquifer, Texas.

Chloride concentrations and chloride/bromide ratios from 198 water wells in the Edwards-Trinity Plateau Aquifer were compiled, mapped, and evaluated within the context of regional geology and land use. The study area occupies eight counties in west-central Texas, within which oil production and agriculture are predominant land uses. Samples from 49 wells had chloride concentrations above the 250 mg/l secondary drinking water standard, 22 samples had greater than 500 mg/l chloride, and 9 samples exceeded 1000 mg/l chloride. Of the 22 samples above 500 mg/l chloride, 10 had relatively low chloride/bromide ratios of less than 300, consistent with oilfield brine, and 2 had ratios above 2000, consistent with groundwater impacted by evaporite dissolution. The remaining ten samples had chloride/bromide ratios ranging from 300 to 2000, consistent with partial mixing of unimpaired groundwater with evaporite-laden water. There were no significant correlations between chloride concentration and well depth, inconsistent with contaminants originating at the land surface. Results of this study suggest that evaporite dissolution and oilfield brine locally impact the Edwards-Trinity Plateau Aquifer, but the problem is not regionally pervasive.

MTBE oxidation by conventional ozonation and the combination ozone/hydrogen peroxide: efficiency of the processes and bromate formation.

The present study investigates the oxidation of methyl tert-butyl ether (MTBE) by conventional ozonation and the advanced oxidation process (AOP) ozone/hydrogen peroxide under drinking water treatment conditions. The major degradation products identified were tert-butyl formate (TBF), tert-butyl alcohol (TBA), 2-methoxy-2-methyl propionaldehyde (MMP), acetone (AC), methyl acetate (MA), hydroxyisobutyraldehyde (HiBA), and formaldehyde (FA). The rate constants of the reaction of ozone and OH radicals with MTBE were found to be 0.14 and 1.9 x 10(9) M(-1) s(-1), respectively. The rate constants for the same oxidation processes were also measured for the degradation products TBF, MMP, MA, and HiBA (k(O3-TBF) = 0.78 M(-1) s(-1); k(OH-TBF) = 7.0 x 10(8) M(-1) s(-1); k(O3-MMP) = 5 M(-1) s(-1); k(OH-MMP) = 3 x 10(9) M(-1) s(-1), k(O3-MA) = 0.09 M(-1) s(-1), k(O3-HiBA) = 5 M(-1) s(-1); k(OH-HiBA) = 3 x 10(9) M(-1) s(-1)). Since all compounds reacted slowly with molecular ozone, only the degradation pathway of MTBE with OH radicals has been determined, including the formation of primary degradation products. In experiments performed with several natural waters, the efficiency of MTBE elimination and the formation of bromate as disinfection byproduct have been measured. With a bromide level of 50 microg/L, only 35-50% of MTBE could be eliminated by the AOP O3/H2O2 without exceeding the current drinking water standard of bromate (10 microg/L). The transient concentrations of MTBE and its primary degradation products were modeled using a combination of kinetic parameters (degradation product distribution and rate constants) together with the ozone and OH radical concentration and were in good agreement with the experimental results.