Investigations of the Formation of Bis-Chloromethyl Ether in Simulated Hydrogen Chloride-Formaldehyde Atmospheric Environments

Kallos, George J.; Solomon, Richard A.

doi:10.1080/0002889738506883

Cited by 42 publications

(6 citation statements)

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“…The reaction may occur in air (Van Duuren et al 1969). Measurable workplace concentrations of BCME have been found in atmospheric reaction mixtures containing formaldehyde and hydrogen chloride (Frankel et al 1974;Kallos and Solomon 1973). Although BCME is an "intense, immediate irritant" (Nelson 1976), it provides insufficient warning to prevent human cancer from BCME exposure in the workplace (and even less warning from small amounts likely produced in residential settings).…”

Section: Figure 2 Structural Formula Of S-2 (S-421mentioning

confidence: 99%

Octachlorodipropyl ether (s-2) mosquito coils are inadequately studied for residential use in Asia and illegal in the United States.

Krieger

Dinoff

Zhang

2003

Environ Health Perspect

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Children and their parents in residences are often protected by insecticides from nuisance and disease-bearing mosquitoes. The annual worldwide consumption of the four major types of residential insecticide products--aerosols, mosquito coils, liquid vaporizers, and vaporizing mats--is in the billions of units. Mosquito coils are burned indoors and outdoors in East Asia and to a limited extent in other parts of the world, including the United States. Coils consist of an insecticide/repellant, organic fillers capable of burning with smoldering, binder, and additives such as synergists, dyes, and fungicide. The number of coil users in China is in the millions. In Indonesia alone, an estimated seven billion coils are purchased annually. Coils containing pyrethroid insecticides, particularly d-allethrin, may contain octachlorodipropyl ether (S-2, S-421) as a synergist or active ingredient. Use of those coils likely exposes children and adults to some level of bis(chloromethyl)ether (BCME). BCME is formed from formaldehyde and hydrogen chloride, combustion products formed from the slow smoldering (about 8 hr/coil) of the mosquito coils. Because BCME is an extremely potent lung carcinogen, the nature and extent of prolonged exposures that recur in homes during the mosquito season in tropical regions must be evaluated with respect to health. In a small analytical study, coils purchased in Indonesia and in the United States contained highly variable amounts of S-2. Some coils that contained S-2 were not labeled, making it impossible for consumers to make an informed decision about coil contents. Mosquito coils containing S-2 are unregistered, and their use is illegal in the United States. Indoor air monitoring under conditions that represent conditions of use in tropical settings and epidemiology to assess health impacts of coil use are essential to permit responsible regulatory decisions regarding continuing S-2 use.

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Section: Figure 2 Structural Formula Of S-2 (S-421mentioning

confidence: 99%

Octachlorodipropyl ether (s-2) mosquito coils are inadequately studied for residential use in Asia and illegal in the United States.

Krieger

Dinoff

Zhang

2003

Environ Health Perspect

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“…The potential for BCME formation increases with the amount of available formaldehyde and chloride (in both gaseous and liquid phases), according to the reaction 2CI + 2HCHO + 2H -»• CICH 2 -OCH 2 CI + H 2 O (Kallos and Solomon, 1973;Rohm & Haas, 1972).…”

Section: Haloethersmentioning

confidence: 98%

Potential carcinogenic and mutagenic industrial chemicals. I. Alkylating agents

Fishbein¹

1980

Journal of Toxicology and Environmental Health

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“…The concentration dependence described by Frankel et al was supported in a study by Kallos and Solomon who did not find any detectable amounts of BCME in the vapor phase or aqueous phase at HCl and formaldehyde concentrations of up to 500 ppm. 28 A maximum of 48 ppb BCME was detected starting from concentrations as high as 3000 ppm formaldehyde and 10,000 ppm HCl. Those findings were later corroborated by a computational study by Bock et al who did not find any "evidence that BCME forms spontaneously whenever formaldehyde and hydrogen chloride coexist in humid air".…”

Section: ■ Introductionmentioning

confidence: 99%

Toward a Scalable Synthesis and Process for EMA401, Part I: Late Stage Process Development, Route Scouting, and ICH M7 Assessment

Hardegger

Mallet

Bianchi

et al. 2020

Org. Process Res. Dev.

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We present the enantioselective synthesis of sodium (3S)-5-(benzyloxy)-2-(diphenylacetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (EMA401, olodanrigan), an angiotensin II type 2 antagonist. The manuscript features the process optimizations of the end game used for late phase clinical supplies, an overview of synthetic strategies identified in a route scouting exercise to a key intermediate phenylalanine derivative, and the analytical control strategy of the potentially formed highly toxic impurity bis(chloromethyl) ether (BCME). Starting from the phenylalanine derivative, we describe the optimizations of the end game from early phase to late phase processes with consequent improvements in the PMI factor. This sequence includes a Pictet–Spengler cyclization and an amide coupling as the last bond-forming steps, and the manufacturing process was successfully implemented on a 175 kg scale in a pilot plant setup. The modified process conditions eliminated one step by in situ activation of the carboxylic acid, avoided the REACH listed solvent DMF, and resulted in a PMI improvement by a factor of 3. In the final crystallization, a new, thermodynamically more stable modification of the drug substance was found in the complex solid-state landscape of EMA401 during an extensive polymorph screening. A process suitable for large-scale production was developed to prepare the new polymorph, avoiding the need of any special equipment such as fluidized bed drying required in the early phase process. In the second section, some of the synthetic approaches investigated for the route scouting of the phenylalanine derivative key intermediate are presented. To conclude, we discuss the analytical control strategy for BCME, the formation of which, due to the simultaneous presence of HCl and CH2O in the Pictet–Spengler cyclization, could not be ruled out. The BCME purge factor calculations using the tools of ICH M7 control option 4 are compared to actual results from spiking experiments.

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Investigations of the Formation of Bis-Chloromethyl Ether in Simulated Hydrogen Chloride-Formaldehyde Atmospheric Environments

Cited by 42 publications

References 0 publications

Octachlorodipropyl ether (s-2) mosquito coils are inadequately studied for residential use in Asia and illegal in the United States.

Octachlorodipropyl ether (s-2) mosquito coils are inadequately studied for residential use in Asia and illegal in the United States.

Potential carcinogenic and mutagenic industrial chemicals. I. Alkylating agents

Toward a Scalable Synthesis and Process for EMA401, Part I: Late Stage Process Development, Route Scouting, and ICH M7 Assessment

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