NHC-CDI Betaine Adducts and Their Cationic Derivatives as Catalyst Precursors for Dichloromethane Valorization

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Abstract

Zwitterionic adducts of N-heterocyclic carbene and carbodiimide (NHC-CDI) are an emerging class of organic compounds with promising properties for applications in various fields. Herein, we report the use of the ICyCDI( p-Tol) betaine adduct ( 1a) and its cationic derivatives 2a and 3a as catalyst precursors for the dichloromethane valorization via transformation into high added value products CH ₂Z ₂ (Z = OR, SR or NR ₂). This process implies selective chloride substitution of dichloromethane by a range of nucleophiles Na ⁺Z ^– (preformed or generated in situ from HZ and an inorganic base) to yield formaldehyde-derived acetals, dithioacetals, or aminals with full selectivity. The reactions are conducted in a multigram-scale under very mild conditions, using dichloromethane both as a reagent and solvent, and very low catalyst loading (0.01 mol %). The CH ₂Z ₂ derivatives were isolated in quantitative yields after filtration and evaporation, which facilitates recycling the dichloromethane excess. Mechanistic studies for the synthesis of methylal CH ₂(OMe) ₂ rule out organocatalysis as being responsible for the CH ₂ transfer, and a phase-transfer catalysis mechanism is proposed instead. Furthermore, we observed that 1a and 2a react with NaOMe to form unusual isoureate ethers, which are the actual phase-transfer catalysts, with a strong preference for sodium over other alkali metal nucleophiles.

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Formaldehyde in the Indoor Environment

Tunga Salthammer, Sibel Mentese, Rainer Marutzky (2010)

1 Introduction 1.1 History Formaldehyde was described in the year 1855 by the Russian scientist Alexander Michailowitsch Butlerow. The technical synthesis by dehydration of methanol was achieved in 1867 by the German chemist August Wilhelm von Hofmann. The versatility that makes it suitable for use in various industrial applications was soon discovered, and the compound was one of the first to be indexed by Chemical Abstracts Service (CAS). In 1944, Walker published the first edition of his classic work Formaldehyde.(1) Between 1900 and 1930, formaldehyde-based resins became important adhesives for wood and wood composites. The first commercial particle board was produced during World War II in Bremen, Germany. Since 1950, particle board has become an attractive alternative to solid wood for the manufacturing of furniture. Particle board and other wood-based panels were subsequently also used for the construction of housing. Adverse health effects from exposure to formaldehyde in prefabricated houses, especially irritation of the eyes and upper airways, were first reported in the mid-1960s. Formaldehyde emissions from particle boards bonded with urea formaldehyde resin were soon identified as the cause of the complaints. As a consequence, a guideline value of 0.1 ppm was proposed in 1977 by the former German Federal Agency of Health to limit human exposure in dwellings. Criteria for the limitation and regulation of formaldehyde emissions from wood-based materials were established in 1981 in Germany and Denmark. The first regulations followed in the United States in 1985 or thereabouts. In Germany and the United States, large-scale test chambers were used for the evaluation of emissions. Although the chamber method is very reliable, it is also time-consuming and expensive. This meant there was a strong demand for simple laboratory test methods.(2) 1.2 Formaldehyde as a Priority Indoor Pollutant Discussion about formaldehyde as a possible carcinogen started in 1980 when the carcinogenicity of formaldehyde in rats and mice after long-term inhalation exposure was reported. 3,4 These publications and the results of studies of human exposure assessment for formaldehyde triggered an avalanche of scientific work as well as stories in the yellow press. Although electronic databases and powerful search engines are now available, it is still difficult to survey all papers in the technical and medical literature. Notwithstanding this, formaldehyde is definitely the most common and the best-known indoor air pollutant. Over the years, the release of formaldehyde from building products has been decreasing. On the other hand, formaldehyde concentrations in ambient air are increasing continuously, especially in the urban environment. For this reason, formaldehyde slipped out of the primary focus of indoor research in the 1990s, although special formaldehyde-related events occasionally come to the attention of the general public. Well-known examples are reports about increasedformaldehyde emission from furniture coatings in Germany (1992) and high formaldehyde concentrations in mobile homes in the United States (2006). However, in 2004, formaldehyde discussions were generally taken up again when formaldehyde was considered as carcinogenic for humans. As a consequence, various authorities and institutions have proposed new indoor air guidelines, giving values that are nearly ubiquitous. Although a prioritized ranking of chemicals and exposures that cause concern is difficult and uncertain, the Scientific Committee on Health and Environmental Risks (SCHER)(5) states that formaldehyde (like carbon monoxide, nitrogen dioxide, benzene, naphthalene, environmental tobacco smoke (ETS), radon, lead, and organophosphate pesticides) is a compound of concern in the indoor environment. 1.3 Review of Literature In this article, the current status of indoor-related formaldehyde research is summarized. This review is based on a literature search carried out using the “Web of Science” (ISI). The keywords “formaldehyde” and “indoor” gave 1240 hits for the period from 1990 to 2008. The results were cross-checked by searching Elsevier’s “ScienceDirect” (1850 hits), “Blackwell Synergy” (174 hits for the Indoor Air journal alone), the American Chemical Society, PubMed, SpringerLink, and Informaworld. Other references known to the authors such as standards (DIN, VDI, CEN, ISO, ASHRAE) and conference proceedings were also included. 2 General Description 2.1 Physical and Chemical Properties Formaldehyde is produced on a large scale by the oxidation of methane or methanol in the presence of a catalyst.(6) At room temperature, it is a colorless gas that is flammable and highly reactive. The compound is soluble in water, ethanol, diethyl ether, and acetone. In aqueous solution, methylene glycol [CH2(OH)2] and polymethylene glycols [H(CH2O) n OH] are formed.(2) Formaldehyde is commonly purchased as a 37% solution in water, known as formalin, with 10% methanol as a stabilizer. The annual production of 37% formaldehyde is about 20 million tons worldwide.(7) In a recent review article, Tang et al.(8) estimate a global output of 32 million tons of formaldehyde in 2006, with the highest producers being China (34%), the United States (14%), and Germany (8%). More than 65% of the total formaldehyde is used to synthesize resins. The name paraformaldehyde describes a polymeric structure with 8−100 formaldehyde units per molecule.(1) The cyclic trimer of formaldehyde C3H6O3 is called 1,3,5-trioxane. Formaldehyde has a dipolar resonance structure (see Table 1), which makes the molecule a typical electrophile. According to Roffael(2) and Walker,(1) the most important reactions apart from polymerization are as follows: Table 1 Physical and Chemical Properties of Formaldehyde parameter ref structure synonyms methanal, methyl aldehyde, methyl oxide CAS registry no. 50-00-0 molecular formula HCHO, CH2O SMILES C=O molecular wt 30.03 g mol−1 (422) melting pointa −92 °C (422) boiling point −21 °C (422) dipole moment 2.33 D (422) solubility soluble in water, ethanol, ether, acetone Henry’s law constant 2.5 × 103 M atm−1 (25 °C) (9) log(K ow)b −0.83 k OH• c 9.37 × 10−12 cm3 molecule−1 s−1 (298 K) (11) k O3 c 2.09 × 10−24 cm3 molecule−1 s−1 (298 K) (15) k NO3 c 5.80 × 10−16 cm3 molecule−1 s−1 (298 K) (12) conversion factor 0.1 ppm = 124.8 μg m−3 (293 K, 1013 mbar) 1 μg m−3 = 0.815 ppb (293 K, 1013 mbar) a In some publications, a boiling point of −118 °C is given. b Calculated with SPARC (http://ibmlc2.chem.uga.edu/sparc/). c See also NIST Kinetics Database (http://kinetics.nist.gov). • Reaction with ammonia to form hexamethylene tetramine • Cannizzaro reaction • Aldol reaction • Tischenko reaction The Henry’s law constant is 2.5 × 103 M atm−1 at 298 K (6.3 × 103 M atm−1 if diol formation is taken into account).(9) The calculated octanol/water partition coefficient is log(K ow) = −0.83. The World Health Organization (WHO) has published a value of log(K ow) = −1.(10) The reaction rate constant with the OH-radical is k OH = 9.3 × 10−12 cm3 molecule−1 s−1 at 298 K.(11) Assuming an atmospheric OH concentration of 106 molecules cm−3, this gives an HCHO lifetime against the OH reaction of 31 h. In the gas phase, formaldehyde shows a structured absorption spectrum between 260 and 360 nm.(12) The lifetimes against the photolytic processes HCHO → H2 + CO and HCHO → H + HCO, calculated for the latitude of 50°, are 6.9 and 2.1 h, respectively.(13) Atkinson(14) has calculated formaldehyde lifetimes in the atmosphere with respect to photolysis (τ = 4 h), reaction with the OH radical (τ = 1.2 days), reaction with the NO3 radical (τ = 80 days), and reaction with O3 (τ > 4.5 years). The gas-phase reaction of ozone with formaldehyde has been studied by Braslavsky and Heicklen.(15) 2.2 Toxicology The high solubility of formaldehyde in water causes rapid absorption in the respiratory and gastrointestinal tract. Here, it can be oxidized to form formate and exhaled as carbon dioxide or incorporated in biological matrices. The biological half-life is extremely short at about 1 min.(16) As an electrophile, formaldehyde can react with nucleophilic biogenic compounds in the body.(17) Formaldehyde itself is produced in small amounts from methanol via the enzyme alcohol dehydrogenase (ADH), 18,19 which is a human metabolite and can be measured in urine. 20,21 According to a report published by “Health Canada”, which is based on human clinical studies and animal experiments, the primary effects of acute exposure to formaldehyde are irritation of the mucosa of the upper respiratory tract and the eyes.(22) The RD50 values (exposure concentration producing a 50% respiratory rate decrease as an indication of respiratory tract irritation) of male mice are 3.1−5.3 ppm for an exposure time of 5−10 min.(23) The lowest observable adverse effect levels (LOAEL) for human sensory irritation range from 0.4 ppm (rhinitis) to 3 ppm (eye, nasal, and throat irritation).(23) A recent study of formaldehyde and sensory irritation in humans showed that eye irritation is the most sensitive parameter. A no observed effect level (NOEL) of 0.5 ppm was derived in the case of constant exposure.(24) Different threshold values are available for the odor perception of formaldehyde. Devos et al.(25) have calculated a standardized human olfactory threshold of 0.87 ppm (1.07 mg m−3). The WHO has estimated absolute odor thresholds (defined as the concentration at which 50% of the panel detects the odor) between 0.06 and 0.22 mg m−3.(10) In the INDEX report 17,26 very low odor thresholds of 0.03 and 0.035 mg m−3 are specified, which refer to an updated WHO report(27) and an unavailable paper from 1917 cited in Devos et al.,(25) respectively. In 2004, the International Agency for Research on Cancer (IARC) has classified formaldehyde as carcinogenic for humans (Group 1).(28) This evaluation is based on information regarding the relationship between nasopharyngeal cancer and leukemia related to the exposure to formaldehyde. In the European Union, formaldehyde is classified under Category 3 as a suspected carcinogen (Directive 2001/58/CEE). Since 1991, the U.S. EPA has regarded formaldehyde as a probable human carcinogen (B1) (http://cfpub.epa.gov/ncea/iris). 2.3 Application of Formaldehyde Formaldehyde is a chemical feedstock for numerous industrial processes. It is also used as a preservative, disinfectant, and biocide. As far as the indoor environment is concerned, its use as a component of thermosetting adhesives is of particular significance. The reactions described below are described in detail by different authors. 1,2,29−31 Urea-formaldehyde (UF) adhesives (so-called aminoplasts) are still the most commonly used products in the manufacturing of wood-based materials and furniture due to their rapid curing, their compatibility with additives, and their low price. In the first step, mono-, di-, and trimethylolurea are formed from formaldehyde and urea in a Mannich reaction. This is followed by condensation reactions to build up the polymer (see eqs 5 and 6). UF adhesives have poor water resistance: the presence of water results in a hydrolysis of the C−N bond and, as a consequence, the release of formaldehyde. Melamine−urea−formaldehyde (MUF) adhesives are similar to UF adhesives. They are produced by mixing portions of UF and melamine−formaldehyde (MF) or by cocondensation of all monomers in one batch. Equation 7 shows the first step of the melamine−formaldehyde reaction. Phenol−formaldehyde (PF) adhesives (so-called phenoplasts) are made by electrophilic substitution to methylol phenol in the first step, as shown in eq 8. In alkaline solution, the reaction results in highly viscous resins of low molecular weight, called resols. A novolac with a high degree of cross-linking is formed in acidic solution. PF adhesives are very stable and water-resistant and have a high adherence to wood. In the past, plastics made of PF resins were also known as Bakelite and were, among other things, used as casings for telephones, radios, etc. Melamine−urea−phenol−formaldehyde (MUPF) adhesives are used for the production of moisture-proofed wood-based products and for construction materials. Like MUF adhesives, they are produced by the addition of small amounts of phenol. Figure 1 provides an overview of the industrial utilization of formaldehyde. Indoor-related applications of formaldehyde in the past and present have been summarized by a number of authors. 32,33 A brief overview is given below: Figure 1 Survey of industrial applications for formaldehyde and formaldehyde products. • Wood-based products (particle board, oriented-strand board (OSB), high-density fiber board (HDF), medium-density fiber board (MDF), plywood) • Cork products (flooring materials) • Insulation materials made of UF foam, mineral wool, or glass wool • Paper products • Coating materials, paints, and lacquers containing formaldehyde as preservative • Textiles • Cleaning and caring products • Disinfectants and preservatives • Photoprocessing chemicals • Cosmetics. 3 Sources of Formaldehyde 3.1 Outdoor Sources 3.1.1 Formaldehyde as a Natural Compound A number of natural and anthropogenic outdoor sources are known for formaldehyde.(34) Like other VOCs, it is a biogenic compound and part of plant physiological and plant/atmosphere exchange processes.(35) In 1927, Freudenberg and Harder identified formaldehyde as a decomposition product of lignin.(36) Müller et al.(37) found formaldehyde within and above a coniferous forest in Germany. Trapp et al.(38) mention formaldehyde as a degradation product of isoprene in a eucalyptus forest in Portugal. Carter and Atkinson(39) proposed a scheme for the formation of formaldehyde from isoprene via reaction with OH and NO. Kesselmeier et al.(40) have measured several parts per billion (ppb) of formaldehyde in a remote forest site in central Amazonia. Smidt et al.(41) have been able to detect low formaldehyde concentrations of 0.24−0.52 ppb in forests in the Austrian Alps (920 m) and 0.16−0.30 ppb at a mountaintop site (1758 m). Long-term measurements at rural European monitoring sites were carried out by Solberg et al.(42) Meyer and Boehme(43) have shown that formaldehyde is released from solid wood. Seco et al.(44) have reviewed VOC emission and uptake by plants. They point out that formaldehyde seems to be a product of methanol oxidation, but the exact origin within plants remains unclear. Other possible mechanisms, such as 5,10-methylene-tetrahydrofolate dissociation, glyoxylate decarboxylation, or oxidative demethylation reactions, have been proposed by Hanson and Roje.(45) Formaldehyde is also produced in the marine environment.(46) 3.1.2 Atmospheric Reactions Thousands of organic compounds are released into the atmosphere from biogenic sources. According to Atkinson and Arey,(47) these organic compounds include isoprene, monoterpenes, sesquiterpenes, and a number of oxygenated compounds. In the troposphere, they react with hydroxyl (OH) radicals, nitrate (NO3) radicals, and ozone (O3), and they play an important role in the chemistry of the lower troposphere. The gas-phase reaction of ozone with unsaturated hydrocarbons is known to produce aldehydes, ketones, and acids as main components. As shown in Figure 2, an ozonide is formed from the reaction of the ozone with the double bond. The two decomposition pathways of the ozonide are of equal importance for alkenes of the structure RCH=CH2, R1CH=CHR, or R1R2C=CR3R4, but for alkenes with the structure R1R2C=CH2 or R1R2C=CHR3, the ozonide decomposes preferentially via pathway 3 while forming formaldehyde or R3CHO.(48) Grosjean and Grosjean(49) have identified formaldehyde in a number of alkene−ozone reactions. Grosjean et al.(50) have studied atmospheric oxidation reactions of biogenic hydrocarbons in a test chamber and have measured formaldehyde concentrations up to 26 ppb at 22 °C with excess cyclohexane to scavenge OH from the reaction of ozone (0.07−0.1 ppm) with β-pinene (1.0 ppm), d-limonene (1.2 ppm), and trans-caryophyllene (0.2−0.5 ppm), respectively. Formaldehyde formation from ozonolysis of carvone, carveol, geraniol, and citral has been reported by Nunes et al.(51) Griesbaum et al.(52) have identified formaldehyde by means of NMR spectroscopy as a byproduct of the gas-phase ozonolysis of terpenes. Relatively high formaldehyde outdoor concentrations can be found in the urban air of heavily polluted megacities. Here, HCHO is directly released into the atmosphere or produced by photochemical gas-phase reaction of hydroxyl radicals with so-called nonmethane hydrocarbons (NMHC). During one ozone episode in the city of Beijing, Duan et al.(53) measured a concentration of 36 μg m−3 formaldehyde in urban air. The rate constant for the reaction of the hydroxyl radical with methane is low (k OH(CH4) = 6.3 × 10−15 cm3 molecule−1 s−1). This means that the formation of formaldehyde from methane is only important in remote areas. Figure 2 Formation of carbonyl compounds from alkene−ozone reactions. 12,421 3.1.3 Outdoor Combustion The combustion of wood is also a natural source of formaldehyde.(54) Hedberg et al.(55) have studied birch combustion and report formaldehyde emission rates of 180−710 mg/kg wood. This is in accordance with data by Schauer et al.(56) for oak (759 mg/kg), pine (1165 mg/kg), and eucalyptus (599 mg/kg). Enhanced formaldehyde concentrations can be found under the influence of wildfire activity.(57) Reisen and Brown(58) have measured levels up to 0.57 ppm for the personal exposure of Australian firefighters. Formaldehyde is a known component of automobile exhaust gas.(59) Public interest in biodiesel fuel has recently stimulated fresh discussion of that topic. Machado Correra and Arbilla(60) and also Guarieiro et al.(61) have shown that carbonyl emissions are dependent on the biodiesel content and that the biodiesel ester molecules are probably the source of these carbonyls. However, Peng et al.(62) arrive at a different conclusion and attribute lower formaldehyde emissions to more complete combustion and increases in engine performance. 3.1.4 Formaldehyde Release into the Atmosphere The WHO(27) pointed out that industrial formaldehyde releases can occur at any stage of the production, use, storage, transportation, or disposal of products with residual formaldehyde. Emissions have been detected from chemical manufacturing plants, pulp and paper mills, forestry product plants, tire and rubber plants, coal processing plants, textile mills, automotive manufacturing plants, and the metal products industry. Hauptmann et al.(7) have evaluated data from different references. On the basis of data from Canada, they provide the following estimated breakdown of emissions into outdoor air: traffic (70%), aircraft (11%), shipping (7%), the formaldehyde processing industry (10%), and power plants and waste incineration ( 12 m3, 1 m3, 0.225 m3 (134) JIS A 1901 20 L to 1 m3 (152) JIS A 1911 >1 m3 to 80 m3 (153) ASTM E 1333 >22 m3 (458) ASTM D 6007 1 m3 (130) desiccator method ASTM D 5582 ≈ 10.5 La (131) JIS A 1460 9−11 L (137) JASb 9−11 L (459)c gas analysis method EN 717-2 4 L chamber (135) flask method EN 717-3 500 mL flask (136) perforator method EN 120 (460) a Inside diameter is 250 mm. b JAS no. depends on product. c Refers to JAS 233 for plywood. 4.3.1 Perforator Method The formaldehyde content of wood-based panels is determined by the perforator method. The content principally correlates with the emission value, especially for wood composites of similar structure and density. The method was developed in the late 1960s by the former European Particleboard Federation (FESYP). Since 1984, it has become established as European standard EN 120. It is a procedure for extracting small samples of wood-based panels by means of boiling toluene and is suitable for unlaminated and uncoated wood-based panels. The extracted formaldehyde is sampled through perforation in water and is measured in the aqueous solution by a suitable analytical procedure. The original method using iodine proved to be too unspecific and was later on replaced by the specific acetylacetone method. The perforator value depends on the moisture content of the tested samples. Correction factors, based on a reference moisture content, are used to compensate for this influence.(181) The test procedure needs comparably simple equipment and has a short total running time of 3 h. For these reasons, it is widely used for production control in the wood-based panel industry, especially in Europe and China. 4.3.2 Flask Method Another simple test for wood-based panels is the flask test. It was developed by Roffael in 1975.(182) The test is based on storing one to three board pieces with a total mass close to 20 g in a closed polyethylene bottle with a volume of 400 cm3. The pieces are stored over 50 mL of distilled water for a defined period of time—usually 24 h—at a constant temperature of 40 °C. The formaldehyde released is absorbed by the water. The formaldehyde content of the aqueous solution is determined photometrically at 412 nm by the acetylacetone method and referred to the dry weight of the tested pieces. A slightly modified version of the method was later standardized as EN 717-3. Disadvantages of the method are the small quantity of material which can be tested and the unrealistic ratio of open edges to surfaces of the tested specimens. In spite of these limitations, the method is most suitable for production control of panels with a similar structure. Variations of the methods have been developed with larger bottles and modified testing times. 4.3.3 Desiccator Methods The so-called desiccator methods 131,137 are based on the same principles as the flask method. Pieces of wood-based panel of known surface area are positioned over water for 24 h at a constant temperature. Instead of a small plastic bottle, a glass desiccator with a volume of 9−13 L is used, thus permitting larger quantities of test material. Analysis of formaldehyde is usually carried out by either the acetylacetone method(137) or the chromotropic acid method.(131) A number of variations of the desiccator method exist (see Table 4). In the meantime, a standard harmonized between the wood-based panel industries of Australia, Japan, and New Zealand has been accepted by the International Standardization Organization as ISO/CD 12460-4. 4.3.4 Gas Analysis An eminently suitable derived formaldehyde test is the gas analysis method, which determines the accelerated formaldehyde release at an elevated temperature of 60 °C. It can be used for all types of panels, including coated boards. This test is also used for testing formaldehyde-emitting impregnated papers, laminates, and insulation foams. The method requires a specimen of 400 mm × 50 mm × thickness. The sample is placed in a test tube at a controlled temperature of 60 °C. A gas stream of 1 L per minute is passed through the tube. The emitted formaldehyde is absorbed by gas-washing bottles and measured photometrically. The bottles are changed once per hour over a total testing time of 4 h. Usually the values measured are averaged, ignoring the first hour. The result is expressed in mg h−1 m−2. This procedure is standardized as EN 717-2.(135) 4.4 Air Sampling Strategies Appropriate sampling strategies for the measurement of formaldehyde in indoor air are discussed by Gavin et al.(183) and in the ISO 16000-2 standard.(184) Discontinuous methods for measuring room-air components can be subdivided into short-term and long-term types. While active sampling is suitable not only for short but also—provided the air flow rate has been reduced correspondingly—for longer measurement intervals, passive sampling is used mostly for long-term measurement. In discontinuous methods, the measured value is first determined by subsequent analysis in the laboratory. In the case of active sampling, air is passed through a sampling device using a pump and the air volume is accurately determined. A passive sampler is a device which is capable of taking air samples at a rate controlled by diffusion through a static layer or permeation through a membrane.(185) The flow of pollutants into the passive sampler is proportional to the difference of concentrations in the ambient air (C air) and on the surface of the passive sampler (C A), as shown in eq 17. D i is the diffusion coefficient for compound i, m i is the collected mass of compound i, A is the surface area of the sampler, l is the length of diffusion, and t is the collection time. In the case of active sampling with short measurement time intervals (10 min to approximately 4 h), international guidelines have been drawn up for interior air measurement.(151) Formaldehyde is a highly volatile compound, which means that the indoor concentration will generally depend on the source strength and on the air exchange rate. Strong sinks such as gypsum board may influence the concentration by adsorption and desorption effects.(186) Due to its high solubility, water and other polar liquids act as permanent sinks for formaldehyde. For a constant emission source and an air exchange rate n, the time required to reach a desired percentage of the steady-state concentration C ∞ is given by eq 18. The solid curve in Figure 9 models the increase in formaldehyde concentration in a room after ventilation for an air exchange rate of n = 0.3 h−1 in the absence of sinks. Two sampling strategies can be applied: the solid circles in Figure 9 stand for a 1 h staggered strategy, in which sampling starts immediately after the windows are closed. The steady-state value must be calculated from eq 18. The open circles in Figure 9 represent possible sampling times at the steady-state level. This method depends on a good guess at the air exchange rate. Figure 9 Modeled increase of the formaldehyde concentration after ventilation for a continuous source and an air exchange rate of n = 0.3 h−1 in the absence of sinks (see eq 18). The solid circles (●) represent a staggered measuring strategy; the open circles (○) represent a steady-state measuring strategy (note: the circles represent possible sampling times, not data from measurements). Passive sampling, whose theoretical fundamentals were described in detail and summarized by Crump,(185) is enjoying increasing popularity in indoor air testing, since it can be employed without causing any nuisance to room users. Different types of formaldehyde passive samplers have been employed. 187−193 However, it must be borne in mind that passive collectors are usually left in a room for days or even weeks at a time without continuous monitoring by the analyst, and this means that the possibility of tampering cannot be excluded. One of the advantages of passive sampling is that person-related exposure can be determined in a simple manner by having the passive collector worn by an individual for a specific period. 194,195 However, the result of passive sampling will depend on temperature, since the accumulation of molecules is driven by diffusion, which is a function of the gas kinetic properties. Another critical parameter is the flow rate, and low air velocities will cause undervalued concentrations. A standard procedure for passive sampling of formaldehyde in indoor air has been described by ISO.(196) 5 Fomaldehyde Indoor Guidelines 5.1 Guidelines by Category Several safety and occupational health authorities worldwide have laid down permissible exposure levels of formaldehyde by inhalation. Most levels are based on results of epidemiological and toxicological test outcomes obtained from both human and animal data for a certain exposure time or are based on health hazard assessments in the relevant toxicological literature. Limit values are basically separated into two main categories: workplace environments in which occupational exposure occurs and nonoccupational (i.e., residential) environments. Such occupational threshold limit values (TLV) are often categorized as time-weighted average (TWA), short-term exposure limit (STEL), and ceiling (C) values, with the last defining the exposure limit, which should not be exceeded at any time. The Occupational Safety and Health Administration (OSHA)(197) has set the STEL for formaldehyde at 2 ppm in 15 min and the permissible exposure limit time-weighted average (PEL-TWA) at 0.75 ppm. The TLV-C proposed by the American Conference of Governmental Industrial Hygienists (ACGIH)(198) is 0.3 ppm. The National Institute for Occupational Safety and Health (NIOSH)(199) has set a more stringent STEL of 0.1 ppm and a recommended exposure limit for occupational exposure of 0.016 ppm. Other occupational formaldehyde guideline values may be found in the papers by Duhayon et al.(200) and Paustenbach et al.(201) In general, occupational limit values are higher than indoor guideline values on account of two important factors. The basic difference between these guideline values depends on the vulnerability of the people staying in these environments. One of the factors is that nonoccupational indoor environments cover the general population, including infants, children, the elderly, pregnant women, and people allergic to formaldehyde. The other factor is that the general population is often exposed to lower formaldehyde levels over long time periods (i.e., during their lifetimes), while workers are assumed to be exposed to formaldehyde for about 8 h in a working day and 5 days a week. In a recent review, Zhang et al.(202) discussed and compared occupational and indoor formaldehyde guideline values. As can be seen from Table 5, indoor guideline values can be roughly categorized into two groups based on exposure durations. The short-time exposure levels are used for preventing acute health effects on individuals while long-term exposure levels are used for preventing the chronic health effects of formaldehyde. The most common short-term exposure limit is 100 μg m−3 as a 0.5 h average value aimed at preventing significant sensory irritation in the general population and is recommended by the WHO. Table 5 International Guideline Values and Recommendations for Formaldehyde in Indoor Air country year issued value comments Australia 1982(226) 0.1 ppm 120 μg m−3 short-duration 2006(227) 0.08 ppm 100 μg m−3 Canada 1987(220) 0.1 ppm 120 μg m−3 action level 1987 0.05 ppm 60 μg m−3 target level 2005(22) 0.1 ppm 123 μg m−3 1 h 2005 0.04 ppm 50 μg m−3 8 h China 2003(225) 0.08 ppm 100 μg m−3 1 h average Denmark 1990(207) 0.15 mg m−3 Finland 2001(209) 30 μg m−3 S1 50 μg m−3 S2 100 μg m−3 S3 France 2008(213) 50 μg m −3 2 h (proposed) 10 μg m −3 long-term exposure (proposed) Germany 1977(216) 0.1 ppm Singapore 1996(224) 0.1 ppm 120 μg m−3 8 h Hong Kong 1999 0.025 ppm 30 μg m−3 level 1 (8 h) 0.081 ppm 100 μg m−3 level 2 (8 h) 0.3 ppm 370 μg m−3 level 3 (8 h) 2003(221) 0.025 ppm 30 μg m−3 excellent 0.081 ppm 100 μg m−3 good Japan 1997(223) 0.08 ppm 100 μg m−3 0.5 h Korea 2004(222) 0.1 ppm 120 μg m−3 8 h Norway 1990(210) 0.05 ppm 60 μg m−3 24 h average 1999(211) 0.05 ppm 100 μg m−3 30 min average Sweden 2000 0.08 ppm 100 μg m−3 adopted from WHO Poland 1996(215) 0.04 ppm 50 μg m−3 category A: 24 h 0.08 ppm 100 μg m−3 category B: 8−10 h U.K. 2004(208) 100 μg m−3 0.5 h USA (California) 1991(217) 0.1 ppm 120 μg m−3 action level 0.05 ppm 60 μg m−3 target level (ALARA)a 1999(203) 0.076 ppm 94 μg m−3 1 h (acute REL)b 2004(219) 0.027 ppm 33 μg m−3 8 h (interim REL) 2005(218) 0.002 ppm 3 μg m−3 annual average (chronic REL) WHO 1987(228) 0.08 ppm 100 μg m−3 0.5 h average a ALARA = as low as reasonably achievable. b REL = reference exposure limit. Long-term exposure values in indoor guidelines are often based on 8 or 24 h time durations. These time-weighted average (TWA) values were set to protect the public in indoor environments from the chronic effects of formaldehyde and are considered to offer adequate protection to individuals exposed to formaldehyde continuously over their lifetimes. Chronic noncancer health effects have been assessed based on a threshold concentration or dose which is below a level at which no adverse health effects would occur. Reference Exposure Levels (RELs), as estimated by the OEHHA,(203) are designed to protect the most sensitive individuals in the population and include margins of safety. Some organizations try to encourage the use of low-emitting products for reducing particular indoor air pollutants, mainly formaldehyde. An example of this is the U.S. Green Building Council (USGBC),(204) which published the Leadership in Energy and Environmental Design (LEED) Green Building Rating System, which is based on voluntarily participation and aims at facilitating high-performance buildings. Similarly, the “Standard for the Design of High-Performance, Green Buildings Except Low-Rise Residential Buildings” set by ASHRAE(205) only accepts urea-formaldehyde being used on the exterior envelope material of the buildings. European labeling systems are surveyed in a report published by the European Commission.(206) 5.2 Guidelines by Regions Table 5 shows the current formaldehyde indoor guideline values set in different countries by different organizations. Most of the cited documents are published as official government publications and are available on the Internet. An overview of guideline values (12 countries in the year 1990) is given in a report published by the European Commission.(207) 5.2.1 Europe In the U.K., the Committee on the Medical Effects of Air Pollutants (COMEAP)(208) recommended a limit value of 100 μg m−3 (0.5 h) for indoor formaldehyde in 2004. Finland(209) has set up a different system. The indoor climate is classified as S1 (individual indoor climate), S2 (good indoor climate), and S3 (satisfactory indoor climate), in which formaldehyde target values were set as 30 μg m−3, 50 μg m−3, and 100 μg m−3, respectively. An indoor formaldehyde level was specified by the Norwegian Health Directorate (NHD)(210) in 1990 in the Guidelines for Indoor Air Quality, in which a 24-h average indoor formaldehyde level was set at 60 μg m−3. Stranger et al.(211) cite a guideline value of 100 μg m−3 (0.5 h exposure), applicable in Norway since 1999. The Danish guideline value of 0.15 mg m−3 has not been revised since 1990.(207) Sweden has adopted the WHO-guideline value, but a further reduction to 60 μg m−3 is currently under discussion.(212) In France, the French Agency for Environmental and Occupational Health Safety (AFSSET) has proposed guideline values of 10 μg m−3 and 50 μg m−3 for long-term exposure and short-term exposure (2 h), respectively. 213,214 The Polish Ministry of Health and Social Welfare(215) issued a decree to reduce the pollutants emitted by building materials and furnishings in inhabited enclosed areas. The maximum allowable concentrations for formaldehyde, categorized as Category A (up to 24 h exposure per day) and Category B (8−10 h exposure per day), are 50 μg m−3 and 100 μg m−3, respectively. Germany established an indoor guideline value of 0.1 ppm in 1977. The Federal Institute for Risk Assessment (BfR) and the Federal Environment Agency stated in 2006 that a revision of this guideline value is not required.(216) 5.2.2 USA/Canada In 1991 the California Environmental Protection Agency set indoor formaldehyde levels at 0.10 ppm as an action level and at 0.05 ppm as a target value.(217) These values were recently lowered by the Office of Environmental Health Hazard Assessment (OEHHA). Formaldehyde levels for acute exposure, 8-h exposure, and chronic exposure were set at 0.076 ppm (94 μg m−3), 0.027 ppm (33 μg m−3), and 0.002 ppm (3 μg m−3), respectively. 203,218,219 Health Canada 22,220 and the Federal Provincial Advisory Committee on Occupational and Environmental Health (CEOH) laid down indoor air quality guidelines in 1987 and revised them in 1989. In these guidelines, formaldehyde target and action levels were set at 0.05 ppm (60 μg m−3) and 0.1 ppm (120 μg m−3), respectively. Following reclassification of formaldehyde as a carcinogen by the IARC and on the basis of the results of epidemiological and toxicological studies, Health Canada set new limits in 2006. These new guidelines, the Proposed Residential Indoor Air Quality Guidelines, specified a short-term (1 h) exposure limit of 0.1 ppm (123 μg m−3) and a long-term (8 h) exposure limit of 0.04 ppm (50 μg m−3). 5.2.3 Asia The Indoor Air Quality Management Group in Hong Kong published indoor formaldehyde guidelines in 1999 entitled “Guidance Notes for the Management of Indoor Air Quality in Office and Public Places”. In these guidelines, the indoor air quality (8 h average) in offices and public environments was classified into three categories: Level 1 represents very good indoor air quality, Level 2 represents the recommended indoor air quality standards for the general public, and Level 3 represents the indoor air quality required as protection for workers. The indoor formaldehyde concentrations corresponding to these three levels were 30 μg m−3, 100 μg m−3, and 370 μg m−3. The guidelines were modified in 2003 in the form of an indoor air quality certification scheme. Two indoor air quality levels (8 h average) were defined as benchmarks, namely “excellent class” ( k b, the first phase ( 300 ppb range (built 1966−1984) (302,475) USA (2008) 360 travel trailers 81 ppb GM (occupied) (306) 90 park models 44 ppb GM (occupied) (306) 69 mobile homes 57 ppb GM (occupied) (306) Canada (2003) 151 homes (summary of 5 studies) 29.8 μg m−3 50-P (476) Canada (2005) 59 residences 29.6 μg m−3 50-P (417) Canada (2008) 96 Quebec homes 9.6−90 μg m−3 range (310) Latin America Brazil (2006) academic institute 0.1 ppm. Hanrahan et al.(303) have measured formaldehyde levels up to 2.8 ppm. The data by Dingle et al.(304) based on 192 caravans are consistent with other studies, but these authors have also found distinct differences between occupied and unoccupied caravans. Furthermore, Dingle et al. point out that the increased formaldehyde concentrations in mobile homes result from higher loading rates with wood-based materials of approximately 1.4 m2 m−3 and lower air exchange rates compared to conventional buildings. Main and Hogan(305) exposed 21 test persons to formaldehyde concentrations between 0.12 ppm and 1.6 ppm in two mobile trailers. Symptoms such as eye and throat irritation, headache, and fatigue were observed. In the United States, discussion about formaldehyde in mobile homes returned to public attention when survivors of hurricane Katrina, who live in trailers provided by the U.S. Department of Homeland Security (FEMA), complained about strange odors and adverse health effects. The U.S. Centers for Disease Control and Prevention (CDC) randomly selected 519 out of 120,000 trailers and mobile homes. The range of concentrations was between 3 and 590 ppb with a geometric mean of 77 ppb. In their study, CDC stated that the indoor temperature was a significant factor for formaldehyde levels irrespective of trailer make or model.(306) Maddalena et al. 307,308 studied four unoccupied FEMA temporary housing units, each produced by a different manufacturer, to assess their indoor emissions. Steady-state indoor formaldehyde concentrations ranged from 378 μg m−3 (0.31 ppm) to 632 μg m−3 (0.52 ppm) in the morning and from 433 μg m−3 (0.35 ppm) to 926 μg m−3 (0.78 ppm) in the afternoon. Air exchange rates ranged from 0.15 h−1 to 0.39 h−1. Wolkoff and Kjaergaard(309) state that formaldehyde emission from wood-based materials is proportional to relative humidity at a given temperature. This might also play a role in the hot and humid climate of the southern U.S. states. 7.5 Influence of Climatic Parameters on Formaldehyde Levels The effect of climatic parameters on indoor formaldehyde concentrations has been considered in several studies. Salthammer et al.(64) found a negative correlation between the formaldehyde concentration and the air exchange rate. A similar observation was made by Gilbert et al.(310) Ninety-six homes were studied in Quebec, and 80% of those homes had air exchange rates < 0.23 h−1. Based on the entire sample, the air exchange rate which ensured a formaldehyde concentration below Health Canada’s long-term exposure limit of 50 μg m−3 in 95% of the homes was 0.26 h−1. Gilbert et al. recommend that an air exchange rate meeting ASHRAE’s recommendation of 0.35 h−1 appears sufficient to ensure a concentration within the Canadian guideline in most homes. CDC has found slight associations of indoor temperature and relative humidity and logarithmic formaldehyde concentrations in occupied FEMA trailers.(306) A temperature effect was also reported by Jo and Sohn.(311) Tuomainen et al.(312) found that ventilation and occupancy had only a small effect on the formaldehyde concentration in one case and one control building. In this study, the formaldehyde concentrations were low (1−27 μg m−3) and the number of samples was 12 or less. Dingle and Franklin(278) investigated indoor formaldehyde concentrations as a function of the season and the age of the house. Higher levels were found in newer homes and in homes monitored in summer. Jaernstroem et al.(313) also report higher formaldehyde concentrations in the summer. Furthermore, these authors applied the method of principal component analysis (PCA)(314) to find out which variables affected indoor air quality most. These variables, which are not necessarily independent, were season, relative humidity, temperature, air exchange, floor coverings, ceilings, wall coverings, and occupancy. Wong et al.(315) attempted to relate indoor formaldehyde concentrations to other pollutants and climatic parameters but found only weak correlations. The data for prefabricated houses shown in Figure 15 were grouped by year. The results for 1996 and 2006 are shown in Figure 15A as Box−Whisker plots. At first sight, it seems surprising that both samples give the same median of 0.4 ppm. On closer inspection, however, the distribution is much smaller for the data from 2006 and, even more important, the air exchange rates (see Figure 15B) decreased from 1996 to 2006. This leads to the conclusion that formaldehyde emission rates in prefabricated houses will have fallen during the last 10 years, but this positive effect has been canceled out by decreasing air exchange rates. Figure 15 Box-and-whisker plots (min, max, mean, 25-P, 50-P, 75-P) of formaldehyde concentrations (A) and air exchange rates (B) for the years 1996, 2001, and 2006 (data from Figure 13). 8 Exposure and Risk Assessment 8.1 Calculation of the Daily Intake Although outdoor air contributes adversely to indoor air quality,(268) it was believed that human exposure to formaldehyde mainly originates in the indoor environment rather than the ambient environment.(316) Two parameters are of major importance in the evaluation of indoor exposure to formaldehyde: (a) the concentration in air and (b) the time spent indoors. The latter depends on the age group and on the daily activities. Brasche and Bischof(317) have investigated the time spent indoors in German homes with regard to age, gender, characteristics, and location of the home. The overall mean time of 15.7 h per day is in line with results from the United States and Canada. Approximations made by the U.S. EPA(318) have been widely applied to calculate the daily intake of formaldehyde. The EPA indicated an inhalation rate of 0.63 m3 h−1 and 10 h per day for residential exposure. Stubenrauch et al.(319) estimate inhalation rates of 0.8 m3 h−1 for adults and 0.25 m3 h−1 for young children over 21 h per day. The total daily intake (DI) for an individual moving in n different environments can be computed from eq 26, where C j , IR j , and t j represent the concentration, inhalation rate, and time spent in the environment j. The WHO(27) has calculated probabilistic estimates of 24 h time-weighted average concentrations of formaldehyde in the air on the basis of five Canadian studies. The results indicate that one in two persons would be exposed to concentrations of 24−29 μg m−3, while 1 in 20 persons would be exposed to 80−94 μg m−3. Baez et al.(320) applied the EPA exposure scenario to Mexican homes and calculated a daily uptake of 173−600 μg day−1 on the 95-P level. It should, however, be pointed out that, for a respiratory tract irritant, the time-weighted average concentration and especially the peak exposure are more meaningful than the daily intake. Acute, chronic (noncancer), and potential carcinogenic effects on humans have been reported for formaldehyde. Numerous case-control studies, cohort studies, and reviews have been published. The most relevant and frequently cited review papers, representing different views and perspectives, are summarized in Table 8. Results are also available for specific subgroups, such as children, 321−327 special indoor environments, such as medical laboratories, 288,328−331 workplaces, 200,332,333 exposure studies, 334−336 and others.(7) Animal studies are not included in this review. It should only be mentioned that Lu et al.(337) have recently reported an effect of inhaled formaldehyde on the learning and memory of mice due to oxidative stress. Table 8 Reviews of Studies of the Acute and Chronic Adverse Health Effects of Formaldehyde topic ref the INDEX report Kotzias et al. (2005)(17) World Health Organization—report on formaldehyde WHO (1989, 2002) 10,27 classification of formaldehyde as human carcinogen IARC (2006)(483) sensory irritation in relation to carcinogenicity Arts et al. (2006)(338) evaluation of data on carcinogenicity Appel et al. (2006)(348) risk assessment for the population in Japan Naya (2005)(357) risk factors for respiratory and allergic effects in children Mendell (2007)(229) evaluation of epidemiological studies (1994−2006) Duhayon et al. (2008)(200) occupational exposure limit based on irritation Paustenbach et al. (1997)(201) hazard characterization and exposure−response relationship Liteplo and Meek (2003)(476) mode of action for carcinogenicity of formaldehyde McGegor et al. (2006)(16) evaluation of epidemiological studies Bosetti et al. (2008)(351) evaluation of literature related to effects with indoor air exposure Arts et al. (2008)(349) formaldehyde exposure and leukemia Zhang et al. (2009)(202) 8.2 Short-Term and Long-Term Exposure (Noncancer) Acute (short-term) human exposure to formaldehyde causes discomfort; irritation of the eyes, nose, and throat; lachrymation; sneezing; coughing; nausea; and finally death.(27) Table 9 has been adopted from WHO(27) and provides an overview of acute human health effects at differrent levels of exposure. In the INDEX report,(17) studies of humans under controlled conditions are summarized as follows: “acute exposures to air concentrations ranging from 0.5 mg m−3 to 3.7 mg m−3 induce reversible eye, nose, and throat irritation, produce changes in nasal lavage fluid contents (indicative of irritation of the nasal epithelium), do not consistently or markedly affect pulmonary function variables in most individuals.” No-observed-(adverse)-effect levels (NO(A)EL) have been published on the basis of different criteria. The NOAEL of 0.03 mg m−3 mentioned in the INDEX report corresponds to the lowest odor threshold reported.(17) Studies of irritation in humans have been reviewed by Paustenbach et al.(201) and Arts et al.(338) These authors concluded that irritation starts at levels around 1 ppm. In a recent study designed on the basis of current standards, Lang et al.(24) examined the possible occurrence of sensory irritation and subjective symptoms in human volunteers exposed to formaldehyde concentrations relevant to the workplace. They concluded that sensory eye irritation is the most sensitive parameter and obtained a NOAEL of 0.5 ppm. This is in contrast to the WHO data in Table 9, which gives a lower threshold for throat and nose irritation of 0.1 mg m−3. However, in the case of the WHO publication cited, it is difficult to trace the original source, which makes a critical evaluation difficult. Wolkoff et al.(339) have also reviewed human odor and sensory irritation threshold values for formaldehyde and other compounds. They conclude that many sensory irritants are formed from alkene oxidation reactions, where formaldehyde is a major product. Table 9 Effects of Formaldehyde in Humans after Short-Term Exposure(274) conc range or avg (mg m−3) time range or avg health effects in general population 0.03 repeated exposure odor detection threshold (10-P)a 0.18 repeated exposure odor detection threshold (50-P)a 0.6 repeated exposure odor detection threshold (90-P)a 0.1−3.1 single and repeated exposure throat and nose irritation threshold 0.6−1.2 single and repeated exposure eye irritation threshold 0.5−2.0 3−5 h decreased nasal mucus flow rate 2.4 40 min on 2 successive days with 10 min of moderate exercise on second day postexposure (up to 24 h) headache 2.5−3.7 b biting sensation in eyes and nose 3.7 single and repeated exposure decreased pulmonary function only during heavy exercise 5−6.2 30 min tolerable for 30 min with lachrymation 12−25 b strong lachrymation, lasting for 1 h 37−60 b pulmonary edema, pneumonia, danger to life 60−125 b death a Frequency of effect in population. b Time range or average unspecified. Formaldehyde is a well-known skin sensitizer, but its interrelationship with asthma has been debated for many years. Publications of different design and quality are available on this subject, 323,324,335,340−346 but considering the widespread exposure to formaldehyde, reports on respiratory sensitization are few. In a recent review focusing on the effects of residential formaldehyde levels, Arts et al.(347) evaluated the data available, especially for children. They concluded that the question is still open whether there is a causal relationship between formaldehyde and allergic asthma or whether formaldehyde induces airway irritation resembling asthmatic reactions. Similarly, Appel et al.(348) were not able to adduce clear evidence for asthma induced by formaldehyde. In occupational and residential environments, long-term exposure (chronic, noncancer) to increased levels of formaldehyde results in irritation of the upper and lower airways and eyes. Most studies related to chronic effects refer to the working environment, where formaldehyde is frequently used. The predominant effect of formaldehyde is sensory irritation at low concentrations, which will progress to cytotoxic irritation with cell destruction at higher concentrations. These effects are concentration- and not time-dependent. The threshold concentrations for sensory and cytotoxic irritation are therefore very similar for acute and chronic exposures. Concentrations not leading to sensory irritation after acute exposures are not expected to result in adverse effects after prolonged exposures. 8.3 Formaldehyde as a Human Carcinogen The classification of formaldehyde as a known human carcinogen by IARC is based on cohort mortality studies of workers exposed to formaldehyde with an increased incidence of nasopharyngeal cancer.(332) However, the evaluation by IARC has been questioned by several authors. Marsh and Youk(349) pointed out that their reanalysis of the available data provided little evidence for a causal association between formaldehyde exposure and mortality and they recently provided evidence that the increased incidence of nasopharyngeal cancer might be related to exposures to several suspected risk factors for upper respiratory system cancer (e.g., sulfuric acid mists, mineral acid, metal dusts, and heat) in the metal industries of that area.(333) Moreover, Marsh et al.(350) criticized that the nasopharyngeal cancer risk models developed by Hauptmann et al.(332) and used by IARC to justify their classification of formaldehyde as a human carcinogen were mis-specified and nonrobust. Thus, the authors claimed that the decision of IARC should be reconsidered. Duhayon et al.(200) and Bosetti et al.(351) have reviewed epidemiological studies published after 1994. The authors state that the evidence for an association between formaldehyde exposure and nasopharyngeal cancer appears debatable and also suggest a need to reconsider the current carcinogenic classification by IARC. The German Federal Institute for Risk Assessment (BfR) and other institutions have stated that results from recent epidemiological studies support a possible causal relationship between inhalation exposure to formaldehyde and nasopharyngeal cancer. 16,348 In their publication, the BfR points out that a slight sensory irritation response can be observed at concentrations of 0.2−0.3 ppm and that ocular and upper respiratory tract sensory irritation is not present below 0.1 ppm. A formaldehyde concentration of 0.1 ppm is therefore proposed as a safe level. According to the evaluation by IARC, the epidemiologic evidence was strong but not sufficient to conclude that formaldehyde exposure causes leukemia in humans. Moreover, a plausible mechanism has not been identified how leukemia may be induced after formaldehyde inhalation. Two large cohort studies 352,353 pointed at possible excesses while Coggon et al.(354) could detect no link between formaldehyde exposure and leukemia risk. Since the discussion is mainly driven by the National Cancer Institute (NCI) study,(352) the observation of Marsh and Youk(355) is relevant that the upward trend noted in the NCI study is produced by a deficit of leukemia cases among the unexposed and low exposed workers. Their reanalysis provided little evidence to support NCI’s suggestion of a causal association between formaldehyde exposure and mortality from leukemia. In the recent follow-up of the NCI study, Beane Freeman et al.(356) admitted that Hauptmann et al. had not included 1006 deaths in their previous analyses. The authors also showed that in some cases the original cause of death had to be changed. Bean Freeman et al.(356) summarize that the overall leukemia risk trends have decreased in comparison to their previous publication but still remain somewhat elevated and that further studies are needed to evaluate the risk of leukemia in other formaldehyde exposed poulations. Some recent studies deal with the risk of cancer in relation to formaldehyde in air. Naya and Nakanishi(357) have evaluated case-control as well as cohort studies in humans and recommend a reference value of 0.01 ppm in outdoor air for the general population in Japan. The U.S. EPA provides an Integrated Risk Information system (IRIS) (http://www.epa.gov/iris) for calculating the cancer risk for formaldehyde and other chemicals.(358) Loh et al.(359) ranked the cancer risks of organic hazardous air pollutants in the United States and applied the unit risk model, where the chronic daily intake is multiplied by a cancer potency factor.(360) The Scientific Committee on Occupational Exposure Limits (SCOEL) recommends that regulations and health-based exposure limits for formaldehyde should be based on an established NOAEL.(361) Irigaray et al.(362) have identified formaldehyde as one of the compounds of major concern when evaluating lifestyle-related factors and environmental agents causing cancer. For the risk assessment approach with regard to carcinogens, the mode of action is of pivotal importance. For genotoxic chemicals that lead to tumors by mutations of the DNA, it is generally accepted that a threshold cannot be defined and linearized mathematical models are used to define an exposure with acceptable risk as regards socioeconomic considerations. A different approach is applicable to nongenotoxic carcinogens which lead to tumors by a threshold mechanism, such as, for example, chronic irritation. Exposures below this threshold are not expected to have a carcinogenic effect. In 2000 the German MAK commission concluded that, at low exposure, concentrations without an increase of cell proliferation genotoxicity “play no or at most a minor part...so that no significant contribution to human cancer risk is expected”. This assessment has so far been annually confirmed by the commission.(363) This mode of action has recently also been supported by Liteplo and Meek(364) and has been refined and put into the context of the 2006 IPCS (International Programme on Chemical Safety) human framework for the analyses of cancer’s mode of action for humans.(16) Accordingly, concentrations not resulting in cytotoxic irritation with an increased cell proliferation would represent a threshold for carcinogenic action upon the upper respiratory tract. As cytotoxic irritation will only occur at concentrations clearly above those leading to sensory irritation, a carcinogenic action is not to be expected so long as sensory irritation is avoided. This sensory irritation is the decisive end point for all indoor air limits proposed in the last years by regulatory bodies, and these limits should therefore provide protection against tumor induction by formaldehyde. 8.4 Formaldehyde and SBS The term “Sick Building Syndrome (SBS)” has been used to describe the mostly nonspecific complaints of occupants of buildings.(365) Brightman and Moss,(366) who have evaluated different studies, pointed out that SBS describes a constellation of symptoms which have no clear etiology and are attributable to exposure to a particular building environment. On the basis of a WHO report,(367) Mølhave(368) has suggested a definition for SBS. The most common symptoms are eye, nose, and throat irritation; dry and itching skin; nonspecific hypersensitivity; sensation of dry mucous membranes; headache, fatigue, and dizziness; airway infections and cough, wheezing and nausea. In general SBS does not correlate with any single factor, and only occasionally has formaldehyde been linked to SBS. Mendell(369) has summarized reported associations between work-related symptoms and a potential 37 factors and measurements from 33 studies conducted between 1984 and 1992. Formaldehyde was only mentioned by Skov et al.,(370) who did not find an association. Formaldehyde was therefore classed by Mendell as a compound with a “consistent lack of association with symptom reports”. Mainly consistent with symptom reports were air-conditioning, job dissatisfaction, and allergies/asthma. Similar results were obtained from the Danish town hall study 371,372 and the German ProKlimA study.(273) An interesting aspect was raised by Sundell et al.,(373) who identified higher formaldehyde and lower TVOC (total volatile organic compound) levels as risk indicators for SBS. This was attributed to VOCs reacting with other air pollutants such as ozone to form irritant byproducts such as formaldehyde. Brightman and Moss(366) have called this theory “the missing VOCs”. A link between VOC exposures and SBS was demonstrated for the first time by TenBrinke et al.(374) SBS should not be confused with the so-called “Sick House Syndrome”. This term is mainly used in Japan and also takes into account the health problems of individuals in private dwellings. 375,376 9 Reduction of Indoor Formaldehyde Pollution Techniques for lowering the concentration of formaldehyde in the indoor environment have been discussed by several authors and can be classified into several groups: • avoidance of sources and prevention of emissions right from the start • removal of the source • surface coating • fumigation with ammonia • increased ventilation • catalytic reactions • adsorption The California Air Resources Board points out that “.. .the most effective way to reduce formaldehyde in indoor air is to remove or reduce sources of formaldehyde in the home and avoid adding new sources”.(219) However, the feasibility of source removal will sometimes depend on the circumstances. It may well be an easy matter in the case of furniture but be much more complicated in the case of a built structure. Surface treatment by use of reactive or diffusion resistant coatings and fumigation with ammonia were mainly applied in the case of very high formaldehyde levels in the 1980s and 1990s. The reaction with ammonia which yields hexamethylene tetramine (see eq 1) was in particular used in prefabricated houses. It is a drastic but very effective and long-lasting solution. 2,377 Uchiyama et al.(378) proposed the application of natural compounds such as urea, catechin, and vanillin to suppress formaldehyde emission from plywood. Kim(379) suggested the use of volcanic pozzolan. These days, formaldehyde source strengths are lower. This means that people are exposed to lower formaldehyde concentrations in the indoor environment, and it is more convenient to reduce pollutant levels by use of intelligent housing construction and ventilation. 380,381 Here it is the responsibility of architects and engineers to ensure adequate air exchange with low heat loss. Sherman and Hodgson(382) suggested using measured formaldehyde emission and authoritative exposure standards to develop minimum ventilation rates for dwellings. Photocatalytic oxidation systems for the removal of formaldehyde have recently become popular.(383) One method works with high-flow photoreactors, where degradation of the pollutants is performed over a solid TiO2 catalyst and with UV light of high intensity. 384−390 Hodgson et al.(391) as well as Mo et al.(392) have shown that such ultraviolet photocatalytic oxidation (UVPCO) systems produce formaldehyde due to incomplete mineralization of VOCs. The other technique uses wall paint equipped with modified TiO2(393) for the purpose of photocatalytically removing air pollutants under indoor conditions. Although such wall paints are frequently advertised, serious publications examining their efficiency have not yet become available. Moreover, Salthammer and Fuhrmann,(93) Gunschera et al.,(95) as well as Auvinen and Wirtanen(94) have shown that, under the influence of light, photocatalytic wall paints produce undesired secondary emissions such as formaldehyde. Quiller et al.(394) have shown that, in the presence of ozone, TiO2 surfaces promote the oxidation of styrene to form formaldehyde. From time to time, it is reported that plants act as air cleaners, but the literature on this topic is contradictory. The results of Godish and Guindon(395) do not support previous suggestions that botanical air purification using only plant leaves is an effective means of reducing residential formaldehyde levels. Giese et al.(396) demonstrated that formaldehyde is efficiently metabolized by the spider plant (Chlorophytum comosum). Schmitz et al.(397) conclude that the assimilation and metabolism of formaldehyde by leaves appears unlikely to be of value for indoor air purification. Wool fiber is also used for adsorption of formaldehyde under indoor conditions. Although there is no question that wool has the capability to adsorb formaldehyde, recent work refers to unreasonably high indoor concentrations of 1 ppm. 398,399 Proof of the applicability of wool at lower formaldehyde concentrations is still absent. Matthews et al.(186) have demonstrated that gypsum board has some storage capacity for sorbed formaldehyde but appears to result in only a minor permanent loss mechanism. A new aspect has recently been mentioned by Mui et al.(400) These authors evaluated the energy impact assessment for the reduction of carbon dioxide and formaldehyde exposure risk in air-conditioned offices in Hong Kong. They conclude that the energy impact should be an important factor in future ventilation strategies regarding indoor air quality. 10 Other Emissions Related to Formaldehyde The appearance of other volatile organic compounds in conjunction with formaldehyde in indoor air can be classified by chemistry or by source. Two compounds are regarded as “chemistry-related” if one is formed by chemical reaction from the other. Two compounds are “source-related” if they are released from the same source but originate in different reactions. Formic acid, which is the oxidation product of formaldehyde (see eq 2), has been recognized as a hazard in the museum environment. Raychaudhuri and Brimblecombe(401) have found that formaldehyde can damage lead objects in display cases via conversion to formic acid. However, they also state that the question posed by Hatchfield and Carpenter,(402)“formaldehyde—how great is the danger to museums collections?”, remains unanswered. Tetrault(403) has pointed out that, with the exception of lead, very few studies support the proposition that formaldehyde is harmful to exhibits in a museum environment. In contrast, acetic acid seems to be a more aggressive indoor organic compound for a larger range of objects. Schieweck et al.(292) and Salthammer et al.(404) have measured formaldehyde, formic acid and acetic acid in different departments of a German museum. More references on museum-related sources, levels and associated damage to materials are available in ref (291). Wood and wood-based materials are good examples for describing the occurrence of VOCs related to formaldehyde, as shown in Figure 16. The volatile ingredients of softwood mainly consist of monoterpenes, of which the most important are α-pinene, β-pinene, 3-carene, limonene, camphene, myrcene, and β-phellandrene. 405,406 As outlined in section , terpenoids and other unsaturated hydrocarbons are precursors of formaldehyde in the presence of strong oxidants. The reaction of terpenes with ozone leads to the formation of terpene aldehydes(407) and secondary organic aerosols. 408−410 Compounds such as methanol, acetaldehyde, and acetic acid are typically released from hardwood.(411) In the case of wood-based materials, aldehydes and other compounds are formed during the manufacturing process. Jiang et al.(412) as well as Makowski et al. 413,414 have measured emissions of saturated and nonsaturated aldehydes (C3−C10) from the hot-pressing of mixed hardwood and Scots pine, respectively. Acetic acid and furfural result from the thermal degradation of hemicelluloses. These two compounds are most prominent in cork products. 415,416 Acetic acid is formed from the degradation of acetyl groups, while furfural is produced from pentoses and hexoses under elimination of water. Furthermore, phenol−formaldehyde resins are frequently used in the manufacture of cork products. For this reason, formaldehyde and phenol are often measured together.(415) Figure 16 Possible VOC emissions related to formaldehyde for the case of a wood-based material. In the case of other building materials such as carpet, latex paint, and so on, the occurrence of formaldehyde is related to the ozone-induced formation of other saturated and nonsaturated aldehydes (C2−C13, 2-octenal, 2-nonenal, 2,4-nonadienal, benzaldehyde, tolualdehyde). 71,78,85,88 Test chamber experiments are often in good agreement with real-room measurements. 243,254 Combustion processes can be identified by the simultaneous appearance of formaldehyde, acetaldehyde, and acrolein. 260,261 Gilbert et al.(417) have pointed out that smoking is a source of acetaldehyde and acrolein in indoor air. 11 Summary and Outlook Among the large variety of gaseous indoor pollutants, formaldehyde has always had an exceptional position, and there is no reason to believe that this view will change in the near future. Formaldehyde is a highly reactive aldehyde, it is an important chemical feedstock, it is a constituent of many industrial products, and it is ubiquitous outdoors and indoors due to natural and anthropogenic processes. As Pluschke(33) pointed out, formaldehyde was the hazardous substance “par excellence” in the 1980s. In 1970s Germany, the release of formaldehyde from wood-based materials and the high pollution levels in classrooms and daycare facilities for children triggered a public debate on indoor air pollutants. Every few years, the “formaldehyde discussion” is resuscitated—in 2004, for example, following classification of formaldehyde by IARC as a Group 1 carcinogen and recently, in the United States, when survivors of hurricane Katrina suffered adverse effects from the poor indoor air quality in their trailers. Emission of formaldehyde from building products and consumer goods has been limited by authorities and by voluntary criteria. Reliable but sophisticated tools are available to measure formaldehyde concentrations even at low levels in rural environments. Indoor concentrations have been systematically monitored over the years. An evaluation of recent emission studies and indoor surveys has demonstrated that the situation has improved due to the progress made over recent decades regarding indoor products with reduced emissions. An examination of international studies carried out in 2005 or after (see Table 7) indicates that the average exposure of the population to formaldehyde seems to lie between 20 μg m−3 and 40 μg m−3 under normal living conditions. Although this trend toward decreasing concentrations is a positive one, it should be kept in mind that such average concentrations do not take into account the higher exposure which may result from new buildings or special indoor conditions, peak concentrations, and individual cases. It can be expected that advanced products and intelligent housing designs will bring about a further fall in formaldehyde concentrations indoors. However, the average indoor air concentrations of other compounds have also decreased and the RIOPA study has shown that among the carbonyls the indoor source strength of formaldehyde is still high in the USA. On the other hand, Eikmann et al.(418) have stated that in Germany formaldehyde exposure in the private environment can be regarded as manageable and controllable. The previously mentioned classification of formaldehyde as a Group 1 carcinogen by IARC has started some controversial discussions. Different authorities in different countries and organizations as well as other epidemiologists have re-evaluated available data and come to different conclusions. Health Canada did not take IARC’s classification into consideration and in 2005 established a new formaldehyde indoor air guideline value of 50 μg m−3 (8 h). The German Federal Institute for Risk Assessment was aware of the IARC classification in 2006(419) but considered 0.1 ppm (124 μg m−3) to be a “safe level” and decided that a revision of the German guideline value was not required. Arts et al.(347) also concluded that 0.1 ppm can be considered a safe and appropriate level. A European working group stated in the INDEX report that formaldehyde should be regarded as a chemical of concern at indoor levels exceeding 1 μg m−3. The same group pointed out that from about 30 μg m−3 mild irritation of the eyes could be experienced by the general population and odor perceived. In other studies, odor thresholds and sensory irritation levels were found to be about one magnitude higher. Wolkoff(420) has stated that the guideline values for formaldehyde and other reactive VOCs appear to be overestimated. Taking into account average formaldehyde concentrations in indoor, rural, and urban air (see Figure 17) and the toxicological data available, interpreting values lower than 30 μg m−3 as guideline values or as recommendations seems to be somewhat unrealistic. Instead, established guideline values in the range of the WHO value could be used as a basis and should be complemented by application of the ALARA principle (ALARA = as low as reasonably achievable) and of recommendations regarding better ventilation and keeping temperatures moderate. Figure 17 Range of formaldehyde concentrations in different environments. No one will reasonably doubt that formaldehyde is a relevant indoor pollutant. Regulations are urgently required, but the lower guideline value is not necessarily the better one. If indoor-related research is focused solely on formaldehyde and all efforts are applied to this compound, other pollutants will be easily neglected, something which can be counterproductive for human health. As an example, radon is also classified by IARC as a Group 1 human carcinogen, but formaldehyde has a considerably higher ranking in the public attention, probably as the result of a large number of previous incidents due to the acute health effects. Moreover, it seems questionable whether formaldehyde concentrations lower than 20 μg m−3 can be permanently achieved under normal living conditions in urban and rural environments. In addition to building materials and household products, we have to consider other formaldehyde sources, such as outdoor air, indoor chemical reactions, candles, cooking, gas heaters, etc. Although quantitative data are not available, we may conservatively estimate that these additional sources contribute 10−50% to formaldehyde indoor concentration levels. However, the uncertainty of this estimation indicates the need for further research on this topic. Today, it is possible to produce low-emitting materials, and such products are already recommended by manufacturers of furniture and housing. On the other hand, the air exchange rates in houses have decreased in almost the same manner. Mechanical ventilation also consumes energy, and all the factors mentioned make for a vicious circle. The formaldehyde story will be continued.

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Low-loading asymmetric organocatalysis.

Francesco Giacalone, Paola Agrigento, Renato Noto … (2012)

Asymmetric organocatalysis is now recognized as the third pillar of asymmetric synthesis. Recent years have witnessed increasing interest towards the use of highly active and stereoselective organocatalysts. This critical review documents the advances in the development of chiral organocatalysts which are systematically used in ≤3 mol% loading in all the sub-areas of the field, namely aminocatalysis, Brønsted acids and bases, Lewis acids and bases, hydrogen bond-mediated catalysis, phase transfer and N-heterocyclic carbene catalyses (194 references).

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The increasing threat to stratospheric ozone from dichloromethane

Ryan Hossaini, Martyn P. Chipperfield, Stephen Montzka … (2017)

It is well established that anthropogenic chlorine-containing chemicals contribute to ozone layer depletion. The successful implementation of the Montreal Protocol has led to reductions in the atmospheric concentration of many ozone-depleting gases, such as chlorofluorocarbons. As a consequence, stratospheric chlorine levels are declining and ozone is projected to return to levels observed pre-1980 later this century. However, recent observations show the atmospheric concentration of dichloromethane—an ozone-depleting gas not controlled by the Montreal Protocol—is increasing rapidly. Using atmospheric model simulations, we show that although currently modest, the impact of dichloromethane on ozone has increased markedly in recent years and if these increases continue into the future, the return of Antarctic ozone to pre-1980 levels could be substantially delayed. Sustained growth in dichloromethane would therefore offset some of the gains achieved by the Montreal Protocol, further delaying recovery of Earth’s ozone layer.

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Journal ID (nlm-ta): J Org Chem

Journal ID (iso-abbrev): J Org Chem

Journal ID (publisher-id): jo

Journal ID (coden): joceah

Title: The Journal of Organic Chemistry

Publisher: American Chemical Society

ISSN (Print): 0022-3263

ISSN (Electronic): 1520-6904

Publication date (Electronic): 01 November 2021

Publication date (Print): 03 December 2021

Volume: 86

Issue: 23

Pages: 16725-16735

Affiliations

[† ]Departamento de Química Orgánica y Química Inorgánica, Instituto de Investigación en Química “Andrés M. del Río” (IQAR) Universidad de Alcalá, Campus Universitario , Alcala de Henares, Madrid 28871, Spain

[‡ ]Instituto de Investigaciones Químicas, CSIC-Universidad de Sevilla , C/Américo Vespucio, 49, Sevilla 41092, Spain

Author notes

[* ]Email: martaeg.mosquera@ 123456uah.es .

[* ]Email: campora@ 123456iiq.csic.es .

Author information

Marta E. G. Mosquera https://orcid.org/0000-0003-2248-3050

Juan Cámpora https://orcid.org/0000-0001-7305-1296

Article

DOI: 10.1021/acs.joc.1c01971

PMC ID: 8650018

PubMed ID: 34724613

SO-VID: 6666b0d8-e1eb-408a-b4ba-9f0cdc1c722a

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Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained ( https://creativecommons.org/licenses/by/4.0/).

History

Date received : 17 August 2021

Funding

Funded by: Universidad de AlcalÃƒÂ¡, doi 10.13039/501100006302;

Award ID: UAH-AE-2017-2

Funded by: Agencia Estatal de InvestigaciÃƒÂ³n, Ministerio de Ciencia, InnovaciÃƒÂ³n y Universidades, doi NA;

Award ID: RTI2018-094840-B-C31

Funded by: Agencia Estatal de InvestigaciÃƒÂ³n, Ministerio de Ciencia, InnovaciÃƒÂ³n y Universidades, doi NA;

Award ID: PGC2018-095768-B-100

Funded by: Junta de AndalucÃƒÂa, doi 10.13039/501100011011;

Award ID: PY20_00104

Funded by: European Regional Development Fund, doi 10.13039/501100008530;

Award ID: RTI2018-094840-B-C31

Funded by: European Regional Development Fund, doi 10.13039/501100008530;

Award ID: PY20_00104

Funded by: European Regional Development Fund, doi 10.13039/501100008530;

Award ID: PGC2018-095768-B-100

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ScienceOpen disciplines: Organic & Biomolecular chemistry

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ScienceOpen disciplines: Organic & Biomolecular chemistry

NHC-CDI Betaine Adducts and Their Cationic Derivatives as Catalyst Precursors for Dichloromethane Valorization

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Most cited references 74

Formaldehyde in the Indoor Environment

Low-loading asymmetric organocatalysis.

The increasing threat to stratospheric ozone from dichloromethane

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