Breath volatile organic compounds (VOCs) as biomarkers for the diagnosis of pathological conditions: A review

Abstract

Normal and abnormal/pathological status of physiological processes in the human organism can be characterized through Volatile Organic Compounds (VOCs) emitted in breath. Recently, a wide range of volatile analytes has risen as biomarkers. These compounds have been addressed in the scientific and medical communities as an extremely valuable metabolic window. Once collected and analysed, VOCs can represent a tool for a rapid, accurate, non-invasive, and painless diagnosis of several diseases and health conditions. These biomarkers are released by exhaled breath, urine, faeces, skin, and several other ways, at trace concentration levels, usually in the ppb_v (μg/L) range. For this reason, the analytical techniques applied for detecting and clinically exploiting the VOCs are extremely important. The present work reviews the most promising results in the field of breath biomarkers and the most common methods of detection of VOCs. A total of 16 pathologies and the respective database of compounds are addressed. An updated version of the VOCs biomarkers database can be consulted at: https://neomeditec.com/VOCdatabase/

Graphical abstract

Introduction

The role of Volatile Organic Compounds (VOCs) in the medical field has been extraordinarily growing in the last two decades. These compounds are produced by numerous biological processes of the human body and can be released to the exterior in several ways. The most well-known ways of VOCs emission from the organism are exhaled breath [1], perspiration [2], urine [3], faeces [4], and even lacrimal fluid [5]. Since they are formed or emitted as a direct result of normal and abnormal biological processes, their detection, identification, and quantification can be an open window to the interior of the organism. They can represent a valuable source of information about health conditions or pathologies under development, and even about eventual consequences of medical treatments [6,7].

As mentioned, the interest of the scientific community in the role of VOCs as biomarkers is considerably increasing. This evolution can be seen in Fig. 1 A) whose graph represents the rising of the number of scientific papers published simultaneously on the topics of volatile organic compounds and exhaled breath. It is possible to notice that, in just a matter of twenty years, the number of scientific articles has risen from around 1000 per year to more than 5000 per year. From this literature research, one can infer the potential of volatile organic compounds as exhaled breath biomarkers for the detection of a wide range of pathologies. Fig. 1 B) represents the percentual relevance of the 16 main diseases with an already developed scientific base regarding the usefulness of VOCs in their detection. These numbers were collected from the scientific database “web of science”.

Fig. 1.

(A) Number of scientific articles published per year during the last twenty years regarding the field of volatile organic compounds as breath biomarkers to the diagnosis of health conditions; (B) Treemap of the percentual value of the number of papers addressing specific pathologies in the field of volatile organic compounds as biomarkers in the exhaled breath. Data was collected from the scientific database “web of science”.

As promising results have been achieved with analyses of breath samples performed in independent studies and with different analytical techniques and procedures, the present work intends to review the most recent and relevant scientific research projects, from January 2010 to December 2021, where the exhaled breath VOCs are addressed and studied as potential biomarkers or identification tools for health conditions and pathologies of the human organism. Here, the main analytical techniques currently used for the detection of VOCs are briefly revised, the most recent works associated with the forwarded pathologies are addressed and, in addition, a database of VOCs is included at the end of the review and can be consulted at: https://neomeditec.com/VOCdatabase/.

Volatile organic compounds: what are they?

The European Union (EU) directive on the limitation of emissions of volatile organic compounds defines VOCs as “… any organic compound …, having at 293.15 $K$ a vapour pressure of 0.01 $kPa$ or more, or having a corresponding volatility …” [8]. The United States Environmental Protection Agency (EPA), in its turn, defines these compounds as “… any organic compound having an initial boiling point less than or equal to 250 $°C$ measured at a standard atmospheric pressure of 101.3 $kPa$.” [9]. Independently of the minor differences, the general definition of VOCs is practically standard: a volatile organic compound is an organic compound, meaning that its main structural atom is carbon, which is volatile at room temperature (20 $°C$) and 1 $atm$ of pressure [[10], [11], [12]].

The range of sources responsible for the emission of VOCs, despite being wide, is constituted of very common and ordinary elements. Ranging from natural products, foods and cooking, personal care and cleaning products, and furniture, to pharmaceutic drugs, plastics, fuels, or construction materials, VOCs can be effortlessly emitted by most of the daily-use objects and elements [[13], [14], [15]]. In this way, the emission of VOCs occurs not only in private (private houses, vehicles, or working locations) and public (schools, hospitals, shopping centres, or public transportation) indoor environments but also in outdoor environments like gardens and public parks [[16], [17], [18]]. The human body is no exception. Numerous VOCs have been scientifically proved to be produced and emitted by several human organs as a result of numerous biological processes [[19], [20], [21], [22]].

Varying from almost inert to extremely reactive, VOCs have the capacity of traversing most of the biological membranes, such as pulmonary, ocular, and cutaneous tissues [[23], [24], [25], [26]]. Due to this fact, the VOCs found in any kind of indoor or outdoor environment can enter or be absorbed by the human body causing health conditions and pathologies as consequences of the exposure [[27], [28], [29]]. Simpler reactions like skin pruritus and ocular allergies have been reported [[30], [31], [32]]. Asthma, Chronic Obstructive Pulmonary Disease (COPD), and other inflammatory respiratory pathologies have also been assessed as VOCs-provoked pathologies [[33], [34], [35]]. In more complex scenarios, several forms of cancer were identified as being caused by chronic exposure to VOCs; in fact, benzene and formaldehyde are among the most carcinogenic VOCs and are directly responsible for some severe forms of cancer like lung cancer, oral cancer, and even prostate cancer [[36], [37], [38]]. In the opposite direction, the endogenously-produced VOCs of the body can also traverse the human tissues and be detected in the exterior through exhaled breath [24], saliva [39], perspiration [40], faeces [41], and urine [42], among other ways [22,40]. Once collected and analysed, the VOCs emitted in these body excretions represent an ideal window for the interior of the body and are potential biomarkers to assess numerous biological processes and health conditions occurring in the human organism.

The current definition states that a biomarker is “… a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention …” [43]. A biomarker can, indeed, be a biological signal of several natures, that can be accurately measured, whose result is reproducible over time, and that is always associated with a specific normal or abnormal event of the human organism [44,45]. As mentioned, VOCs are among the main human-produced biomarkers and have enabled the study and diagnosis of a vast range of pathologies and health conditions, addressed in due time.

Volatile organic compounds: detection and analysis

It is relevant to briefly summarize the main analytical techniques that are currently being used for detecting and analysing these analytes.

A significant part of the scientific papers published in the field of VOCs as exhaled breath biomarkers claim to have used an electronic nose (E-nose) for the detection of the analytes. In fact, the concept of e-nose is quite vast because it does not correspond to a specific and independent analytical technique. E-nose is the nomenclature typically applied to define any electronic prototype or device that enables the analysis of VOCs so, any system based on arrays of gas sensors/detectors or that employ some type of separation technology can be referred to as E-nose. Chromatographic and spectrometric techniques, for example, are vulgarly called e-nose by some authors [46,47], while others use this terminology to talk exclusively about electronic devices based on arrays of gas sensors [48]. Independently of the terminology, there are a considerable number of interesting papers addressing the implementation of gas sensors arrays for the detection of VOCs in exhaled breath and, among the analytical techniques, the most utilized ones are gas chromatography (GC), mass spectrometry (MS), ion mobility spectrometry (IMS), and combinations between them [49,50].

Gas sensors array-based E-noses

The development of electronic prototypes and devices based on arrays of gas sensors is a common practice in the fields of VOCs detection and biomarkers identification. Gas sensor is a vulgar definition for a sensor specifically developed to detect one or a limited number of analytes. There are several types of sensors, namely quartz crystal microbalance sensors (QCMS), photoionization detector sensors (PIDS), surface acoustic wave sensors (SAWS), solid-state electrochemical sensors (SSES), and metal oxide sensors (MOS) however, independently of the used type, all of them are highly responsive, selective, stable, simple, and low-priced [48]. Since the sensors only enable the detection of a limited number of analytes, it is common to assemble arrays of sensors with distinct finalities, widening the range of detectable analytes with a single system [51,52].

The arrays are usually assembled in a microcontroller and once connected to a computer, they allow the collection of qualitative and quantitative data regarding the detected analytes [53]. To access that data, the sensors array is exposed to the volatile sample and, if the sample contains the analytes that the sensors are prepared to detect, they will respond to the presence of those compounds. This response is different for the several types of sensors. In the case of the MOS, for example, these sensors change the conductivity of their sensing element in response to being exposed to the gases [54]. The response of the sensors is, then, registered and converted to a spectrum or to numerical data by the computer to be posteriorly processed [55]. The described procedure was used by Binson et al. (2021) in their study. The authors assembled an e-nose based on an array of five distinct sensors to analyse exhaled breath samples of a cohort of 88 volunteers (39 healthy individuals, 22 chronic obstructive pulmonary disease patients and 27 lung cancer patients). The gas sensors array-based system developed in the study enabled the authors to classify the lung cancer patients with accuracy, sensitivity, and specificity levels of 78.7, 72.5 and 82.4%, respectively. Similar values were achieved in the classification of COPD patients [56]. Fig. 2 describes a generic analysis through a sensor array-based system.

Fig. 2.

Schematic of a generic Gas Sensors Array-based system for breath analysis.

Gas chromatography

Gas chromatography (GC) is an analytical technique often applied as a pre-separation method prior to further analyses with other analytical devices like mass spectrometers or ion mobility spectrometers. These devices enable the separation of a sample into its constituting analytes and provide information about their molecular composition and concentration. The GC section, specifically, can separate volatile analytes based on their solubility, based on their capacity of adsorbing to the walls of the chromatographic column, and whose boiling point ranges from near 0 to over 700 K. The temperature is an important factor for the column performance and, as said, the GC works at a wide range of temperatures so, proper temperature control is crucial for a correct analysis [57,58].

During a GC measurement, the sample is introduced into the system and the analytes are distributed between two phases, the stationary phase, and the mobile phase. The mobile phase moves in a specific direction and is responsible for transporting the compounds through the entire column. This transportation can occur due to gravitational, capillary or pressure forces. In opposition, the stationary phase, usually a solid or an immobilized liquid, counteracts the transport rate of the mobile phase. Since the different analytes have different capacities to adsorb to the walls and different solubility, they will elute from the column at distinct moments. The detector, at the end of the system, registers the time that each compound requires to cross the entire circuit, called retention time. This time enables the identification of all the analytes present in the initial sample [59,60]. Fig. 3 schematizes a GC measurement. As mentioned, the sample is introduced into the chromatographic column where the analytes are separated considering their intrinsic capacity of adsorbing to the coating of the inner wall of the columns. Once the analytes elude from the column, they are detected, and a final spectrum is produced. This detection is achieved at exact times that are analyte-specific and correspond to the time required by each analyte to elude from the chromatographic column.

Fig. 3.

Schematic of Gas Chromatography (GC) measurements.

Mass spectrometry

Mass spectrometry (MS) is, perhaps, the most used detection technique among all the addressed ones. It enables to selectively identify and quantify a vast range of analytes, as well as, to study their molecular structure and composition. MS is the analytical technique that generates more data from the measurements of the analytes and even enables the analysis of any element that can be ionized, organic or not. To assess all this data, MS bases its working principle on the experimental measurement of the mass of gas-phase ions produced from the molecules of an analyte. Its detection limits can go, for some cases, as low as ppb_v, without the necessity of employing any kind of pre-concentration steps, however, it has some limitations regarding VOCs analysis in clinical settings due to the elevated temperatures used during the analysis that can contribute to the degradation of the sample and consequent loss of some analytes [61,62].

Very briefly, an MS measurement starts with the injection of the sample into the spectrometer. By bombarding it with a beam of energetic electrons, the molecules are ionized and disintegrate into multiple fragments. Some of these fragments are positive gas-phase ions. Once formed, the product ions are accelerated by an electric field and deflected by a magnetic field. Since the ions are separated according to their mass-to-charge ratio, only the desired ions are detected at the end of the process. The detection occurs, in this way, in proportion to their abundance. Finally, a mass spectrum of the molecule is produced. The spectrum provides the relation of ion abundance versus mass-to-charge ratio. Usually, the most intense peak is assigned with the relative abundance of 100% and the abundances of all the other peaks are given their proportional values, as percentages of the base peak. To avoid interferences from any other forms of matter, the ions must be analysed in a vacuum atmosphere [63,64]. Fig. 4 schematizes the working principle of a mass spectrometer. Here, a sample composed of three distinct analytes is injected and, once accelerated by an electric field, the analytes suffer different deflections when exposed to a magnetic field, allowing their detection and characterization, as addressed.

Fig. 4.

Schematic of a generic measurement with Mass Spectrometry (MS).

Ion mobility spectrometry

When compared with the MS, ion mobility spectrometry (IMS) is a more recent technology but with equally proven results in the fields of identification and quantification of VOCs. Its high levels of sensitivity and specificity added to its analytical flexibility, almost real-time monitoring and portability make IMS one of the most suitable analytical techniques to be applied in-situ, in clinical contexts and out-of-the-laboratory scenarios [65]. In addition, its detection limits can go as low as ppb_v and even ppt_v, enabling IMS to detect even the analyte with the tiniest concentration of the entire sample [66,67].

The working principle of an IMS device is rather simple. The spectrometer is equipped with an ionization source responsible for ionizing all the analytes existent in a sample. Once ionized, the ions are exposed to a weak but homogeneous electric field that makes them traverse the entire length of the drift tube at specific velocities. These velocities are ion-specific, which enables that each ion reaches the detector, usually a Faraday plate, at different and, also specific, times. After being detected, the different analytes can be identified accordingly with their characteristic ion mobility constant (calculated from their drift velocities). Fig. 5 illustrates a complete measurement occurring in the interior of an IMS tube. As mentioned, the sample is ionized inside the ionization chamber and then, the product ions are exposed to an electric field that drags them through the entire length of the tube. In the end, the ions are detected by a Faraday plate at their respective drift times [68,69].

Fig. 5.

Schematic of a generic measurement by Ion Mobility Spectrometry (IMS).

Besides their individual capacities and qualities, none of the mentioned techniques is used independently or, at least, is not ordinary. It is quite common to couple at least two different analytical techniques to obtain a hybrid technique that combines the advantages of both methods in a single device. Marriott et al. (2012), for example, described the utility of coupling GC with GC, creating a multidimensional gas chromatographer (MDGC) [70]. Das et al. (2014), in their turn, used a GC–GC system coupled with a mass spectrometer (GC-GC-MS) to analyse exhaled breath samples and prove the suitability of this technique in the study of the human volatome [71]. The combination between GC and MS is, perhaps, the analytical technique used for the highest number of different scientific subjects. Its vast array of applications ranges from drug detection, fire investigation and environmental analysis, to forensic and medical studies [72]. Several research groups have applied GC–MS for the study of the VOCs exhaled in the breath as is possible to confirm in this review paper.

Regarding the MS limitations on identifying some exact VOCs, IMS and, in specific, the coupling of IMS with GC, has gained relevance in several scientific fields but mainly in clinical contexts [73]. The coupling of these two techniques results in a device with improved selectivity, sensitivity, analytical flexibility, and high capacity for analysing complex matrices [17,67]. The GC-IMS has been largely applied in clinical scenarios and, specifically, in the exhaled breath assessment. Several scientific studies that used GC-IMS are addressed in this review. Besides being an extremely new technology, some research groups are working on coupling MS and IMS in a single device. The coupling of these two spectrometric techniques will result in a device with outstanding levels of sensibility and specificity, and with an enormous capacity for analysing a vast range of analytes in the most diverse and complex scenarios. These characteristics will also make IMS-MS, one of the analytical techniques most suitable for exhaled breath and metabolomics analyses [74,75].

Volatile organic compounds: the role as biomarkers

As addressed, VOCs have gained relevancy as breath biomarkers to diagnose a vast range of pathologies. Respiratory diseases are among the most VOCs-related health conditions. Their potentiality as biomarkers of pathologies like asthma [76], chronic obstructive pulmonary disease (COPD) [77], lung cancer [78], and even COVID-19 [79], have been frequently studied. Hepatic [80], renal [81] and colorectal [82] disorders are equally studied regarding the produced and emitted VOCs. Volatile metabolites related to gastric [83], laryngeal [84], oesophageal [85] and oral [39] cancers are already known as potential biomarkers. Numerous cancers have characteristic VOCs that can act like biomarkers, namely ovarian [86], prostate [42], pancreatic [87], bladder [88], and breast [89] cancer. Characteristic VOCs of pathologies known for their lower complexity or mortality have also been assessed; celiac disease [90], cystic fibrosis [91], muscle dystrophy [92], and diabetes [93] are examples of those health conditions. In addition, several scientific works have been studying the potential of a vast range of pathologies regarding their eventual diagnosis through exhale breath. This recently studied pathologies are Alzheimer's disease [94], Chron's disease [95], epilepsy [96], multiple sclerosis [97], obesity [98], sepsis [99], and thyroid cancer [100], among others. As proved, the applicability of VOCs as biomarkers is wide, contemporary, and promising.

In accordance with the main goals of the present work, one intended to review the main research works developed in the field of potential exhaled breath biomarkers in the form of volatile organic compounds. From this research, a total of 16 pathologies are alphabetically addressed regarding their respective breath biomarkers. In addition, a summary table, Table 1, with all the reviewed VOCs related to the addressed pathologies is included in the appendix of the document. The respective bibliographic sources addressed in this table can be consulted elsewhere (https://neomeditec.com/VOCdatabase/).

Conclusions

The characterization of the volatile organic compounds existing in the human exhaled breath has gained relevance for the identification and diagnosis of a vast range of pathologies and health conditions. This work aimed to assess the state of the art regarding the relevancy and current role of the VOCs as breath biomarkers. A total of 16 pathologies and health conditions were considered of special interest for the bibliographic search. All the VOCs identified as potential biomarkers in breath for the diagnosis of a specific pathology were gathered in an overall database that matches these analytes with the diseases and with the respective bibliographic source. An online database, which the authors intend to keep updated and can be accessed through the link https://neomeditec.com/VOCdatabase/, was exclusively developed to share with the academia an open source tool to consult all this gathered information and divulge new findings in the future.

Considering all the works reviewed in this work, it is important to notice that pretty much all the addressed studies were developed around biological samples collected from human cohorts. Most of the studies compared their findings considering healthy volunteers and patients suffering from the target disease. As addressed, for the detection and identification of the breath biomarkers, most of the authors employed sensor arrays-based electronic noses or spectrometric techniques. More than a couple of hundred biomarkers have been reported in the bibliography addressed here.

All the aforementioned facts and the hundreds of reviewed works unequivocally show that the field of VOCs as breath biomarkers has an auspicious future as a non-invasive, painless, rapid and accurate methodology to identify and diagnose a vast range of health conditions.

Conflicts of interest

The authors declare no conflicts of interest.

Appendix.

Table 1.

Summary of all the reviewed breath biomarkers/VOCs related to the addressed pathologies with high potentiality for further developments. An updated version of the VOCs biomarkers database with the respective bibliographic sources can be consulted at: https://neomeditec.com/VOCdatabase/.

Volatile Organic Compounds as Exhaled Breath Biomarkers		Pathologies
Name	CAS No.	Asthma	Breast Cancer	CKD	CLD	COPD	Colorectal Cancer	Covid-19	Cystic Fibrosis	Diabetes	Gastric Cancer	Lung Cancer	Malaria	Prostate Cancer	Sleep Apnoea	Squamous Cell Cancer	Tuberculosis
A
Acetaldehyde	75-07-0				X	X		X	X					X
Acetic Acid	64-19-7		X					X			X
Aceticamide	60-35-5										X
Acetone	67-64-1	X		X	X		X	X	X	X	X	X	X		X
Acetophenone	98-86-2		X		X											X
Acetyl acetate	108-24-7													X
2-Acetylpyridine	1122-62-9					X
Allylmethylsulphide	10,152-76-8												X
Ammonia	7664-41-7			X
Ammonium acetate	631-61-8															X
Aniline	62-53-3			X
(+)-Aromadendrene	489-39-4		X
B
Benzaldehyde	100-52-7		X			X	X									X
Benzene	71-43-2					X						X	X
Benzoic acid	65-85-0						X
Benzonitrile	100-47-0					X
Benzothiazole	95-16-9								X
Bicyclo [4.1.0]hepta-1,3,5-triene	4646-69-9			X
Biphenyl	92-52-4	X
2,5-Bis-1,1-dimethylethylphenol	5875-45-6															X
Bis-(3,5,5-trimethylhexyl) phthalate	14,103-61-8																X
Butanal	123-72-8					X						X
Butane	106-97-8					X						X
1,4-Butanediol	110-63-4										X
2,3-Butanediol	513-85-9															X
2,3-Butanedione	431-03-8								X							X
Butanoic acid	107-92-6						X
Butanol	71-36-3								X
2-Butanone	78-93-3			X	X			X	X		X	X				X
2-Butenol	504-61-0								X
4-Butoxybutanol	4161-24-4										X
2-Butoxyethanol	111-76-2										X
Butyl Acetate	123-86-4								X
Butylatedhydroxytoluene	128-37-0					X	X
2-Butyloctanol	3913-02-8		X			X											X
6-t-Butyl-2,2,9,9-tetramethyl-3,5-decadien-7-yne	–						X
Butyric Acid	107-92-6								X							X
C
Camphene	79-92-5																X
Carbon disulphide	75-15-0											X
3-Carene	13,466-78-9												X
Caryophyllene	87-44-5		X		X
[E]-Cinnamaldehyde	14,371-10-9					X
2-Chloroethylester-carbonochloridic acid	627-11-2			X
Chloroform	67-66-3											X
3-Chloropropanoylchloride	625-36-5			X
Cyclohexane	110-82-7						X					X
Cyclohexanol	108-93-0		X
Cyclohexanone	108-94-1		X			X	X						X
Cyclooctylmethanol	3637-63-6						X
Cyclopentane	287-92-3		X
Cyclopentanone	120-92-3		X
o-Cymene	527-84-4			X
Cymol	99-87-6																X
D
Decanal	112-31-2						X									X
Decane	124-18-5	X				X						X			X
1,2-Decanediol	1119-86-4															X
Decene	872-05-9		X		X
E−3-Decen-2-ol	18,402-84-1															X
1,4-Dichlorobenzene	106-46-7	X														X
Dichloronitromethane	7119-89-3			X					X
Dihydro-2(3H)-furanone	96-48-0															X
2,4-Dimethylbenzaldehyde	15,764-16-6		X
1,3-Dimethylbenzene	108-38-3		X				X
1,4-Dimethylbenzene	106-42-3						X
2,2-Dimethylbutane	75-83-2		X													X
2,3-Dimethylbutane	79-29-8															X
Dimethyl Carbonate	616-38-6								X
1,4-Dimethylcyclohexane	589-90-2		X
2,2-Dimethyldecane	17,302-37-3						X						X			X
3,6-Dimethyldecane	17,312-53-7	X											X
3,7-Dimethyldecane	17,312-54-8												X				X
Dimethyl disulphide	624-92-0					X
4,6-Dimethyl-dodecane	61,141-72-8															X
2,4-Dimethylheptane	2213-23-2	X		X								X				X
2,6-Dimethylheptane	1072-05-5					X
2,3-Dimethylhexane	584-94-1		X
3,3-Dimethylhexane	563-16-6								X
1,7-Dimethylnaphtalene	575-37-1	X
4,5-Dimethylnonane	17,302-23-7															X
2,6-Dimethyloctane	2051-30-1		X
2,3-Dimethylpentane	565-59-3										X
2,4-Dimethylpentane	108-08-7	X	X
2,2-Dimethylpropanoic acid	75-98-9															X
Dimethyl Selenide	593-79-3				X
2,6-Dimethylstyrene	2039-90-9																X
Dimethyl sulphide	75-18-3			X	X				X	X		X
3,7-Dimethylundecane	17,301-29-0															X
4,7-Dimethylundecane	17,301-32-5					X
6,10-Dimethyl-5,9-undecadien-2-one	689-67-8						X								X
1,4-Dioxane	123-91-1								X
1,3-Dioxolan-2-one	96-49-1										X
1,3-Di-ter-butylbenzene	1014-60-4		X
2,5-Ditert-butylcyclohexa-2,5-diene-1,4-dione	2460-77-7		X
2,6-Ditert-butylcyclohexa-2,5-diene-1,4-dione	719-22-2		X
Δ-Dodecalactone	713-95-1					X
Dodecane	112-40-3	X	X				X				X					X
Dodecanoic acid	143-07-7						X
2-Dodecanone	6175-49-1		X
E
Ethanal	75-07-0							X
Ethanol	64-17-5		X	X	X		X		X	X		X				X
Ethenesulfonyl chloride	6608-47-5			X
2-Ethenylnaphtalene	939-27-5	X
2-Ethoxyethyl acetate	111-15-9								X
Ethyl acetate	141-78-6		X				X		X
Ethyl acrylate	140-88-5								X
Ethylaniline	103-69-5						X
Ethylbenzene	100-41-4	X					X					X	X		X
Ethyl butyrate	105-54-4								X					X
Ethylcyclohexane	1678-91-7												X
1-Ethyl-3,5-dimethylbenzene	934-74-7		X
Ethylene	74-85-1										X
Ethylene Carbonate	96-49-1		X
Ethylidenecyclopropane	18,631-83-9		X
2-Ethylhexanol	104-76-7		X										X
M-Ethylmethylbenzene	620-14-4			X
6,2-Ethylmethyldecane	62,108-21-8					X
5-Ethyl-2-methylheptane	13,475-78-0																X
3,4-Ethylmethylhexane	3074-77-9					X
2-Ethyl-4-methylpentanol	106-67-2	X
4-Ethyl-1-octyn-3-ol	5877-42-9						X
2-Ethylpentane	589-34-4			X
3-Ethylpentane	617-78-7			X
Ethylphenol	90-00-6															X
Ethyl propanoate	105-37-3		X
2-Ethyltoluene	611-14-3															X
3-Ethyltoluene	620-14-4															X
4-Ethyltoluene	622-96-8															X
Ethyl-Tris (Trimethylsilyl)-Silicate	18,030-67-6		X
Ethyl vinyl ketone	1629-58-9													X
F
Formic acid propylester	110-74-7										X
Furan	110-00-9											X
Furfural	98-01-1										X
H
Heptanal	111-71-7		X	X		X		X				X
Heptane	142-82-5		X			X									X
Heptanoic Acid	111-14-8															X
2-Heptanone	110-43-0		X
4-Heptanone	123-19-3					X
Heptene	592-76-7				X
Hexadecane	544-76-3					X										X
Hexamethyldisilane	1450-14-2		X
Hexanal	66-25-1			X		X			X			X	X
Hexane	110-54-3	X									X				X
Hexanoic Acid	142-62-1															X
Hexanol	111-27-3										X
2-Hexanone	591-78-6	X
3-Hexanone	589-38-8					X
Hexene	592-41-6											X
Hexylcyclohexane	4292-75-5																X
Hexylethylphos-phonofluoridate	135,445-19-1					X
2-Hexyloctanol	19,780-79-1		X
Hydrogen cyanide	74-90-8								X							X
2-Hydroxy acetaldehyde	141-46-8											X
3-Hydroxy-2-butanone	513-86-0								X			X
4-Hydroxyhexenal	17,427-21-3											X
4-Hydroxy-4-methylpentan-2-one	123-42-2												X
3-Hydroxy-2,4,4-trimethylpentyl 2-methylpropanoate	74,367-34-3						X
I
Indole	120-72-9				X	X	X
Iodide cycloheptatrienylium	142,182-71-6			X
β-Ionone	14,901-07-6														X
Isobutyl acetate	110-19-0								X
Isobutyric acid	79-31-2		X
Isoprene	78-79-5		X	X	X	X		X	X	X	X	X	X		X
Isopropanol	67-63-0		X		X	X				X		X
Isopropylacetate	108-21-4								X								X
Isopropylmyristate	110-27-0		X
4-Isopropoxylbutanol	42,042-71-7										X
1-Isopropyl-3-methylbenzene	535-77-3	X
Isopropyl myristate	110-27-0								X
L
Limonene	138-86-3		X	X	X	X										X
(+)-Longifolene	475-20-7		X
M
Menthol	89-78-1		X								X						X
Methane	74-82-8								X
Methane sulfonyl chloride	124-63-0			X
Methanethiol	74-93-1			X					X
Methanol	67-56-1		X		X			X	X	X		X
3-Methoxy-1,2-propanediol	623-39-2		X
1-(3-Methoxypropoxy)propanol	1589-49-7								X
Methyl Acetate	79-20-9								X
9-Methylacridine	611-64-3														X
Methylacrylic acid	79-41-4		X
Methylamine	74-89-5			X
Methylbenzene	108-88-3						X										X
2-Methyl-1,2-bis(trimethylsiloxy)-propane	6651-34-9		X
2-Methylbutanal	96-17-3															X
3-Methylbutanal	590-86-3															X
2-Methylbutane	78-78-4						X					X
2-Methylbutanoic acid	116-53-0		X			X
3-Methyl-2-butanone	563-80-4															X
3-Methylbutanonitrile	625-28-5				X
3-Methyl-3-butenol	763-32-6		X
Methyl butyrate	623-42-7													X
Methylcyclohexane	108-87-2						X
Methylcyclopentane	96-37-7						X
3-Methylcyclopentanone	1757-42-2					X
4-Methyldodecane	6117-97-1																X
3-(1-Methylethyl)oxetane	10,317-17-6																X
Methylene Chloride	75-09-2			X
4-Methyl-2-heptanone	6137-06-0		X
6-Methyl-5-hepten-2-one	110-93-0		X			X					X
2-Methylhexane	591-76-4	X		X	X						X
3-Methylhexane	589-34-4		X		X						X					X
5-Methyl-3-hexanone	623-56-3															X
4-Methylhexene-1,4-diol	40,646-08-0																X
Methylisobutylketone	108-10-1										X
Methylisobutyrate	547-63-7					X
1-Methyl-4-(1-methylethenyl)cyclohexene	5989-54-8	X
(R)-1-Methyl-5-(1-methyl)cyclohexene	1461-27-4		X
N-Methyl-2-methylpropylamine	39,190-66-4								X
2-Methylnaphthalene	91-57-6								X
3-Methylnonane	5911-04-6															X
4-Methyloctane	2216-34-4					X	X				X	X				X
2-Methylpentane	107-83-5	X					X				X					X
3-Methylpentane	96-14-0	X		X			X				X					X
4-methyl-2-pentanone	108-10-1						X
Methylphenol	620-17-7															X
2-Methylpropene	115-11-7				X
Methylpropylsulphide	3877-15-4					X
3-Methylpyridine	108-99-6		X
α-Methylstyrene	98-83-9										X
1-(Methylsulphonyl)propane	1977-37-3	X
2-Methyltetrahydrofuran	96-47-9															X
Methylthiocyanate	556-64-9								X
1-(Methylthio)propane	3877-15-4				X								X
Methylthiopropene	10,152-77-9												X
Methylundecane	1632-70-8												X
4-Methylundecane	2980-69-0						X
N
Naphthalene	91-20-3		X
6-Nitro-2-picoline	18,368-61-1			X
Nonadecane	629-92-5					X
4,6,9-Nonadecatriene	874,302-34-8	X
Nonanal	124-19-6	X		X		X	X	X				X	X
Nonane	111-84-2	X			X										X
Nonanoic Acid	112-05-0					X
Nonanol	28,473-21-4										X
2-Nonanone	821-55-6		X						X
(E)-2-Nonene	6434-78-2				X
O
Octadecane	593-45-3					X
Octadecyne	629-89-0	X
Octamethylcyclo-tetrasiloxane	556-67-2		X
Octanal	124-13-0							X				X
Octane	111-65-9	X			X	X									X
Octanoic acid	124-07-2						X
3-Octanone	106-68-3										X
2-Octenal	2363-89-5	X
Octene	111-66-0				X											X
2-Octene	13,389-42-9								X
3-Octene	14,919-01-8								X
P
Pentadecane	629-62-9		X
1,2-Pentadiene	591-95-7						X
1,4-Pentadiene	591-93-5		X						X
2,2,4,6,6-Pentamethylheptane	13,475-82-6	X
Pentanal	110-62-3			X								X				X
Pentane	109-66-0				X							X
Pentanoic acid	109-52-4						X									X
Pentanol	71-41-0								X
3-Pentanol	584-02-1																X
2-Pentanone	107-87-9		X		X	X						X				X
3-Pentanone	96-22-0				X
2-Pentylfuran	3777-69-3				X
Phenyl acetate	122-79-2										X
Phenylacetic acid	103-82-2														X
Phenylbutene	935-00-2	X
2-Phenyl-2-propanol	617-94-7		X
4-(1-Phenyl-2-propenyloxy)-benzaldehyde	447,428-96-8			X
Phenol	108-95-2		X		X		X		X		X					X
α-Pinene	80-56-8		X		X	X							X
β-Pinene	127-91-3				X										X		X
Pivalic acid	75-98-9										X
Propanal	123-38-6					X		X	X		X	X
Propane	74-98-6											X
1,2-Propanediol	57-55-6		X
1,3-Propanediol	504-63-2										X
Propanoic Acid	79-09-4					X
Propanol	71-23-8	X			X			X				X
2-Propenal	107-02-8											X
Propene	115-07-1											X
2-Propenenitrile	107-13-1										X					X
2-Propenoic acid	79-10-7		X
Propylcyclohexane	1678-92-8												X
Propyl propionate	106-36-5													X
1H-Pyrazole-4-carbonitrile	31,108-57-3			X
2-Pyridinecarbonitrile	100-70-9			X
1H-Pyrrole-3-carbonitrile	7126-38-7			X
Pyrrolidine	123-75-1		X
S
Silicon tetrafluoride	7783-61-1			X
Styrene	100-42-5			X	X							X
T
α-Terpinene	99-86-5				X
γ-Terpinene	99-85-4				X
Terpineol	8006-39-1					X
Tetrachloroethene	127-18-4														X
Tetradecane	629-59-4	X	X		X	X	X				X				X
9-Tetradecenol	52,957-16-1															X
1,2,3,5-Tetramethylbenzene	527-53-7		X
1,2,4,5-Tetramethylbenzene	95-93-2		X
Tetramethylsilicane	75-76-3		X
1,1,3,3-Tetramethylurea	632-22-4		X
Tolualdehyde	1334-78-7								X
Toluene	108-88-3		X			X
Trans-2-dodecenol	69,064-37-5						X
4H-1,2,4-Triazol-4-amine	584-13-4			X
Trichlorethylene	79-01-6		X
Trichloromethane	67-66-3			X
Tridecane	629-50-5		X		X		X						X				X
Trifluoroacetic acid	76-05-1		X
Triglyceride	32,765-69-8															X
Trimethylamine	75-50-3			X	X											X
1,2,3-Trimethylbenzene	526-73-8										X					X
1,2,4-Trimethylbenzene	95-63-6											X				X
1,3,5-Trimethylbenzene	108-67-8										X				X	X	X
Trimethyldecane	98,060-54-9						X
2,4,6-Trimethyldecane	62,108-27-4					X
2,6,10-Trimethyldodecane	3891-98-3	X
2,6,11-Trimethyldodecane	31,295-56-4		X								X
2,7,10-Trimethyldodecane	74,645-98-0		X
2,2,4-Trimethylheptane	14,720-74-2	X
2,2,3-Trimethylhexane	16,747-25-4			X									X
2,3,5-Trimethylhexane	1069-53-0												X		X
4,6,8-Trimethylnonene	54,410-98-9																X
2,2,6-Trimethyloctane	62,016-28-8			X
2,6,6-Trimethyloctane	54,166-32-4															X
2,3,6-Trimethyloctane	62,016-33-5	X
2,4,4-Trimethylpentene	107-39-1					X
1,3,5-Tri-tert-butylbenzene	1460-02-2					X
Tolualdehyde	1334-78-7										X
Toluene	108-88-3			X								X	X		X	X
U
2-Undecanal	53,448-07-0	X
Undecane	1120-21-4		X			X			X							X
V
Vinylpyrazine	4177-16-6					X
X
m-Xylene	108-38-3										X
o-Xylene	95-47-6											X					X
p-Xylene	106-42-3	X	X									X			X	X