NAC/Interim 1: 07/2008

INTERIM 

ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs) 

FOR 

FORMALDEHYDE

(CAS Reg. No. 50-00-0) 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 2 of 71

1 PREFACE

2 

3 Under the authority of the Federal Advisory Committee Act (FACA) P. L. 92-463 of 

4 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous 

5 Substances (NAC/AEGL Committee) has been established to identify, review and interpret 

6 relevant toxicologic and other scientific data and develop AEGLs for high priority, acutely toxic 

7 chemicals. 

8 

9 AEGLs represent threshold exposure limits for the general public and are applicable to 

10 emergency exposure periods ranging from 10 minutes to 8 hours. Three levels C AEGL-1, 

11 AEGL-2 and AEGL-3 C are developed for each of five exposure periods (10 and 30 minutes, 1 

12 hour, 4 hours, and 8 hours) and are distinguished by varying degrees of severity of toxic effects. 

13 The three AEGLs are defined as follows: 

14 

15 AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per 

cubic meter [ppm or mg/m3 16 ]) of a substance above which it is predicted that the general 

17 population, including susceptible individuals, could experience notable discomfort, irritation, or 

18 certain asymptomatic, non-sensory effects. However, the effects are not disabling and are 

19 transient and reversible upon cessation of exposure. 

20 

AEGL-2 is the airborne concentration (expressed as ppm or mg/m3 21 ) of a substance above 

22 which it is predicted that the general population, including susceptible individuals, could 

23 experience irreversible or other serious, long-lasting adverse health effects or an impaired ability 

24 to escape. 

25 

AEGL-3 is the airborne concentration (expressed as ppm or mg/m3 26 ) of a substance above 

27 which it is predicted that the general population, including susceptible individuals, could 

28 experience life-threatening health effects or death. 

29 

30 Airborne concentrations below the AEGL-1 represent exposure levels that could produce 

31 mild and progressively increasing but transient and nondisabling odor, taste, and sensory 

32 irritation or certain asymptomatic, non-sensory effects. With increasing airborne concentrations 

33 above each AEGL, there is a progressive increase in the likelihood of occurrence and the 

34 severity of effects described for each corresponding AEGL. Although the AEGL values 

35 represent threshold levels for the general public, including susceptible subpopulations, such as 

36 infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized 

37 that individuals, subject to unique or idiosyncratic responses, could experience the effects 

38 described at concentrations below the corresponding AEGL.
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 3 of 71

1 

2 TABLE OF CONTENTS 

3 PREFACE.....................................................................................................................................................2 

4 LIST OF TABLES........................................................................................................................................6 

5 EXECUTIVE SUMMARY...........................................................................................................................7 

6 1. INTRODUCTION................................................................................................................................9 

7 2. HUMAN TOXICITY DATA.............................................................................................................10 

8 2.1. Acute Lethality ..............................................................................................................................10 

9 2.2. Nonlethal Toxicity .........................................................................................................................10 

10 2.2.1. Odor threshold...........................................................................................................................10 

11 2.2.2. Indoor Air Exposures ................................................................................................................11 

12 2.2.3. Occupational Exposures ............................................................................................................11 

13 2.2.4. Clinical Studies..........................................................................................................................13 

14 2.3. Neurotoxicity .................................................................................................................................26 

15 2.4. Developmental/Reproductive Toxicity..........................................................................................27 

16 2.5. Genotoxicity...................................................................................................................................27 

17 2.6. Carcinogenicity..............................................................................................................................27 

18 2.7. Summary........................................................................................................................................28 

19 3. ANIMAL TOXICITY DATA............................................................................................................29 

20 3.1. Acute Lethality ..............................................................................................................................29 

21 3.1.1. Rats............................................................................................................................................30 

22 3.1.2. Mice...........................................................................................................................................31 

23 3.2. Nonlethal Toxicity .........................................................................................................................31 

24 3.2.1. Nonhuman Primates ..................................................................................................................32 

25 3.2.2. Rats............................................................................................................................................32 

26 3.2.3. Mice...........................................................................................................................................34 

27 3.2.4. Guinea Pigs................................................................................................................................35 

28 3.3. Neurotoxicity .................................................................................................................................36 

29 3.4. Developmental/Reproductive Toxicity..........................................................................................36 

30 3.5. Genotoxicity...................................................................................................................................36 

31 3.6. Chronic Toxicity/Carcinogenicity .................................................................................................37 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 4 of 71

1 3.7. Summary........................................................................................................................................41 

2 4. SPECIAL CONSIDERATIONS ........................................................................................................43 

3 4.1. Metabolism and Disposition ..........................................................................................................43 

4 4.2. Mechanism of Toxicity..................................................................................................................43 

5 4.3. Structure-Activity Relationships....................................................................................................44 

6 4.4. Other Relevant Information ...........................................................................................................44 

7 4.4.1. Species Variability.....................................................................................................................44 

8 4.4.2. Susceptible Populations.............................................................................................................45 

9 4.4.3. Concentration-Exposure Duration Relationship........................................................................46 

10 4.4.4. Concurrent Exposure Issues ......................................................................................................47 

11 5. DATA ANALYSIS FOR AEGL-1 ....................................................................................................47 

12 5.1. Summary of Human Data Relevant to AEGL-1 ............................................................................47 

13 5.2. Summary of Animal Data Relevant to AEGL-1............................................................................47 

14 5.3. Derivation of AEGL-1 ...................................................................................................................48 

15 6. DATA ANALYSIS FOR AEGL-2 ....................................................................................................48 

16 6.1. Summary of Human Data Relevant to AEGL-2 ............................................................................48 

17 6.2. Summary of Animal Data Relevant to AEGL-2............................................................................49 

18 6.3. Derivation of AEGL-2 ...................................................................................................................50 

19 7. DATA ANALYSIS FOR AEGL-3 ....................................................................................................50 

20 7.1. Summary of Human Data Relevant to AEGL-3 ............................................................................50 

21 7.2. Summary of Animal Data Relevant to AEGL-3............................................................................50 

22 7.3. Derivation of AEGL-3 ...................................................................................................................51 

23 8. SUMMARY OF AEGLS ...................................................................................................................51 

24 8.1. AEGL Values and Toxicity Endpoints ..........................................................................................51 

25 8.2. Comparison with Other Standards and Guidelines ........................................................................51 

26 8.3. Data Adequacy and Research Needs .............................................................................................54 

27 9. REFERENCES...................................................................................................................................54 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 5 of 71

1 APPENDIX A: LEVEL OF DISTINCT ODOR AWARENESS ..............................................................63 

2 APPENDIX B: CARCINOGENICITY ASSESSMENT...........................................................................64 

3 APPENDIX C: DERIVATION OF AEGL VALUES ...............................................................................65 

4 APPENDIX D: CATEGORY GRAPH OF TOXICITY DATA AND AEGL VALUES..........................68 

5 APPENDIX E: DERIVATION SUMMARY FOR FORMALDEHYDE AEGLS....................................69 

6 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 6 of 71

1 

2 LIST OF TABLES 

3 

4 TABLE 1. Summary of AEGL Values for Formaldehyde .........................................................................................8 

5 TABLE 2. Chemical and Physical Properties ..........................................................................................................10 

6 TABLE 3. Irritant Effects of Formaldehyde in Controlled Human Studies .............................................................13 

7 TABLE 4. Summary of Acute Lethal Inhalation Data in Laboratory Animals........................................................30 

8 TABLE 5. Summary of Subchronic and Chronic/Carcinogenicity Studies in Laboratory Animals.........................39 

9 TABLE 6. AEGL-1 Values for Formaldehyde ........................................................................................................48 

10 TABLE 7. AEGL-2 Values for Formaldehyde ........................................................................................................50 

11 TABLE 8. AEGL-3 Values for Formaldehyde ........................................................................................................51 

12 TABLE 9. Summary of AEGL Values ....................................................................................................................51 

13 TABLE 10. Extant Standards and Guidelines for Formaldehyde ..............................................................................53 

14 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 7 of 71

1 EXECUTIVE SUMMARY

2 

3 Formaldehyde is a colorless flammable gas with a pungent, suffocating odor. It is 

4 ubiquitous in the atmosphere as a constituent of smog, in homes that contain urea-formaldehyde 

5 foam insulation or particle board construction, and at production sites. It is a naturally-occurring 

6 constituent of many foods and is a normal metabolite in the human body. 

7 

8 The data base on formaldehyde is robust, with human and animal studies that address 

9 various endpoints and cover acute through chronic exposure durations. The primary effect 

10 during short-term exposures is irritation of the eye, nose, and throat. At low concentrations of 

11 1 to 3 ppm, formaldehyde is well scrubbed in the nasal passages of both humans and rodents and 

12 does not reach the lower respiratory tract. At higher concentrations, formaldehyde is an extreme 

13 irritant. Chronic studies with moderate concentrations (14 ppm) result in carcinomas of the 

14 anterior nasal passages of the rat. Formaldehyde is a weaker carcinogen in the mouse and is not 

15 carcinogenic in the hamster. Because formaldehyde is so highly reactive and rapidly 

16 metabolized/detoxified by the tissues of the nasal passages, inhalation is unlikely to result in 

17 cancers at remote sites. Epidemiology studies have failed to show a clear relationship between 

18 exposure and carcinogenicity. 

19 

20 The irritant properties of formaldehyde and its effects on pulmonary function parameters 

21 have been reported in 22 clinical studies with over 500 healthy and sensitive subjects (potentially 

22 sensitive subjects included both asthmatics and subjects who reported sensitivity to 

23 formaldehyde). In most of the studies, eye irritation was the most sensitive endpoint. At 

24 concentrations <1 ppm, there is no clear dose-response to the irritant properties of formaldehyde, 

25 and responses do not differ greatly from those of control atmospheres. At 1 ppm, the eye 

26 irritation response ranges from slight to moderate, with adaptation occurring with prolonged 

27 exposure. At 3 ppm for several hours, the response in heavily exercising individuals and 

28 moderately exercising individuals is similar (Green et al. 1987). Eye, nose, and throat irritation 

29 ranged from mild to moderate, and there were small, transient decrements in pulmonary function 

30 parameters in healthy subjects. In the absence of exercise, there are no decrements in pulmonary 

31 function parameters in either healthy or asthmatic subjects inhaling 3 ppm for 3 hours 

32 (Sheppard et al. 1984; Sauder et al. 1986; 1987). 

33 

34 The AEGL-1 was based on a NOAEL for eye irritation in a single study with subjects 

35 whose eyes were sensitive to formaldehyde (Bender et al. 1983). In this study, groups of 5 to 28 

36 healthy subjects were exposed eye-only for 6 minutes to 0, 0.35, 0.56, 0.7, 0.9, or 1.0 ppm. The 

37 subjects had been selected for their response to formaldehyde at 1.3 or 2.2 ppm, i.e., subjects that 

38 did not report eye irritation during previous exposures to 1.3 or 2.2 ppm were excluded from the 

39 study. At 0.35 to 0.9 ppm, the subjects= subjective eye irritation responses ranged from none to 

40 slight, the same as their responses to clean air. The 0.9 ppm concentration was selected as the 

41 basis for the AEGL-1. No intraspecies uncertainty factor was applied as no additional sensitive 

42 populations were identified [there were no significant decrements in pulmonary function 

43 parameters in exercising asthmatic subjects at 2 or 3 ppm, and asthmatic subjects reported less 

44 than moderate eye irritation, the same as healthy subjects, at these concentrations (Green et al. 

45 1987; Kulle et al. 1987; Sauder et al. 1987)]. Because several studies show there is adaptation to 

46 irritation at this low concentration, the 0.9 ppm concentration was applied across all exposure 

47 durations. This value is supported by the fact that animal studies show there is no damage to the 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 8 of 71

1 respiratory epithelium during single (Morgan et al. 1986b) or repeated exposures to 1 or 2 ppm 

2 (Rusch et al. 1983; Maronpot et al.1986; Woutersen et al. 1987). 

3 

4 The AEGL-2 was based on the clinical study of Sim and Pattle (1957). Twelve healthy 

5 male subjects inhaled 13.8 ppm for 30 minutes. Initially, the exposure caused considerable nose 

6 and eye irritation. Mild lacrimation continued for some period of time. The eye irritation was 

7 not considered severe, and adaptation occurred in about 10 minutes. Mild lacrimation at 13.8 

8 ppm (rounded to 14 ppm) with adaptation was considered the threshold concentration for the 

9 inability to escape. The lacrimation experienced by Barnes and Speicher (1942) at 20 ppm 

10 during short exposures might impair the ability to escape. The 14 ppm concentration may also 

11 be close to the threshold for an increase in airways resistance (Douglas 1974). No intraspecies 

12 uncertainty factor was applied to the 14 ppm concentration because application of an uncertainty 

13 factor of $3 would lower the value to close to a no-effect concentration in several studies with 

14 exercising asthmatics. Because the endpoint is eye and nose irritation to which adaptation 

15 occurs, the same value was used across all exposure durations. 

16 

17 The AEGL-3 values were based on the highest non-lethal value for the rat following a 4-

18 hour exposure to 350 ppm (Nagorny et al. 1979). The value was adjusted by interspecies and 

19 intraspecies uncertainty factors of 3 each for a total of 10. These uncertainty factors, applied to 

20 irritants, are protective of sensitive populations. Furthermore, application of larger uncertainty 

21 factors, e.g., a total of 30, would reduce the value to the level of the AEGL-2. No data on time22 scaling were found. Therefore, the default value of n = 3 when scaling to shorter exposure 

23 periods (NRC 2001) was applied. The 8-hour value was set equal to the 4-hour value because 

24 formaldehyde is well scrubbed in the nasal passages. Furthermore, application of the default of n 

25 = 1 when scaling to longer time periods would result in an 8-hour value of 18 ppm, similar to the 

26 8-hour AEGL-2. The 8-hour value is supported by sublethal concentrations in additional animal 

27 studies. For example, no deaths occurred in rats that inhaled 35 ppm for 18 hours 

28 (Murphy et al. 1964). 

29 

30 The calculated values are listed in Table 1 below. 

31 

TABLE 1. Summary of AEGL Values for Formaldehyde 

Classification 10-min 30-min 1-h 4-h 8-h Endpoint (Reference) 

AEGLB1a

(Nondisabling) 

0.90 ppm 

(1.1 mg/m3

) 

0.90 ppm 

(1.1 mg/m3)

0.90 ppm 

(1.1 mg/m3)

0.90 ppm 

(1.1 mg/m3 ) 

0.90 ppm 

(1.1 mg/m3) 

NOAEL for eye irritation -

sensitive human subjects 

(Bender et al. 1983) 

AEGLB2 

(Disabling) 

14 ppm 

(17 mg/m3

) 

14 ppm 

(17 mg/m3) 

14 ppm 

(17 mg/m3) 

14 ppm 

(17 mg/m3) 

14 ppm 

(17 mg/m3) 

Mild lacrimation with 

adaptation - humans (Sim 

and Pattle 1957) 

AEGLB3 

(Lethal) 

100 ppm 

(123 mg/m3

) 

70 ppm 

(86 mg/m3) 

56 ppm 

(69 mg/m3) 

35 ppm 

(43 mg/m3) 

35 ppm 

(43 mg/m3) 

Highest non-lethal value - 

rat (Nagorny et all 1979) 

a 32 Most individuals will notice the distinct, pungent odor of formaldehyde at the AEGL-1. The Level of Distinct Odor 

33 Awareness is 3.6 ppm.

34 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 9 of 71

1 1. INTRODUCTION

2 

3 Formaldehyde is a flammable colorless gas with a pungent, suffocating odor. Its high 

4 chemical reactivity, good thermal stability, and ability to polymerize make it a useful material in 

5 the synthesis of a wide variety of products. The most common form of the material is aqueous 

6 solutions (formalin), with a formaldehyde content of 37-50%, by weight. Paraformaldehyde is a 

7 solid polymer of formaldehyde which can be easily vaporized to its monomeric form (O=Neil et 

8 al. 2001). Chemical and physical properties are listed in Table 2. 

9 

10 Total annual capacity for production in the United States in 1998 was 11.3 billion 

11 pounds. The primary method of manufacture is from methanol with either silver or a metal oxide 

12 as catalyst (ATSDR 1999). Most formaldehyde produced in the United States (23%) is used in 

13 urea-formaldehyde resins. Other uses include phenolic resins (19%), acetylenic chemicals 

14 (12%), polyacetal resins (11%), methylene diisocyanate (6%), pentaerythritol (5%), urea15 formaldehyde concentrates (4%), hexamethylenetetramine (4%), melamine resins (4%), and 

16 miscellaneous (12%) (ATSDR 1999). The phenolic, urea, and melamine resins are used in the 

17 manufacture of plywood, fiberboard, and particle board. Worldwide production in 2000 was 21, 

18 547 thousand tons (IARC 2006). 

19 

20 Formaldehyde is ubiquitous in the environment as it is found in a great number of 

21 consumer products such as cosmetics, permanent press fabrics, particle board, plywood, floor 

22 coverings, office furniture, and urea-formaldehyde foam insulation. Cigarette smoke may 

23 contain up to 40 ppm formaldehyde (Turoski 1984). Outdoors, the major source of atmospheric 

24 formaldehyde is from auto emissions and from the photooxidation of hydrocarbons in auto 

25 emissions (NRC 1981). 

26 

27 Formaldehyde is found in a large number of common foods and drinks. It occurs as a 

28 natural constituent of raw fruits including pears, apples, tomatoes, and white radish in amounts 

29 varying from 3.7 to 60 ppm. It also occurs in raw vegetables such as cabbage, carrots, green 

30 onions, and spinach in amounts varying from 3.3 to 26.3 ppm. Its maximum oral intake is 

31 estimated to be 14.2 mg/person/day (Feron et al. 1991). 

32 

33 Formaldehyde is an essential metabolic intermediate in all cells. It is produced during 

34 the normal metabolism of serine, glycine, methionine, and choline and also by the demethylation 

35 of N-, S-, and O-methyl compounds. As such, it is a normal metabolite, and enters into the chain 

36 of biochemical events in humans and other animals to give rise to essential cellular substances 

37 (NRC 1981). 

38 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 10 of 71

TABLE 2. Chemical and Physical Properties 

Parameter Value Reference 

Synonyms Methanal, oxomethane, 

oxymethylene, methylene oxide 

formic aldehyde, methyl aldehyde 

O=Neil et al. 2001 

Chemical formula CH2O O=Neil et al. 2001 

Molecular weight 30.03 O=Neil et al. 2001 

CAS Reg. No. 50-00-0 ATSDR 1999 

Physical state Gas O=Neil et al. 2001 

Solubility in water Very soluble, up to 55% 

980 L/L water at 20EC 

O=Neil et al. 2001 

Andersen and Molhave 1983 

Vapor pressure @ 25EC 3883 mm Hg ATSDR 1999 

Vapor density (air =1) 1.067 O=Neil et al. 2001 

Liquid density (water =1) 0.815 g/mL ATSDR 1999 

Melting point S 92EC O=Neil et al. 2001 

Boiling point S19.5EC O=Neil et al. 2001 

Flammability limits @ 25EC 7-73% ATSDR 1999 

Ignition temperature 300EC O=Neil et al. 2001 

Conversion factors 1 ppm = 1.23 mg/m3

1 mg/m3

 = 0.813 ppm 

ATSDR 1999 

1 

2 

3 2. HUMAN TOXICITY DATA

4 2.1. Acute Lethality

5 

6 No reports of deaths from short-term inhalation of formaldehyde were located. 

7 

8 2.2. Nonlethal Toxicity

9 

10 Formaldehyde is an eye, upper respiratory tract, and skin irritant. Dermal contact may 

11 cause sensitization. Because it is extremely water soluble, it is extensively Ascrubbed@ in the 

12 anterior nasal passages. The irritant effects of formaldehyde from construction products in the 

13 home, occupational exposures, and controlled clinical studies have been reported. 

14 

15 2.2.1. Odor threshold

16 

17 Formaldehyde has a distinct, pungent odor. The odor threshold has been studied by 

18 several groups. The odor of formaldehyde can be recognized by most individuals at 

19 concentrations below 1 ppm. The concentration at which a group of observers can detect the 

20 odor in 50% of the presentations is between 0.05 and 0.18 ppm. The individual odor detection 

21 threshold covers Aover two powers of ten,@ and the distribution is extremely positively skewed 

(WHO 1989). Berglund et al. (1987) reported that the 50th 22 percentile detection threshold was 

23 0.145 ppm, the 10-percentile threshold was 0.020 ppm and the 90-percentile threshold was 0.5 

24 ppm. The Level of Distinct Odor Awareness (LOA) was derived using the data of Berglund et 

25 al. (1987). Calculations are contained in Appendix A. The LOA for formaldehyde is 3.6 ppm. 

26 

27 The odor threshold was measured for 64 subjects, ages 17-64 years, in a climate28 controlled chamber (Pettersson and Rehn 1977). The subjects placed their heads in a hood 

29 during the exposures. The exposures were alternately to a formaldehyde-air mixture or clean air, 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 11 of 71

1 given in a random manner, and the subjects had to determine in which of the two exposures 

2 formaldehyde was present. Concentration ranged from 0.01 to 1.0 ppm. The lowest detectable 

3 odor was 0.04 ppm. There was a dose-response to odor detection above this level. At slightly 

4 greater than 1.0 ppm all 64 subjects could correctly detect the odor. 

5 

6 In another study that addressed the odor threshold as well as effects on the central 

7 nervous system, a panel of 12 persons, ages 19-64, judged 0.09 ppm as the threshold 

8 concentration for odor perception (Melekhina 1964). Following adaptation to a climate 

9 controlled chamber, the threshold for odor perception was 0.06 ppm. Additional odor threshold 

10 values cited in U.S. EPA (1992) range from 0.06 to 0.3. Amoore and Hautala (1983) cite 0.83 

11 ppm and Billings and Jonas (1981) cite 1.0 ppm as odor thresholds. The threshold for odor 

12 recognition by a trained odor panel was 1.0 ppm (Leonardos et al. 1969). The odor was 

13 characterized as hay/straw-like, pungent. 

14 

15 2.2.2. Indoor Air Exposures

16 

17 As noted, formaldehyde is a commonly encountered environmental chemical. 

18 Consumers may be exposed to formaldehyde from a number of sources, including cigarette 

19 smoke, formaldehyde-containing resinous products, and cooking. Formaldehyde is present 

20 indoors as an off-gassed product of construction materials such as plywood and urea21 formaldehyde foam insulation. An important source of indoor formaldehyde is cigarette smoke 

22 (WHO 1989). The majority of complaints registered with the Consumer Product Safety 

23 Commission involved eye and upper respiratory tract irritation attributed to off-gassing from 

24 formaldehyde foam insulation, particle board, or plywood; concentrations ranged from 0.01 to 32 

25 ppm (NRC 1980). Indoor air exposures can exceed 1.0 ppm (ATSDR 1999), but are generally 

26 lower than in the work environment. A study of nearly 2000 residents of mobile and 

27 conventional homes that reported symptoms related to formaldehyde was undertaken by Ritchie 

28 and Lehnen (1987). Measured concentrations ranged from <0.1 ppm to ≥0.3 ppm. The study 

29 reported a positive dose-response between formaldehyde concentrations and self-reported health 

30 complaints. In all cases complaints were substantially more frequent with concentrations above 

31 0.3 ppm. The percentage of respondents reporting eye irritation at <0.1, 0.1 to <0.3, and ≥0.3 

32 ppm were similar between mobile and conventional homes (2 vs 1%, 32 vs 12%, and 93 vs 89%, 

33 respectively). The contribution of smoking to eye irritation was noted in both types of homes, 

34 but exposure to other chemicals was not evaluated. The participants received a free medical test 

35 and so were self-selected with a potential bias. 

36 

37 2.2.3. Occupational Exposures 

38 

39 Occupational sources and concentrations have been reviewed by several agencies. 

40 Several such surveys are cited here as examples of past routine exposures. In some cases 

41 symptoms were also reported, but many of the survey results are complicated by the presence of 

42 other chemicals in the manufacturing process. Usually the frequency, exact concentration, and 

43 duration of exposure are not provided. A few recent occupational studies are also cited. 

44 

45 NIOSH (1976) reviewed early reports on occupational exposures to formaldehyde. In these 

46 reports, irritation of the upper respiratory tract was reported at formaldehyde concentrations 

47 between 0.09 and 11 ppm. Sampling periods varied, but periods of 15 and 30 minutes were 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 12 of 71

1 reported in some studies. Examples of occupations and workplace concentrations follow: 

2 handling flame-proof fabrics, 1-11 ppm; dress shop, 0.13-0.45 ppm; resin manufacturing and 

3 paper plant, 16-30 ppm; paper conditioning installation, 0.9-1.6 ppm; funeral home (use of 

4 formaldehyde and paraformaldehyde in embalming process), average 0.25-1.39 ppm with range 

5 up to 5.26 ppm; clothing store, 0.9-3.3 ppm; textile garment factory, 0.9-2.7 ppm (irritation noted 

6 followed by adaptation), wood processing plant, 2.1-8.9 ppm, ranging up to 31 ppm (illnesses 

7 noted); and two laminating plants using phenol-resorcinol glue (which emits formaldehyde), 

8 0.04-10.9 ppm. Concentrations in the latter two plants depended on area of the plant and the 

9 specific glue used. The authors reported that employees objected when airborne concentrations 

10 exceeded 1 ppm, and the odor at concentrations of 4.2 to 10.9 ppm was considered unbearable. 

11 Dermatitis was a common complaint in workers handling formaldehyde-impregnated materials. 

12 

13 OSHA (1996) estimated that in the late 1980s over 2 million workers were exposed to 

14 formaldehyde. Most of these workers were in the garment industry. About 1.9 million workers 

15 in the apparel, furniture, paper mill and plastic molding industries were exposed to between 0.1 

16 and 0.5 ppm. Approximately 123,000 workers were exposed to between 0.5 and 0.75 ppm, and 

17 about 84,000 were exposed to 0.75 to 1 ppm. A U.S. EPA (1982) survey of occupational 

18 exposures found mean concentrations of 0.1 to 0.9 ppm, with ranges up to 2.2 ppm. Exposures 

19 were highest during the direct manufacture of formaldehyde. IARC (2006) also summarized 

20 workplace concentrations. Mean concentrations in formaldehyde and resin manufacturing 

21 plants, plywood mills, particle-board mills, furniture factories, textile mills and garment 

22 factories, foundries, mortuaries, building sites, etc., ranged from 0.1 to 38 ppm (range, <0.01 to 

23 61 ppm). 

24 

25 Horvath et al. (1988) conducted a well-designed study with a formaldehyde exposed 

26 group and an unexposed group. The exposed workers were employed in a particle board and 

27 molded plastics plant; the duration of exposure was from <1 to 20 years. Formaldehyde 

28 concentrations ranged from 0.17 to 2.93 ppm (mean 0.69 ppm). Formaldehyde concentrations 

29 were determined by both passive and active sampling procedures. On the day of examination, 

30 test subjects were monitored with formaldehyde monitors (3M, St. Paul, MN; lower limit of 

31 sensitivity of 0.1 ppm). Area samples were taken with an sampling train that employed a liquid 

32 medium impinger containing 1% sodium bisulfite. Both types of samples were analyzed 

33 according to NIOSH 77-157A. Nuisance particles of softwood dust were present at similar 

34 concentrations at the particle board plant and the two control plants. The control group was 

35 employed in the food-processing industry. A symptom questionaire and spirometry were 

36 administered to all participants before and after the workshift. 

37 

38 Spirometry results showed that exposed workers had some evidence of an acute decline 

39 in some pulmonary function parameters. The authors considered the respiratory changes “small 

40 and probably transient.” As baseline values were similar among controls and exposed workers, 

41 the authors concluded that exposure to these low levels for up to ten years did not appear to 

42 cause permanent respiratory impairment. Spirometry results showed that exposed workers had 

43 some evidence of an acute decline in some pulmonary function parameters. These consisted of 

44 statistically significant postshift decreases in forced expiratory volume in 1 second divided by 

45 percent forced vital capacity (1%), peak expiratory flow rate during the middle half of the forced 

46 vital capacity (5%), forced expiratory flow at 50% and 75% of the forced vital capacity (4% and 

47 7%). The authors considered the respiratory changes “small and probably transient.” Controls 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 13 of 71

1 showed 1% declines in forced expiratory volume in 1 second and forced vital capacity (not 

2 significant in the control group). As baseline values were similar among controls and exposed 

3 workers, the authors concluded that exposure to the low levels of formaldehyde for up to ten 

4 years did not appear to cause permanent respiratory impairment. Respiratory complaints were 

5 higher in the exposed group than the control group for cough (35% vs 19%), chest pains (9% vs 

6 2%), production of mucus (27% vs 10%) burning sensation of the nose (28% vs 2%), nasal 

7 congestion (34% vs 14%), and dry or burning throat (22 vs 4%). The exposed group also 

8 reported burning eyes with a greater frequency that the control group (40% vs 9%). Frequencies 

9 between the control and exposed group were similar for shortness of breath and wheezing. 

10 

11 The responses of medical students to formaldehyde in a gross anatomy laboratory 

12 compared with those of non-exposed students were reported in two studies. In the first study, 

13 Akbar-Khanzadeh et al. (1994) found no statistically significant differences in pulmonary 

14 function parameters (FVC, FEV1, FEV3 and FEF25-75%) in 12 subjects exposed to an estimated 

15 TWA of 1.24 ppm for 2- to 3-hour periods. In the second study (Akbar-Khanzadeh and Mlynek 

16 1997), 50 medical students were exposed to a mean concentration of 1.88 ppm (range, 0.30-4.45 

17 ppm) for 3 hours. These 157-minute samples were taken in the breathing zone of the students. 

18 The control group consisted of 36 nonexposed physical therapy students. Eye and nose irritation 

19 were reported by more than 70% of the exposed students. Respiratory function parameters for 

20 both groups increased in a manner related to diurnal variation, but there was no relationship 

21 between concentration of formaldehyde in the breathing zone and changes in respiratory function 

22 of exposed subjects. 

23 

24 2.2.4. Clinical Studies

25 

26 Twenty-three clinical studies with human subjects were located (Table 3). Most of the 

27 studies were conducted with controlled environmental exposure chambers supplied with filtered 

28 air. Formaldehyde was generated from purified paraformaldehyde, although heated solutions of 

29 formaldehyde were used in some studies. In the older studies, analytical measurements involved 

30 the NIOSH-recommended chromotropic acid method, and more recent studies involved 

31 formaldehyde specific air monitors. Pulmonary function parameters were measured with a 

32 spirometer and included forced vital capacity (FVC or VC), forced expiratory volume in 1 

33 second (FEV1), forced expiratory flow during the middle half of the functional residual capacity 

34 (FEF25-75), and PEF or PEFR (peak expiratory flow or flow rate). Airway resistance (Raw) and 

35 functional residual capacity (FRC) were measured with a whole-body pressure plethysmographic 

36 technique. Airway resistance was converted to specific airway conductance (SRaw or SGaw). 

37 Exercise was incorporated into some of the protocols in order to increase minute ventilation 

38 (VE). 

39 

40 Entries in Table 3 are listed generally in order of increasing concentrations. Some of the 

41 studies address the response of healthy and asthmatic subjects as well as subjects sensitized to 

42 formaldehyde. Several studies address eye irritation only which has been identified as the most 

43 sensitive irritant response to formaldehyde (Paustenbach et al. 1997). 

44 

TABLE 3. Irritant Effects of Formaldehyde in Controlled Human Studies 

Concentration 

(ppm) Time 

Subjects/Effect 

(number of subjects) Reference 

0, 0.35, 0.56, 0.7, 6 min Healthy subjects (groups of 7-28), excluded Bender et al. 1983 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 14 of 71

TABLE 3. Irritant Effects of Formaldehyde in Controlled Human Studies 

Concentration 

(ppm) Time 

Subjects/Effect 

(number of subjects) Reference 

0.9, 1.0 non-responders at 1.3 or 2.2 ppm; 

Eye irritation evaluated: average scores of 

none to slight at 0.35 to 0.9 ppm; slight to 

moderate at 1.0 ppm; slight adaptation with 

time 

0, 0.10, 0.69 90 min Asthmatic nonsmoking subjects (15): 

No significant change in pulmonary 

function parameters (FEV1 and airway 

resistance) or in bronchial reactivity; no 

association of subjective ratings of 

asthmatic symptoms with increasing air 

concentrations 

Harving et al. 1986; 

1990 

0, 0.41 2 h Healthy occupationally exposed (5) and 

contact dermatitis subjects (13): 

No effect on pulmonary parameters (VC, 

FEV1); immune response in subjects with 

contact dermatitis (increased 

chemiluminescense of neutrophils) 

Gorski et al 1992 

0, 0.41 2 h Healthy (11) and patients with skin 

hypersensitivity to formaldehyde (9) (all 

nonsmokers): 

No differences in response between groups; 

transient increase in symptoms of sneezing, 

rhinorrhea, or eye irritation; nasal washings 

showed increases in eosinophils, albumin, 

total protein, but not neutrophil, basophil or 

mononuclear cells 

Pazdrak et al. 1993 

0, 0.41 2 h Healthy, non-occupationally exposed (10) 

and occupationally exposed asthmatic 

subjects (10): 

No differences in response between groups; 

transient increase in symptoms of sneezing, 

rhinorrhea, edema, or itchy eyes; increases 

in leucocytes and eosinophils in nasal 

washings; no allergic response; no clinical 

symptoms of bronchial irritation or effects 

on pulmonary function parameters (FEV1, 

PEF) 

Krakowiak et al. 1998 

0, 0.40 1 hr 12 volunteers with intermittent asthma and 

allergy to pollen: 

No change in lung function (FEV1); no 

enhanced response to allergens 

Ezratty et al. 2007 

0, 0.17, 0.39, 0.9 5.5 h Formaldehyde exposed workers (32); 

controls (29): 

subjective symptoms (headache, tiredness) 

did not correlate with exposure; no clear 

effect of concentration on memory; some 

concentration-related effects in a few tests 

(additional speed, response time) but 

limitations in experimental design and 

control issues 

Bach et al. 1990 

1.0 90 min Healthy (9) and formaldehyde-sensitive (9) 

subjects (previously complained about nonDay et al. 1984 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 15 of 71

TABLE 3. Irritant Effects of Formaldehyde in Controlled Human Studies 

Concentration 

(ppm) Time 

Subjects/Effect 

(number of subjects) Reference 

respiratory effects of urea formaldehyde 

foam insulation): 

No effects on pulmonary function 

parameters (FVC, FEV1, max and midexploratory flow rate); complaints of eye 

irritation, nasal congestion, tearing, and 

throat irritation; no severity index 

0, 1.0 3 h Control asthmatic subjects (4); subjects 

with asthma attributed to urea formaldehyde 

foam (23): 

no differences between groups in 

immunologic parameters, either before or 

after exposure; minor immunologic changes 

in both groups postexposure 

Pross et al. 1987 

0, 0.2, 0.4, 0.8, 

1.6 (no concurrent 

control) 

5 h Healthy subjects (16): 

No differences in nasal airway resistance or 

pulmonary function parameters; decrease in 

nasal mucus flow at all concentrations; no 

discomfort at 0.2 or 0.4 ppm for 2 hours 

(some slight discomfort reported in the 3 to 

5 hours period [conjunctival irritation, 

dryness of nose and throat] but discomfort 

rated higher at 0.2 ppm than at 0.4 ppm and 

only 5 or fewer subjects reported any 

discomfort); average discomfort scored as 

slight during exposure to 1.6 ppm and first 

noted in the latter part of the first hour but 

decreased somewhat after three hours; no 

effect on performance on mathematical tests 

or number transfer tasks 

Andersen and Molhave 

1983 

0, 0.15, 0.3, 0.5 

ppm; 0.3 with 4 

peaks to 0.6 ppm; 

0.5 ppm with 4 

peaks to 1.0 ppm; 

some exposures 

combined with 

ethyl acetate as 

masking agent 

4 h Healthy volunteers, 11 males and 10 

females: 

All concentrations: no significant effects on 

nasal flow and resistance, pulmonary 

function, and decision reaction time; slight 

to moderately increased blinking frequency 

and conjunctival redness at 0.5 ppm with 

peaks to 1.0 ppm; subjective eye and 

olfactory symptoms reported at 0.3 ppm 

(no-effect level when “negative affectively” 

considered); subjective nasal irritation at 

0.5 ppm with peaks to 1.0 ppm 

Lang et al. 2008 

0, 2.0 (at rest) 

0, 2.0 (exercise) 

40 min Healthy (15) and asthmatic (15) nonsmoking subjects: 

No significant decrement in pulmonary 

function parameters (flow-volume 

parameters and airway resistance) or 

bronchial reactivity both at rest and with 

exercise; subjective symptoms ranged up to 

severe (but not incapacitating) for odor for 

some individuals, but median scores for 

nose, throat and eye irritation were 

#moderate; no increase in symptomology 

Witek et al. 1986; 

1987; Schachter et al. 

1985; 1986 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 16 of 71

TABLE 3. Irritant Effects of Formaldehyde in Controlled Human Studies 

Concentration 

(ppm) Time 

Subjects/Effect 

(number of subjects) Reference 

with exercise 

0, 0.1, 1.0, 3.0 20 min Asthmatic patients who suspected 

formaldehyde as the cause (13): 

No significant difference in pulmonary 

function parameters (FEV1, VC); no 

asthmatic response to formaldehyde 

challenge 

Frigas et al. 1984 

0, 0.5, 1.0, 2.0, 

3.0 at rest; 

2.0 with exercise 

3 h Healthy non-smoking subjects (19): 

(9 exposed to 3 ppm and 10 exposed to 0.05 

ppm) 

No significant decrements in pulmonary 

function parameters (FVC, FEV1, FEF25-75%, 

SGaw) or increases in bronchial reactivity 

(methacholine challenge) at any 

concentration; nasal flow resistance 

increased at 3.0 ppm; significant doseresponse relationship for odor sensation and 

eye irritation, but eye irritation scored mild 

(5/9) or mild to moderate 4/9) at 3 ppm; eye 

irritation began at 1 ppm 

Kulle et al. 1987; 

Kulle 1993 

0, 3.0 ppm With 

heavy exercise 

(healthy subjects); 

moderate exercise 

(asthmatic 

subjects) 

1 h Healthy (22) and asthmatic (16) nonsmoking subjects: 

No difference in symptoms between groups; 

eye, nose and throat irritation scored mild to 

mild-moderate (group means); small 

decreases in some pulmonary function 

parameters in healthy individuals engaging 

in heavy exercise 

Green et al. 1987 

0, 3.0 With heavy 

exercise (15 

minutes every 

half hour) 

2 h Healthy non-smoking subjects (24): 

Increase in subjective symptoms of eye, 

nose and throat irritation, rated mild to 

moderate on average; small, but statistically 

significant increase in two (FEF25-75%, 

SGaw) of several pulmonary function 

measurements at some time intervals (no 

effect on FEV1, FVC, FEV3), no increase in 

cough 

Green et al. 1989 

0, 3.0 With 

intermittent 

exercise 

3 h Healthy non-smoking subjects (9) 

non-biologically significant, transient 

change in some pulmonary function 

parameters (FEV1, FEF25-75%); increase in 

nose/ throat and eye irritation, rated mild to 

moderate by individuals; only one subject 

rated eye irritation as moderate 

Sauder et al. 1986 

0, 3.0 3 h Asthmatic non-smoking subjects (9): 

no significant group change in pulmonary 

function parameters (FEV1, FVC, FEF25-75%, 

SGaw, or FRC) or airway reactivity; 

significant increase in nose, throat (at 30 

minutes), and eye irritation (at 60 minutes), 

rated as none to mild-moderate except for 

one subject who reported severe eye 

irritation 

Sauder et al. 1987 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 17 of 71

TABLE 3. Irritant Effects of Formaldehyde in Controlled Human Studies 

Concentration 

(ppm) Time 

Subjects/Effect 

(number of subjects) Reference 

0, 1, 3 10 min Asthmatic non-smoking subjects (7): 

Similar responses in airway resistance 

following exposure to 0, 1, or 3 ppm with 

and without exercise (exercise increased all 

responses) 

Sheppard et al. 1984 

0.03 to 3.2; 

0, 1.0, 2.0, 2.9, 

4.0 

or 1.2, 2.1, 2.8, 

and 4.0 

37 min 

(n = 33); 

1.5 min (n = 48) 

Healthy subjects (exposure groups of 33 

and 48): 

Poorer air quality and greater nose irritation 

reported during the short exposures than 

during the 37-minute exposure, whereas the 

opposite was true for eye irritation; with 

increasing concentrations, both eye and 

nose irritation increased from none to Aa 

little;@ objectively-measured eye blinking 

not affected at 1.2 ppm, but was statistically 

significantly increased at 2.1 ppm 

Weber-Tschopp et al. 

1977 

0, 1, 2, 4, 5 5 min except for 2 

ppm (12 min) 

Healthy students (groups of 7 to 75): 

Addressed eye irritation only (subjects 

exposed via goggles): 1 ppm considered 

threshold for detection; 5 ppm produced 

severe eye irritation 

Stephens et al. 1961 

8, 13 Short exposures 

(<15 sec) 

Healthy/atopic subjects (1-6): 

Eye irritation for 5 of 6 subjects at 12 ppm 

but not at 8 ppm for 4 of 5; irritation of the 

throat at both concentrations; changes in 

airway resistance 

Douglas 1974 

13.8 30 min Healthy male subjects (12): 

Nasal and eye irritation with mild 

lacrimation; 

adaptation to the eye irritation 

Sim and Pattle 1957 

20 Several min Healthy subjects (2): 

Lacrimation (within 15-30 seconds); eye, 

nose, and throat irritation considered 

objectionable 

Barnes and Speicher 

1942 

1 FVC = 

2 FEV1 = 

3 FEF25-75%, = 

4 FRC = 

5 PEF = 

6 SGaw = 

7 

8 In an early study that addressed the threshold for eye irritation, Shuck et al. (1966) 

9 reported that a linear relationship between reported eye irritation and formaldehyde 

10 concentration does not hold below 0.3 ppm. Most subjects experienced the same eye irritation at 

11 0.05 and 0.5 ppm. The atmospheres in this study were generated by photooxidation of propylene 

12 or ethylene in order to simulate photochemical air pollution. Although formaldehyde was 

13 measured in the atmospheres, additional photochemical smog irritants were present. 

14 

15 In a similar study by the above group (Stephens et al. 1961), the eye irritation potential of 

16 both photochemical smog and its individual constituents was examined. Healthy students in 

17 groups of 7 to 75 were exposed to formaldehyde via eye goggles. Eye irritation (none, medium, 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 18 of 71

1 or severe) was reported every 30 seconds over 5- to 12-minute periods. Medium and severe 

2 irritation were considered positive responses. In a static flow system, positive responses ranged 

3 from 8% (6/75 individuals) during exposure to 1 ppm to 67% (18/27 individuals) at 5 ppm. In a 

4 dynamic flow system, positive responses ranged from 24% (9/37 individuals) for 2 ppm to 100% 

5 (7/7 individuals) for 4 ppm. One ppm was considered the threshold for detection and 5 ppm 

6 produced severe eye irritation. 

7 

8 In a study to determine the threshold for eye irritation, Bender et al. (1983) exposed a 

9 series of 7-member test panels to increasing concentrations of formaldehyde: 0, 0.35, 0.56, 0.7, 

10 0.9, and 1.0 ppm. Several panels were used for most concentrations, i.e., groups of 5-28. The 

11 panelists were selected for their ability to respond to formaldehyde at 1.3 and 2.2 ppm (i.e., 

12 subjects that were unresponsive to these concentrations were not used). The exposures were 

13 eye-only for 6 minutes. Response time in seconds was used as a measure of irritation, and 

14 irritation was rated on a scale of 1-3, with 0 = none, 1 = slight, 2 = moderate, and 3 = severe. 

15 Response time decreased with increasing exposure concentration, becoming statistically 

16 significant, i.e., different from clean air, at 1.0 ppm. The severity index was similar for 

17 concentrations of 0.35 ppm to 0.9 ppm (none to slight). The 1.0 ppm was rated slightly to 

18 moderately irritating, both at first exposure and after 6 minutes of exposure. There was a slight 

19 diminution of response at the end of the 6-minute exposure. 

20 

21 Harving et al. (1986; 1990) exposed 15 male and female non-smoking asthmatic subjects 

22 (ages 15 to 36 years) to concentrations of formaldehyde typically found in the indoor air 

23 environment. The study was conducted in a double-blind fashion with the order of exposure 

24 randomized. The subjects were selected on the basis of their bronchial reactivity to histamine 

25 (mean provocation challenge of 0.37 mg/mL for a 20% reduction in peak expiratory flow rate) 

26 and all subjects except one required bronchodilator therapy regularly. Bronchodilator therapy 

27 was discontinued 4 hours prior to the study. Subjects were exposed once a week for 90 minutes 

28 to 0, 0.10, or 0.69 ppm. Pulmonary parameters consisting of FEV1, Raw, SRaw, as well as the 

29 flow-volume curves showed no significant changes in the group as a whole or in any individuals. 

30 Histamine challenge tests performed for up to 24 hours after the exposures showed no increase 

31 in bronchial reactivity. There was no difference in subjective asthmatic symptoms (not 

32 described) among the exposure days. 

33 

34 Gorski et al. (1992) exposed 5 healthy subjects and 13 patients with formaldehyde35 sensitive contact dermatitis to 0.41 ppm for 2 hours in order to measure pulmonary and 

36 immunological responses. All patients had smoked for 10-15 years. The immunological 

37 response was measured by of neutrophil chemiluminescence (due to the release of free radicals) 

38 in the blood. Ventilatory parameters, which were also measured (VC, FEV1, and PEF), were not 

39 affected by exposure in either group. Chemiluminescence of neutrophils was higher in the 

40 sensitive group prior to exposure, increased to a greater degree than in the healthy subjects at 30 

41 minutes postexposure, and remained elevated at 24 hours postexposure. Subjective symptoms 

42 were not studied. 

43 

44 In a second study by the above group (Pazdrak et al. 1993), 11 patients with specific skin 

45 sensitization to formaldehyde and 5 healthy subjects were evaluated for nasal response to 0.41 

46 ppm as observed by changes in nasal lavage fluid. All subjects were nonsmokers. Nasal lavage 

47 (saline washings) was performed prior to, immediately after the 2-hour exposure period, and at 4 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 19 of 71

1 and 18 hours after exposure. Albumen, total protein, numbers of eosinophils and basophils, and 

2 the proportion of epithelial, neutrophil, eosinophil, basophil, and mononuclear cells were 

3 counted or computed. Symptoms of the upper respiratory tract including sneezing, rhinorrhea, 

4 mucosal edema, and itching, ranging on a scale 0-7, were summed. A positive clinical challenge 

5 was defined as >3. The exposure to formaldehyde caused increases in the number and 

6 proportion of eosinophils and elevated albumin and total protein levels in nasal lavage fluid. 

7 These elevations were still present 16 hours postexposure. There were no differences in the 

8 percent of neutrophil, basophil, or mononuclear cells. No differences in the nasal response 

9 between healthy subjects and patients with skin sensitization were observed. Clinical symptoms 

10 of itching, sneezing, and congestion were similar between the two groups (approximate score of 

11 4 for both groups). Analytical measurements were not made on the day of testing. 

12 

13 In a third study by the above investigators, the airway response to 0.41 ppm 

14 formaldehyde for 2 hours in 10 asthmatic subjects with suspected formaldehyde allergy was 

15 compared to that of 10 healthy subjects (Krakowiak et al. 1998). The asthmatic subjects had 

16 been exposed to gaseous formaldehyde or formaldehyde solutions in the workplace. The 

17 primarily male subjects ranged in age from 19 to 52 years. Spirometry at rest and following 

18 bronchial provocation with histamine were recorded before and after the exposure. The study 

19 was conducted in a single-blind manner. Clinical symptoms of the upper and lower respiratory 

20 tract and evaluation of morphological and biochemical changes in the nasal washings were 

21 examined after placebo and formaldehyde exposures. Atopy of the workers was measured as 

22 formaldehyde specific serum antibody (IgE). Responses to the challenge were evaluated by 

23 saline washings (before and after exposure), nasal symptoms (sneezes, rhinorrhea, edema, and 

24 itching; rated on a scale of 0-7), respiratory tract symptoms, and pulmonary function testing. 

25 Nasal symptoms were scored on a scale of 0-7, with >3 considered a positive clinical challenge. 

26 The exposure Acaused sneezing, itching and congestion in all subjects.@ Immediately after 

27 inhalation, nasal symptoms were scored 4.6 and 4.3 by asthmatic and healthy subjects, 

28 respectively, with no significant difference between the two groups. This effect was transient. 

29 There were no clinical symptoms of bronchial irritation as measured by FEV1 PEF, and 

30 bronchial challenge with histamine. Statistically significant increases in eosinophils in the nasal 

31 washings 30 minutes after the exposure were similar in the healthy and asthmatic subjects; 

32 leucocytes were also increased in the nasal washings of healthy subjects. There was no increase 

33 in basophilic cells or in the mediators tryptase and eosinophil cationic protein. No specific IgE 

34 antibodies to formaldehyde were detected in the serum of workers with exposure to 

35 formaldehyde. The authors concluded that inhalation of formaldehyde did not induce a specific 

36 allergic response in either asthmatic or healthy subjects and that the observed rhinitis was 

37 transient. 

38 

39 Ezratty et al. (2007) found no change in lung function (measured as a change in FEV1, 

40 FVC, or PEF) in volunteers exposed to 0.4 ppm formaldehyde for 1 hour. The 12 volunteers (7 

41 men and 5 women) ranged in age form 18 to 44 years. All had been diagnosed with intermittent 

42 asthma and allergy to pollen. Exposure to formaldehyde had no effect on lung function. Pre43 exposure to formaldehyde had no significant deleterious effect on air allergen responsiveness 

44 (methacholine challenge following inhalation of a standardized pollen extract) or sputum 

45 inflammatory markers including eosinophilic response. Subjective symptoms were similar 

46 between the air only and formaldehyde exposures. No distinct odor was reported by the 

47 volunteers. 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 20 of 71

1 

2 Bach et al. (1990) compared the reaction performance of 32 subjects chronically exposed 

3 to formaldehyde in the workplace (>5 years) with that of 29 control subjects. The subjects (all 

4 male, ages 18-64) were exposed in groups of 4 for 5.5 hours, with the concentration reached 

5 within the chamber during the first 30-minutes; exposure concentrations were 0, 0.12, 0.33, or 

6 1.0 ppm (measured concentrations of 0, 0.17, 0.39, or 0.9 ppm). Furfurylmercaptan, a coffee 

7 aroma constituent, was used to mask the odor of formaldehyde in the chamber. Exposures were 

8 arranged in a 4x4 balanced design, involving 4 days of exposure in each of four weeks. This 

9 computes to a total of 8 workers and 8 controls being exposed to each concentration. During the 

10 exposures, general comfort was assessed with a standard questionnaire with questions involving 

11 headache and physical and mental tiredness (Aheavy head@). An earlier publication (Bach et al. 

12 1987), summarized subjective ratings of irritation in this study. Subjective ratings of irritation 

13 did not correlate with a dose-response relationship. The performance tests consisted of digit 

14 span, digit symbols, graphic continuous performance, and a computerized addition test. These 

15 tests measure short-term memory, ability to concentrate, changes in psychomotor functions. 

16 Heavy head and headache, the latter late in the exposure, were reported more often by the control 

17 subjects than by the workers. On a linear scale of 60 mm, scores for these parameters for the 

18 respective worker and control populations were 6.0 and 8.0 (heavy head; p<0.05) and 2.0 and 5.5 

19 (headache; p<0.01). Significant differences were found among the exposures and between the 

20 worker and control group, but the results were often confounded by the Ainhomogeneity@ of the 

21 dose-response. For example, the total time used for the graphic continuous performance test was 

22 longest for the worker population at the intermediate dose, 0.33 ppm. Performance was also 

23 poorest for the digit span test at 0.33 ppm. 

24 

25 Lang et al. (2008) conducted a double-blind study in which 21 healthy volunteers (11 

26 males and 10 females; ages 19-39 years) were subjected to 10 different formaldehyde exposure 

27 conditions: (1) 0 ppm, (2) 0.15 ppm, (3) 0.3 ppm, (4) 0.3 ppm with 4 peaks to 0.6 ppm, (5) 0.5 

28 ppm, (6), 0.5 ppm with 4 peaks to 1.0 ppm, (7) 0 ppm, (8) 0.3 ppm and 12-16 ppm ethyl acetate 

29 (used as a masking agent), (9) 0.5 ppm with 12-16 ppm ethyl acetate, and (10) 0.5 ppm with 4 

30 peaks to 1.0 ppm plus ethyl acetate. Monitoring of the chamber atmospheres was carried out 

with an Interscan formaldehyde monitor (Asynco® 31 ). Two air samples were also taken during 

32 each exposure and analyzed using dinitrophenylhydrazine followed by HPLC with UV detection. 

 Up to four subjects at a time were exposed in a 30m3 33 chamber; all exposures were for 4 hours. 

34 Groups were tested in a random fashion over a 2-week period. Exercise, three 15-minute 

35 sessions on a bicycle at 80 watts, took place at 0, 120, and 195 minutes. Objective symptoms 

36 (blinking frequency and conjunctival redness), and subjective symptoms (standard questionnaire; 

37 scored on 6 levels) were reported after 195 minutes. Reaction time to visual and acoustic stimuli 

38 was tested before and after exposure. There were no effects on nasal flow and resistance, 

39 pulmonary function or decision reaction time under any condition. There were no significant 

40 effects on nasal flow and resistance, pulmonary function, and decision reaction time. Slight to 

41 moderately increased blinking frequency and conjunctival redness were measured at 0.5 ppm 

42 with peaks to 1.0 ppm. Subjective eye and olfactory symptoms were reported at 0.3 ppm; 

43 however, when personality traits were evaluated (evaluated in a personality questionnaire) the 

44 concentration of 0.3 ppm was no longer an effect concentration. Subjective nasal irritation was 

45 reported during the exposure to 0.5 ppm with peaks to 1.0 ppm. Increased symptom scores were 

46 reversed 16 hours after exposure. The authors concluded that eye irritation was the most 

47 sensitive measurement of formaldehyde exposure. 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 21 of 71

1 

2 In a double-blind, exposure-randomized study, Witek et al. (1986; 1987; see also 

3 Schacter et al. 1985; 1986) exposed 15 healthy male and female subjects, mean age 25, and 15 

4 male and female subjects classified as mild asthmatics, mean age 22, to clean air or 2.0 ppm 

5 formaldehyde for 40 minutes. On a separate day, all subjects exercised for 10 minutes at 450 

6 kpm/min prior to the exposure to 2.0 ppm. Subjects refrained from taking medications for 24 

7 hours prior to the sessions. Pulmonary function parameters including FVC, FEV1, peak 

8 expiratory flow rate (PERF), the maximal flow at 50% of the vital capacity, and Raw were 

9 measured. Baseline airway reactivity was assessed with progressive doses of methacholine. 

10 Subjects completed a symptom survey upon entering the exposure chamber and at 30 minutes 

11 into the exposure. Measurements were also taken at 24 hours after exposure. No significant 

12 bronchoconstriction or airway resistance was noted during or 24 hours following exposure, 

13 although methacholine challenge for some individuals showed non-significant lower thresholds 

14 during the exposures to 2.0 ppm. Ratings for respiratory symptoms averaged mild to moderate 

15 but ranged up to severe (non-incapacitating) for some individuals. This was especially true for 

16 unusual odor. There was no difference in symptomology between rest and exercise sessions. 

17 

18 Nine subjects that had previously complained of nonrespiratory adverse effects from the 

19 urea formaldehyde foam insulation (UFFI) in their homes and nine subjects that were either 

20 unaffected by the insulation or had not been exposed to insulation inhaled 1.0 ppm of 

21 formaldehyde for 90 minutes or the off-gas from UFFI (Day et al. 1984). The latter material 

22 yielded a formaldehyde concentration of 1.2 ppm; the exposure was for 30 minutes. None of the 

23 measured pulmonary parameters consisting of FVC, FEV1, or FEF25-75% showed any clinically or 

24 statistically significant response to exposure in either group. Incidences of subjective symptoms 

25 were equally divided between the two groups of subjects. Fifteen of 18 subjects complained of 

26 eye irritation during the exposure to 1.0 ppm formaldehyde (severity of symptoms was not 

27 described). Fewer subjects complained of nasal congestion (7), tearing (6), and throat irritation 

28 (5). Tolerance developed rapidly. 

29 

30 In a second study by this group (Pross et al. 1987), a broad range of immunologic 

31 parameters was studied in subjects with a history of asthma attributed to UFFI. Twenty-three 

32 asthmatic subjects came from homes insulated with urea-formaldehyde foam, and four asthmatic 

33 control subjects came from conventionally insulated homes. All subjects were exposed to room 

34 air for 30 minutes, formaldehyde gas at 1.0 ppm for 3 hours, or the UFFI off products for 3 hours 

35 as described in Day et al. (1984) above. Data from the UFFI group were not different from data 

36 of the subjects whose homes were insulated with conventional methods, either before or after the 

37 exposures. Minimal but statistically significant increases in the percent of eosinophils and T8 

38 positive lymphocytes were observed after the exposures to urea-foam off-products (including 

39 mold) and formaldehyde. Natural killer lymphocyte response to α-interferon was decreased in 

40 both groups of subjects after exposure to UFFI. The authors stated that the significance of these 

41 changes is unclear. 

42 

43 A series of 5-hour exposures, during which 16 healthy male and female students, ages 

44 20-33, inhaled 0.2, 0.4, 0.8, or 1.6 ppm, was conducted by Andersen and Molhave (1983). The 

45 students entered the chamber in groups of four, each group undergoing a different exposure on 

46 each of four days. Five of the subjects were smokers. Control data were generated each day 

47 during a 2-hour period in the chamber prior to the exposures. The following parameters were 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 22 of 71

1 measured: nasal mucociliary flow, nasal airflow resistance, FVC, FEV1, and FEF25-75. Subject 

2 airway irritation was noted by each subject using a scale of 1-100. Three times a day, once 

3 during the control session and twice during the exposures, the subjects performed two of three 

4 mathematical tests, each of 15-minutes duration. These tests involved addition, multiplication, 

5 and transfer of numbers to punchcards. The mucus flow rate slowed during exposures to 0.2 and 

6 0.4 ppm, with no further slowing at the higher exposures or after 3 hours. The decrease in mucus 

7 flow was most pronounced in the anterior two thirds of the nose; the posterior nasal passage was 

8 unaffected. No significant differences were found in nasal airway resistance or pulmonary 

9 parameters. At 0.2 and 0.4 ppm, no discomfort was registered during the first two hours of 

10 exposure. Discomfort increased and was registered earlier with higher concentrations. For 

11 example, at the two higher concentrations, discomfort was reported during the first hour of 

12 exposure. Some subjects reported no discomfort at any time during any exposure. Although at 

13 least one individual reported a discomfort rating of 50 (described as Adiscomfort@) during the 

14 exposure to 1.6 ppm, the average rating was 18 which fell in the middle of the Aslight 

15 discomfort@ range. Performance on the mathematical tests was unaffected by the exposures. 

16 

17 Frigas et al. (1984) studied 13 patients with symptoms suggestive of formaldehyde18 induced asthma for response to a formaldehyde inhalation challenge. These patients had been 

19 exposed either occupationally or in the home to formaldehyde at concentrations of 0.1 to 1.2 

20 ppm for 4 months to 9 years. Reported symptoms during the home or work exposure involved 

21 chest tightness, coughing, or wheezing. Five of the patients were being treated with 

22 bronchodilators. Treatment was discontinued 24 hours prior to the challenge, and patients were 

23 free of symptoms when tested. Patients were challenged with placebo (room air), 0.1, 1.0, or 3.0 

24 ppm for 20 minutes via a face mask. Subjective symptoms were also noted. Following the 

25 challenge and for up to 24 hours after, no patient had a decrease in FEV1 greater than during the 

26 room air challenge. Irritation of the eyes, nose, and throat and tightness of the chest were 

27 reported as frequently with the placebo as with the formaldehyde challenges. The authors were 

28 unable to substantiate that formaldehyde exposure in the home or workplace was the cause of the 

29 asthmatic symptoms. 

30 

31 The following series of studies (Kulle et al. 1987; Kulle 1993; Green et al. 1987; Sauder 

32 et al. 1986; 1987) were performed by the same group of investigators. Kulle et al. (1987) 

33 exposed 19 healthy nonsmoking male and female subjects, mean age 26.3"4.7 years, to each of 

34 five randomly assigned exposures for three hours. Exposures were separated by one week. Ten 

35 subjects were exposed to 0, 0.5, 1.0, or 2.0 ppm at rest or 2.0 ppm with exercise; nine subjects 

36 were exposed to 0, 1.0, 2.0, or 3.0 ppm at rest or 2.0 ppm with exercise. The exercise consisted 

37 of an 8-minute session on a bicycle ergometer every half hour. Each subject served as his or her 

38 own control. Spirometric measurements including FVC, FEV1, FEF25-75% were performed at 

39 time = 0, 30, 60, 90, 120, 150, and 180 minutes and on the postexposure day. Airway resistance 

40 and thoracic gas volume were measured prior to and at completion of each exposure. 

41 Nonspecific airway reactivity was measured with a methacholine challenge at the completion of 

42 each exposure. Nasal resistance was measured prior to and following each exposure. Symptoms 

43 (nose or throat and eye irritation, chest discomfort, cough, and headache) were recorded via a 

44 questionnaire at six intervals during the exposures. Symptoms were scored as 0 = none, 1 = mild 

45 (not annoying), 2 = moderate (annoying), or 3 = severe (debilitating). There were no significant 

46 decrements in pulmonary function parameters or increases in bronchial reactivity at any 

47 concentration; nasal flow resistance increased at 3.0 ppm. The dose-response relationship for 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 23 of 71

1 odor sensation and eye irritation were both significant (p<0.0001), but respective scores were 

2 only mild (1.0) or mild to moderate (1.4) at 3 ppm. The nose/throat irritation dose-response was 

3 close to significant, but the mean subjective symptom score at 3.0 ppm was between none and 

4 mild (0.22). At 2.0 ppm with exercise, nose/throat irritation increased significantly (p<0.05), but 

5 the symptom score was <1 (less than mild irritation). Exercise had no effect on eye irritation or 

6 odor sensation. There was great variability in the odor threshold; four of nine subjects sensed 

7 the odor of formaldehyde at 0.5 ppm. In a reexamination of the above study, Kulle (1993) 

8 estimated the thresholds for odor and irritant responses. Estimated thresholds were <0.5 ppm for 

9 odor sensation, 0.5-1.0 ppm for eye irritation and 1.0 ppm for nose/throat irritation. No 

10 substantial differences were seen between the symptom responses of male and female subjects. 

11 

12 Green et al. (1987; see also Kulle et al. 1986) found small but significant decrements in 

13 lung function in healthy normal subjects inhaling 3.0 ppm while engaged in heavy exercise. 

14 Some individuals in the study exhibited decrements in FEV1 of >10%. In this study, 22 healthy 

15 male and female subjects, average age 27, and 16 male and female asthmatic subjects, average 

16 age 27, were exposed to 3 ppm for 1 hour. All of the subjects were nonsmokers. Asthmatic 

17 subjects discontinued medications within 12 hours of the study. Asthmatic subjects performed 

18 intermittent moderate exercise (VE = 37 L/min), so as to minimize exercise-induced 

19 bronchoconstriction, and healthy subjects engaged in intermittent heavy exercise (VE = 65 

20 L/min). The study was performed in a double blind fashion in that both subjects and pulmonary 

21 technicians were unaware of the exposure concentrations. Symptoms and pulmonary function 

22 were assessed during exposure and SGaw was assessed after the exposure (see Kulle et al. 1987). 

23 Both groups exhibited similar, significant increases in perceived odor, nose/throat irritation, and 

24 eye irritation throughout the exposure. Mean scores for both groups for each of the three 

25 parameters attained a score of approximately 1.8 (mild to mild/moderate) at 17 minutes which 

26 decreased only slightly throughout the remaining exposure. There were small but significant 

27 decrements in lung function in the healthy subjects near the end of the exposure. Although the 

28 mean decrement in FEV1 was 2%, 2 healthy individuals had decrements of >10% as did 2 

29 asthmatic subjects. 

30 

31 In a follow-up study, Green et al. (1989) exposed 24 non-smoking healthy male and 

32 female subjects, average age 24, to 3.0 ppm for 3 hours. For 15 minutes of each hour the 

33 subjects performed heavy exercise on a bicycle that raised their minute ventilation to 60-70 

34 L/min. Symptom questionnaires were completed and spirometric measurements were made as in 

35 the study of Kulle et al. (1987). Symptoms ratings and scores ranged from none = 0 to severe = 

36 5. All symptoms were significantly increased over the air exposures, but average scores were 

37 <0.5 for headache and chest discomfort (none to mild) and between 1.0 and 1.5 for eye, nose, 

38 and throat irritation (mild to mild-moderate) at all time points. There was no significant effect of 

39 formaldehyde on FEV, FEV2 or FEV3. There was a significant effect of formaldehyde exposure 

40 on FEF25-75% at 50 and 80 minutes and a decrease in peak flow at 120 minutes. Although 

41 statistically significant, mean decrements were <6%. Formaldehyde exposure was not associated 

42 with increased cough compared to clean air exposure. 

43 

44 Sauder et al. (1986) exposed nine healthy nonsmokers to 3 ppm for 3 hours. Each subject 

45 served as his or her own control. Spirometric measurements (FVC, FEV1, and FEF25-75) were 

46 performed at 0, 20, 60, 90, 120, 150, and 180 minutes. A body plethysmograph technique was 

47 used to determine FRC and Raw; SGaw was computed from Raw. A bicycle ergometer exercise 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 24 of 71

1 was completed two minutes prior to each spirometric measurement (except at 0 time). Airway 

2 reactivity was measured with a methacholine challenge following the exposures to both clean air 

3 and 3 ppm. Odor and symptoms of irritation (nose or throat and eye irritation, chest discomfort, 

4 tingling in feet or hands, cough, and heart palpitations) were recorded via a questionnaire at six 

5 intervals during the exposures. Symptoms were scored as none (0), mild (1), moderate (2), or 

6 severe (3). Statistically significant changes in FEV1 of 2% and FEF25-75% of 7% were not 

7 biologically significant. No statistically significant changes were observed in FVC, FRC, SGaw, 

8 or airway reactivity. Odor and nose /throat irritation were scored as mild to moderate, 1.22 and 

9 1.33, respectively. Eye irritation was scored as none to mild (0.78). Five of the subjects scored 

10 the nose/throat irritation as moderate whereas only one subject scored the eye irritation as 

11 moderate. 

12 

13 Using the same protocol as in the above study, Sauder et al. (1987) exposed nine 

14 nonsmoking subjects with a characteristic clinical history of asthma and airway hyperreactivity 

15 to 3 ppm of formaldehyde for 3 hours. The male and female subjects ranged in age from 26 to 

16 40 years. Seven of the nine subjects were on regular medications prior to the study; all 

17 medications were discontinued 12 hours prior to the study. Based on prestudy pulmonary 

18 parameters, three subjects had mild airway obstruction and one subject had moderate airway 

19 obstruction. All subjects had marked airway hyperreactivity to methacholine. Eight of the nine 

20 subjects had a history of hayfever. During the study, each subject served as his or her own 

21 control and received clean air for 3 hours during day 1. The following week, each subject was 

22 exposed to 3 ppm formaldehyde for 3 hours (day 2). Pulmonary function parameters including 

23 FVC, FEV1, FEF25-75, SGaw, and FRC were recorded several times during the exposures. 

24 Airway reactivity was measured with a methacholine challenge following the exposures to both 

25 clean air and 3 ppm. Symptoms (nose or throat and eye irritation, chest discomfort, tingling in 

26 feet or hands, cough, and heart palpitations) were recorded via a questionnaire at six intervals 

27 during the exposures. Symptoms were scored as mild, mild/moderate, moderate, 

28 moderate/severe, or severe. Inhalation of 3 ppm resulted in no significant group change in 

29 pulmonary function parameters or airway reactivity. On an individual basis, none of the changes 

30 were biologically significant. There was a significant increase in some nose or throat and eye 

31 irritation during the 3-hour exposure to 3 ppm. But, the group mean value for nose or throat 

32 irritation, statistically significant at p<0.05 at only the 30-minute interval, was rated as mild. For 

33 the group, eye irritation was rated as mild/moderate beginning at 2 minutes into the exposure and 

34 continuing throughout the exposure. However, one subject scored the eye irritation as severe. 

35 This score was in response to a questionnaire (not self-reported) and the subject remained in the 

36 room for the entire 3-hour exposure. This subject did not experience bronchoconstriction or 

37 changes in pulmonary function during the entire exposure. It should be noted that in this study, 

38 22% of the subjects reported eye irritation and 33% responded with nose/throat irritation during 

39 the exposure to clean air. 

40 

41 Sheppard et al. (1984) exposed 7 nonsmoking male and female subjects, ages 18 to 37 to 

42 0, 1, or 3 ppm for 10 minutes at rest or while exercising on a bicycle ergometer at a work rate of 

43 100 watts. The study was performed in a double-blind manner. Formaldehyde was delivered by 

44 a mouthpiece. All subjects had a history of mild asthma as evidenced by recurrent episodes of 

45 wheezing, chest tightness, and reversible airways obstruction. The subjects had marked airway 

46 hyperresponsiveness to histamine. Six of the 7 subjects had responded with airways resistance 

47 to <1 ppm sulfur dioxide in a previous study. All medications were discontinued prior to the 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 25 of 71

1 study. Inhalation of 1 or 3 ppm of formaldehyde at rest or during moderate exercise did not 

2 significantly increase airway resistance compared to the control exposure. In two subjects, 

3 exercise increased airway resistance in a similar manner following the control, 1, or 3 ppm 

4 exposure. 

5 

6 Weber-Tschopp et al. (1977) exposed a group of 33 healthy male and female students to 

7 concentrations that increased from 0.03 to 3.2 ppm over a period of 37 minutes. At discrete 

8 concentrations (0.03, 0.5, 1.2, 1.7, 2.1, 2.5, 2.8, and 3.2 ppm), eye, nose and throat irritation were 

9 rated on a scale of 1 to 4, with ratings of 1 = none, 2 = a little, 3 = moderate, and 4 = strong. 

10 Compared with control scores of approximately 1.2, 1.2, and 1.1, respectively for eye, nose and 

11 throat irritation (values read from graphs), respective scores for exposure to 3.2 ppm were 

12 approximately 2.0, 2.0, and 1.1, respectively. Average severity scores for exposure to 1.2 ppm 

13 were approximately 1.4, 1.3, and 1.1. In a second part of this study, 48 healthy students inhaled 

14 0, 1, 2, 3, or 4 ppm, each for 1.5 minutes. Irritation as well as eye blinking were scored. 

15 Average rates of eye blinking were not significantly affected at 1.2 ppm, but significantly 

16 increased at higher exposures (from about 22 blinks/minute to 35 blinks/minute at 2.1 ppm and 

17 38 blinks/minute at 3.2 ppm). Compared with the 37 minute exposure, eye irritation scores were 

18 lower during the 1.5 minute exposures, whereas nose irritation scores were higher. The lower 

19 scores during the longer exposure indicate some adaptation to the irritancy. The authors 

20 considered the threshold for both eye and nose irritation to be 1.2 ppm, the threshold for throat 

21 irritation to be 2.1 ppm, and the threshold for eye blinking to be 1.7 ppm. 

22 

23 The above authors (Weber-Tschopp et al. 1977) also compared the irritation scores 

24 during the formaldehyde exposures to the irritation scores of sidestream cigarette smoke from an 

25 earlier study (Weber et al. 1976). The atmosphere for the earlier exposure was generated by 

smoking cigarettes in a 30 m3 26 controlled-air chamber. Mainstream smoke was directed out of 

27 the laboratory. Following smoking of 10 cigarettes, the carbon monoxide, formaldehyde, and 

28 acrolein levels in the room were 24, 0.46, and 0.11 ppm, respectively. On a scale of good (1), 

29 acceptable (2), and bad (3), the quality of the air was considered bad (3); whereas, for the 

30 formaldehyde exposure that ranged from 0.03 up to 3.2 ppm over 37 minutes, the highest score 

31 was 2.2, and the 1.5 minute exposure to 4.0 ppm approached a score of 3. Auerbach et al. (1977) 

32 notes that undiluted cigarette smoke may contain 32-114 ppm of formaldehyde. 

33 

34 In a study of eye irritation and reflex bronchoconstriction response to irritant gases, 

35 Douglas (1974) exposed 1-6 healthy and atopic male and female subjects individually to 

36 approximately 6, 8, 12, 18, 24, or 30 ppm (eye irritation) or 4, 8, 10, or 12 ppm (broncho–

37 constriction). Atmospheres were generated by bubbling air through formalin solutions. 

38 Following collection of formaldehyde from the airstream in 3-methyl-2-benzothiazolone, 

39 measurements were made with a colorimetric/spectrophotometric system. Separate eye and 

40 inhalation exposures were conducted using goggles in the former case and a mouth tube in the 

41 latter. Eye exposures lasted for 15 seconds. Time to onset of eye irritation was measured; no 

42 symptom scores were recorded. During inhalation exposures, subjects inhaled 10 one-liter 

43 breaths. A body plethysmograph was used for measuring bronchoconstriction. A single subject 

44 exposed to 6 ppm reported no eye irritation. Four of five subjects reported no eye irritation at 8 

45 ppm, whereas, 5 of 6 subjects exposed to 12 ppm reported undefined irritation (one within 5 

46 seconds). Neither of two subjects exposed to 18 ppm reported eye irritation. Single subjects 

47 exposed to 24 or 30 ppm reported eye irritation within 10 seconds. 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 26 of 71

1 

2 During mouth breathing (which bypasses the scrubbing capacity of the nose), the single 

3 subject exposed to 4 ppm reported no subjective throat symptoms. Subjects inhaling 8 or 10 

4 ppm reported mild sensations in the throat and subjects inhaling 12 ppm reported Airritancy@ in 

5 the throat. There was a drop of 0 to 43% in airway resistance at 8 ppm and a drop in airway 

6 resistance of 50-108% at 12 ppm. Neither eye irritation nor bronchoconstriction appeared 

7 related to atopy. 

8 

9 One of the earliest controlled studies aimed at assessing irritation from smog components 

10 was performed by Sim and Pattle (1957). They exposed 12 healthy males, ages 18 to 45 to 

11 13.8 ppm of formaldehyde in a chamber for 30 minutes. Initially, the exposure caused 

12 considerable nose and eye irritation. Mild lacrimation continued for some period of time. The 

13 eye irritation was not considered severe, and adaptation occurred in about 10 minutes. 

14 Formaldehyde was dispersed into the chamber by bubbling air through a known volume of liquid 

15 until all the liquid had evaporated. Chamber atmospheres were measured with a titration 

16 technique. 

17 

18 During analytical determinations of chamber concentrations, Barnes and Speicher (1942) 

19 entered the chamber Aa number of times.@ Analytical measurements by two procedures, a 

20 chemical method and the dropping mercury electrode method, both indicated a concentration of 

21 20 ppm. Upon entering the chamber, the authors noticed irritation of the eyes and upper 

22 respiratory tract. Lacrimation started within 15 to 30 seconds, and irritation of the nose and 

23 throat became quite pronounced. On some occasions, sneezing occurred within a minute or two. 

24 The authors commented that they could continue the exposure Afor some length of time but it 

25 was distinctly uncomfortable...@ and objectionable. They suggested that formaldehyde in 

26 workroom air should be at a value somewhat less than 20 ppm. 

27 

28 A panel of experts, the Industrial Health Foundation Panel, identified an occupational 

29 exposure limit that would prevent irritation (Paustenbach et al. 1997). Following a critique of 

30 approximately 150 scientific articles, Athe panel concluded that for most persons, eye irritation 

31 clearly due to formaldehyde does not occur until at least 1.0 ppm. Information from controlled 

32 studies involving volunteers indicated that moderate to severe eye, nose, and throat irritation 

33 does not occur for most persons until airborne concentrations exceed 2.0-3.0 ppm.@ The panel 

34 concluded that exposure to 0.3 ppm for several hours in controlled studies was no different than 

35 exposure to room air. At 0.5 ppm, eye irritation is not observed in the majority of workers. 

36 Consequently, the panel recommended an 8-hour TWA of 0.3 ppm with a ceiling concentration 

37 of 1.0 ppm. The panel failed to identify a hypersensitive population or individuals that could be 

38 sensitized. The panel also concluded that there was sufficient evidence to show that persons 

39 with asthma respond no differently than healthy individuals following exposures up to 3.0 ppm. 

40 

41 2.3. Neurotoxicity

42 

43 Two studies on neurotoxicity are described in Section 2.2.3 above. Andersen and 

44 Molhave (1983) found no affect of 5-hour exposures to 0.2, 0.4, 0.8, or 1.6 ppm on performance 

45 of mathematical tests. 

46 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 27 of 71

1 As noted in the Bach et al. (1990) study above, there was no concentration-response 

2 relationship for changes in performance tests consisting of digit span, digit symbols, graphic 

3 continuous performance, and addition during 5.5-hour exposures. These tests measure short4 term memory, ability to concentrate, and changes in psychomotor functions. However, the 

5 investigators did attribute the poorer performance at the intermediate dose, 0.33 ppm (compared 

6 with 0, 0.12, or 1.0 ppm), to either CNS effects or to distraction due to irritation caused by the 

7 exposure. 

8 

9 2.4. Developmental/Reproductive Toxicity

10 

11 Few studies addressed developmental or reproductive effects in humans. No effect on 

12 sperm number or morphology was found in a small group of pathologists (Ward et al. 1984). 

13 There was no evidence for increased rates of miscarriage among a group of 275 persons with 

14 presumed residential exposure to formaldehyde (Garry et al. 1980). 

15 

16 2.5. Genotoxicity

17 

18 The genotoxicity of formaldehyde has been reviewed by many groups including NRC 1980, 

19 WHO (1989), Feron et al. (1991), ATSDR (1999), and IARC (2006). Results from occupational 

20 studies, which usually involved exposures to low concentrations, are conflicting. Where 

21 increased incidences of sister chromatid exchanges, chromosomal aberrations, or micronuclei 

22 formation were recorded in exposed workers, differences were small when compared with those 

23 of control workers. Formaldehyde easily haptenates human proteins (Maiback 1983). IARC 

24 (2006) reviewed studies that showed increased DNA-protein cross-links in workers exposed to 

25 formaldehyde. 

26 

27 2.6. Carcinogenicity

28 

29 According to ATSDR (1999), there are over 40 epidemiology studies that examine the 

30 potential for occupational exposure to formaldehyde to cause cancer in humans. Various 

31 agencies and panels have reviewed the data and taken varying positions on this issue. The 

32 reviews all suggest that formaldehyde induces cancer (nasal squamous cell carcinoma) in rats 

33 and mice exposed to airborne levels that are associated with significant irritation resulting in 

34 hyperplasia and tissue damage with repeated exposure. In humans, the overall evidence for 

35 cancer is inconsistent and associations are relatively weak when significant. 

36 

37 Formaldehyde is carcinogenic to the Fischer 344 rat at dose levels that are within the 

38 same order of magnitude as those to which humans are exposed. However, epidemiology studies 

39 have failed to show any convincing evidence correlating formaldehyde exposure and nasal 

40 cancer in exposed populations (Federal Panel on Formaldehyde 1982; Starr et al. 1983; Blair et 

41 al. 1986; Ad Hoc Panel on Health Aspects of Formaldehyde 1988). Carcinogenicity risk has 

42 been evaluated in occupational groups with known exposure to formaldehyde; these include 

43 pathologists, anatomists, morticians, and chemical workers. Cancers at remote sites have 

44 occasionally been correlated with exposure, but because formaldehyde is so highly reactive and 

45 rapidly metabolized/detoxified, inhalation is unlikely to affect a distant site. The Industrial 

46 Health Foundation panel of experts concluded that cancer risk of formaldehyde is negligible at 

47 airborne concentrations that do not produce chronic irritation (Paustenbach et al. 1997). 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 28 of 71

1 

2 An independent international panel of scientists, the Ad Hoc Panel on Health Aspect of 

3 Formaldehyde (1988) reviewed and evaluated more than 30 epidemiology studies. The panel 

4 concluded that A(1) for no malignancy in man is there convincing evidence of a relationship with 

5 formaldehyde exposure, and (2) furthermore, if a relationship does exist, the excess risk, in 

6 absolute terms, must be small.@

7 

8 The U.S. EPA (2003) in their Weight-of-Evidence characterization classifies 

9 formaldehyde as B1, probable human carcinogen. This classification is based on limited 

10 evidence in humans and sufficient evidence in animals. AHuman data include nine studies that 

11 show statistically significant associations between site-specific respiratory neoplasms and 

12 exposure to formaldehyde or formaldehyde-containing products. An increased incidence of 

13 nasal squamous cell carcinomas was observed in long-term inhalation studies in rats and in mice. 

14 The classification is supported by in vitro genotoxicity data and formaldehyde=s structural 

15 relationships to other carcinogenic aldehydes such as acetaldehyde.@ The discussion provided in 

16 the IRIS report points out the inadequacies and non-site specificity of many of the epidemiology 

17 studies. Although several studies were well-conducted, all suffered from one or more of the 

18 following problems: lack of control for smoking, lack of trend with increasing concentration or 

19 cumulative exposure, cancers at sites other than the nasopharynx, lack of atmospheric 

20 measurements, small sample size, and exposure to other agents. 

21 

22 In 2006, IARC reevaluated their previous assessment of cancer based on epidemiologic 

23 studies and concluded that there was “sufficient epidemiological evidence that formaldehyde 

24 causes nasopharyngeal cancer in humans.” They upgraded their evaluation from Group 2A, 

25 “probably carcinogenic to humans” to Group 1. IARC also concluded that “there is strong but 

26 not sufficient evidence for a causal association between leukemia and occupational exposure to 

27 formaldehyde.” 

28 

29 The Consumer Product Safety Commission has acted to ban formaldehyde in products as 

30 a cancer risk (Fed. Reg. 47:14366). This ban was set aside by a reviewing court in 1983. 

31 

32 In the carcinogenicity study of Kerns et al. (1983; see Section 3.6), the target dose of 

33 formaldehyde in the nasal mucosa of rats was not linearly proportional to the airborne 

34 concentration, so that a linear extrapolation of the target doses at concentrations above 5.6 ppm 

35 would overestimate the target doses at low concentrations (Starr 1990). Therefore, a quantitative 

36 risk assessment using airborne formaldehyde concentrations would overestimate the tumor risk 

37 at low exposure concentrations. This group (Kerns et al. 1983; Heck et al. 1990; Starr 1990) also 

38 found that at the same concentrations, doses in the monkey were about 5-10 times lower than 

39 those in the rat. This indicates that tumor risk for primates would be overestimated if the 

40 quantitative risk assessment were done using the dosimetry data in the rat. Animal studies are 

41 summarized in Section 3.6. A carcinogenicity assessment using the rat data of Section 3.6 is in 

42 Appendix B. 

43 

44 2.7. Summary

45 

46 The discomfort of sensory irritation is difficult to measure with certainty. Studies with 

47 controlled human exposures indicate that short-term exposure to 1 to 3 ppm induces eye, nose, 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 29 of 71

1 and throat irritation that is generally described as slight to mild/moderate by most subjects 

2 (Weber-Tschopp et al. 1977; Andersen and Molhave 1983; Bender et al. 1983; Day et al. 1984; 

3 Witek et al. 1986; Kulle et al. 1987; ATSDR 1999). Sensory irritation below 1 ppm is difficult 

4 to distinguish from the control situation (Bender et al. 1983; 2002). At the upper end of the 1-3 

5 ppm range, a greater number of subjects experience mild irritation, i.e., at 3 ppm most subjects 

6 rated eye, nose, or throat irritation mild. The multi-dose clinical studies (Weber-Tschopp et al. 

7 1977; Andersen and Molhave 1983; Bender et al. 1983) show that minimal to no discomfort is 

8 observed at levels up to 1 ppm; at 1 ppm and above some subjects show definite signs of 

9 discomfort. Elevated eosinophil counts and protein in nasal lavage fluid consistent with mild 

10 irritation were observed following 4 hours of exposure to 0.41 ppm (Gorski et al. 1992; Pazdrak 

11 et al. 1993; Krakowiak et al. 1998; ATSDR 1999). There were no changes in pulmonary 

12 parameters at concentrations between 0.41 and 3 ppm in healthy subjects, asthmatics, or subjects 

13 with dermal sensitivity to formaldehyde (Andersen and Molhave 1983; Day et al. 1984; Frigas et 

14 al. 1984; Sheppard et al. 1984; Harving et al. 1986; 1990; Witek et al. 1986; 1987; Pross et al. 

15 1987; Sauder et al. 1987). Furthermore, there were no biologically significant differences in 

16 pulmonary parameters or symptoms greater than moderate irritation in exercising healthy 

17 subjects (Witek et al. 1986; Green et al. 1987; Kulle et al. 1987), asthmatics at rest (Frigas et al. 

18 1984; Sheppard et al. 1984), or exercising asthmatics (Sheppard et al. 1984; Witek et al. 1986; 

19 Green et al. 1987) exposed to 2 or 3 ppm for up to 3 hours. In all studies, symptoms were related 

20 to eye and upper respiratory tract irritation. There was no evidence of these low concentrations 

21 having an effect on the lower respiratory tract. 

22 

23 The studies of Gorski et al. (1992); Pazdrak et al. (1993); and Krakowiak et al. (1998) 

24 were not summarized with the above studies because (1) the authors found irritation at levels not 

25 found irritating in approximately 20 other well-conducted clinical studies (that included 

26 analytical measurements), and (2) the authors did not make chamber measurements on the days 

27 the study was conducted. 

28 

29 Concentrations of 5 to 13.8 ppm were considered extremely irritating to the eyes of some 

30 subjects (Stephens et al. 1961), but not others (Douglas 1974). Unfortunately, some of the 

31 procedures and methods of exposure in the Douglas (1974) study make it of limited relevance for 

32 AEGL consideration. Mild lacrimation occurred at 13.8 ppm, but adaptation took place during 

33 the 30-minute exposure (Sim and Pattle 1957). Barnes and Speicher (1942) considered short 

34 exposures to 20 ppm objectionable. Only one study addressed airway Aconductance@ (Douglas 

35 1974). Air was inhaled through a mouth tube in this study, thus bypassing the scrubbing 

36 capacity of the nasal passages. 

37 

38 3. ANIMAL TOXICITY DATA

39 3.1. Acute Lethality

40 

41 Salem and Cullumbine (1960) exposed groups of 50 mice, 20 guinea pigs, and 5 rabbits 

42 to 15.3 ppm formaldehyde vapor or 16.1 ppm formaldehyde aerosol for up to 10 hours or until 

the animals died. Exposure took place in 1 m3 43 glass flow-through chamber. Most deaths 

44 occurred on subsequent days (not specified). Total mortalities for mice (deaths during exposures 

45 plus deaths on subsequent days) for the vapor and aerosol were 34% (17/50) and 96% (48/50), 

46 respectively. Total mortalities for guinea pigs for the vapor and aerosol were 40% (8/20) and 

47 5% (1/20), respectively. Total mortalities for rabbits for the vapor and aerosol were 60% (3/5) 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 30 of 71

1 and 20% (1/5), respectively. At autopsy, all species displayed expanded, edematous, and 

2 hemorrhagic lungs and fluid in the pleural cavity. These lethal values appear low in comparison 

3 to the human experience and additional animal studies discussed below. Studies utilizing lethal 

4 concentrations are summarized in Table 4. 

5 

TABLE 4. Summary of Acute Lethal Inhalation Data in Laboratory Animals 

Species 

Concentration 

(ppm) Exposure Time Effecta Reference 

Rat 820 30 min LC50 Skog 1950 

Rat 350 

478 

4 h 

4 h 

No deaths 

LC50

Nagorny et al. 1979 

Rat 250 4 H 33-66% Mortality Carpenter et al. 1949 

Mouse 1000 

2162 

10 min 

10 min 

No deaths 

LC50

Alarie 1981 

Mouse 900 

140 

2 h 

2 h × 4 d 

100% Mortality 

No substantial 

distress 

Horton et al. 1963 

Mouse 320 

320 

100 min 

55 min 

Lt50

5% Mortality 

Bitron and Aharonson 1978 

Mouse 98 

410 

2 h 

2 h 

No deaths 

LC50

Nagorny et al. 1979 

6 

7 3.1.1. Rats

8 

9 Skog (1950) exposed groups of 8 rats to concentrations ranging from approximately 490-

10 1400 ppm for 30 minutes. Rats were observed for 3 weeks postexposure. Extreme respiratory 

11 difficulty was observed immediately after exposure. This sign lasted for several days. The first 

12 deaths occurred 6 hours postexposure. At autopsy, microscopic changes in the lungs included 

13 hemorrhages and intra-alveolar and perivascular edema. Hyperemia, perivascular edema, and 

14 necroses were found in the livers and perivascular edema was observed in the kidneys. The late 

15 death of one rat, 15 days postexposure, was attributed to purulent bronchitis and diffuse 

16 bronchopneumonia. The LC50 was 810 ppm. In referring to a series of experiments with 

17 aldehydes, the authors stated that the lowest doses generally produced 0% mortality, and the 

18 highest dose generally produced 100% mortality. 

19 

20 Nagorny et al. (1979) exposed 21 groups of 6-12 male rats to various concentrations for 4 

21 hours. Concentrations of 228 to 350 ppm were not lethal. Some deaths may have occurred in 

22 groups exposed to 317 to 732 ppm (data not clear), and all rats died at >732 ppm with the 

23 exception of the group exposed to 764 ppm. The 4-hour LC50 was 478 ppm. Clinical signs 

24 preceding death included excitement, increased respiration, open mouth, and bloody discharge 

25 from the nose, followed by a prone position. Deaths occurred one or more days after exposure. 

26 Some of the deaths were attributed to the combination of toxicity and pneumonia. 

27 

28 Carpenter reported that 2 to 4 of 6 rats died following a 4-hour exposure to 250 ppm. 

29 The postexposure observation period was 14 days. No further details were reported in this 

30 screening study. 

31 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 31 of 71

1 Kamata et al. (1996) exposed groups of 6 male Fischer rats to 0, 128, or 295 ppm for 6 

2 hours in order to study effects on pulmonary surfactant. Dyspnea and closed eyes were observed 

3 immediately after the start of exposure, and lacrimation, bloody nasal discharge, and salivation 

4 were observed shortly afterwards. No mortalities occurred during the treatment, but one rat in 

5 the high-concentration group died just after completion of treatment. Autopsy showed the 

6 following dose-related findings: edema surrounding the trachea, hydrothorax, congestion of the 

7 lungs and nasal cavities and retention of mucus in the lungs. Lung washes showed that 

8 surfactant production was depressed. A number of hematological and clinical chemistry changes 

9 were also observed. Animals were sacrificed immediately after the exposures; therefore, the true 

10 mortality incidence could not be ascertained. 

11 

12 3.1.2. Mice

13 

14 As part of a study on respiratory depression by irritant chemicals, Alarie (1981) also 

15 determined 10-minute LC50 values. The 10-minute LC50 for formaldehyde in Swiss-Webster 

16 mice was 2162 ppm (95% confidence interval, 1687-2770 ppm). Mortality was recorded during 

17 the following 3-hour period. From the concentration mortality graph provided in the report, the 

18 10-minute concentration resulting in no deaths was estimated at 1000 ppm. The California 

19 Environmental Protection Agency (1999) estimated MLE05 and BC05 of 1440 and 778 ppm, 

20 respectively. Because deaths may occur later than 3 hours postexposure, these values should be 

21 considered estimates. 

22 

23 A single 2-hour exposure to 900 ppm resulted in deaths from massive pulmonary 

24 hemorrhage and edema in C3H mice. When mice were subjected to 163 ppm for three 1-hour 

periods each week, substantial deaths occurred after the 6th 25 exposure. Concentrations of 41 and 

26 81 ppm were well tolerated for up to 35 weeks. Mice inhaling 114 ppm for 2 hours daily for 4 

27 days did not show signs of substantial distress (Horton et al. 1963). 

28 

29 Nagorny et al. (1979) exposed 14 groups of 6-8 male and female mice to formaldehyde 

30 for 2 hours. Concentrations of 64 to 98 ppm were not lethal. Concentrations of 109 to 745 ppm 

31 caused 12.5-83.3% lethality. At 746 to 820 ppm all mice died. The 2-hour LC50 was 410 ppm. 

32 The authors also calculated a 2-hour LC16 of 126 ppm and a 2-hour LC84 of 695 ppm. 

33 

34 Bitron and Aharonson (1978) exposed groups of 28-112 mice to 320 ppm for varying 

35 periods of time and then calculated the Lt50, the time at which 50% of the mice died. The mice 

36 were restrained in tight-fitting cylindrical chambers. The postexposure observation period was 

37 45 days. The Lt50 was 100 minutes. Exposure durations of 55, 90, 150, and 320 minutes 

38 resulted in mortalities of approximately 5, 44, 81, and 100%, respectively (data read from a 

39 graph). 

40 

41 3.2. Nonlethal Toxicity 

42 

43 Few studies involving acute exposures were located. Those studies that did employ acute 

44 exposures were usually directed at histopathological changes in the nasal tissues, and animals 

45 were sacrificed immediately after exposures. A few repeat-exposure studies are included in the 

46 discussions below. 

47 
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1 3.2.1. Nonhuman Primates

2 

3 Groups of three Rhesus monkeys inhaled 0 or 6 ppm for 6 hours/day, for one week, or 

4 6 ppm, 6 hours/day, 5 days/week, for 6 weeks in order to study effects on the respiratory 

5 epithelium (Monticello et al. 1989). The formaldehyde-exposed animals showed signs of ocular 

6 irritation - mild lacrimation and conjunctival hyperemia - throughout each exposure period. 

7 Open mouth breathing was observed during the first 15 minutes of each exposure. After one 

8 week of exposure, bilateral changes in the respiratory epithelium included loss of goblet cells 

9 and cilia, minimal to mild epithelial hyperplasia with or without early stages of squamous 

10 metaplasia, and an associated neutrophilic inflammatory response. After six weeks of exposure, 

11 there was minimal progression of lesions, although the affected area was more extensive. After 

12 one week of exposure, lesions showed a progression of severity with the anterior most sections 

13 being the most severely affected; the larnyx/trachea was little affected. After six weeks, lesions 

14 were more similar in the anterior and posterior areas of the nasal cavity. The maxillary sinuses 

15 showed no response to exposure, and there were no treatment-related lesions present in the 

16 lungs. Tritiated thymidine labeling indices of the nasal passages, larynx, trachea, and carina 

17 showed highest labeling indices in the transitional epithelium; the elevation was less than two18 fold greater than that of the controls. 

19 

20 3.2.2. Rats

21 

22 In an early study, Murphy et al. (1964) examined the biochemical effects in 8 adult male 

23 Sprague-Dawley rats following exposure to a Asublethal concentration@ of 35 ppm for 18 hours. 

24 Dyspnea, eye and nasal irritation, and other signs of generalized debility were observed in the 

25 rats during the exposures. No further details of the clinical signs were given, and 

26 histopathological results were not reported. The level of serum alkaline phosphatase was 

27 unaffected by exposure, whereas, the liver alkaline phosphatase was elevated five-fold. 

28 

29 Tobe et al. (1985) exposed groups of 12 male Wistar rats to 0, 10, 20, or 30 ppm for 6 

30 hours in order to observe behavioral as well as biochemical and hematological responses. Signs 

31 in the group exposed to 10 ppm were similar to those of the control group. In the group inhaling 

32 20 ppm, rats sniffed the air about 1 minute after the start of exposure; this was followed by face33 washing movements. Movements in the 30-ppm group were similar to those in the 20-ppm 

34 group. Yellowing of hair around the genital areas was observed in both the 20 and 30-ppm 

35 groups. Irritation of the nasal mucosa membrane and trachea (undefined) were observed in these 

36 two groups. Biochemical changes included a decrease in leukocytes and plasma alkaline 

37 phosphatase and an increase in lung alkaline phosphatase activity. The 10- and 30-ppm groups 

38 had a decrease in the mean corpuscular volume and mean corpuscular hemoglobin. The 30-ppm 

39 group has a decrease in white blood cells. 

40 

41 Boja et al. (1985) described the behavior and neurotoxicity of adult male Sprague42 Dawley rats exposed to 0, 5, 10, or 20 ppm formaldehyde for 3 hours on 2 consecutive days. 

43 Rats were sacrificed after the second exposure and brains were analyzed for neurotransmitters. 

44 Data were presented for only the 5 ppm exposure. On day 1, motor activity decreased within 15 

45 minutes of exposure with controls showing 80% activity at 15 minutes compared with 45% in 

46 the exposed group. Exposure to 5 ppm increased 5-hydroxyindoleacetic acid, 3,4-
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1 dihydroxyphenylacetic acid, and dopamine in the hypothalmus, but did not affect norepinephrine 

2 or 5-hydroxytryptamine. 

3 

4 Chang et al. (1981) conducted an RD50 study (concentration that lowers the respiratory 

5 rate by 50%) with F-344 rats. The RD50 value was 31.7 ppm. The RD50 in male Wistar rats was 

6 10.0 ppm (C.L., 4.7-13.7 ppm) (Cassee et al. 1996). A maximum decrease in breathing 

7 frequency was observed within three minutes of exposure followed by marked desensitization 

8 during the remaining exposure (total exposure 30 minutes). The RD50 in male Crl:Cd (Sprague9 Dawley) rats was 13.8 ppm (Gardner et al. 1985). Concentrations of ≥5.5 ppm produced 

10 considerable depressions in respiratory rate within the first minute of exposure, reaching a 

11 maximum at about 3 minutes. Incomplete recovery took place during the remainder of the 15-

12 minute exposure. 

13 

14 Chang et al. (1983) exposed groups of male Fischer 344 rats to 0, 6, or 15 ppm for 6 

15 hours in order to study nasal cavity deposition, cell proliferation, and histopathology. Both 

16 exposures resulted in approximately a 15% depression in respiratory rate and minute volume. 

17 The nasal respiratory epithelium of control rats had a very slow rate of cell turnover. Eighteen 

18 hours after a single 6-hour exposure to 15 ppm, a 13-fold increase in cell proliferation was 

19 observed. The proliferative response was most pronounced in the basal cell layer. Treatment for 

20 5 days almost doubled the labeling index. Early degeneration and sloughing of respiratory 

21 epithelial cells were observed immediately following the single 6-hour exposure. Necrobiotic 

22 cells were observed in the most anterior areas of nasal cavity. When rats were sacrificed 18 

23 hours after the exposure, hyperplasia, characterized by a thickened epithelium, scattered 

24 degenerate cells, neutrophilic infiltrates, and isolated areas of epithelial sloughing were 

25 observed. The olfactory epithelium appeared normal. Lesions observed following a 5-day 

26 exposure were much more extensive and more severe. Lesions following the exposure to 6 ppm 

27 were not described. 

28 

29 Morgan et al. (1986a) evaluated the effect of exposure on the nasal mucociliary apparatus 

30 of groups of F-344 rats exposed to 0.5, 2, 6, or 15 ppm. for 6 hours. Additional groups of rats 

31 were exposed to the same concentrations for up to 3 weeks. The relationship between inhibition 

32 of the mucociliary clearance mechanism and histopathologic changes in the underlying 

33 epithelium was also evaluated. No signs of irritation were observed in rats exposed to 0 or 0.5 

34 ppm. Rats exposed to 2, 6, or 15 ppm exhibited concentration-related evidence of eye and nose 

35 irritation including ocular and nasal discharge. These signs were minimal at 2 ppm. After a 

36 single 6-hour exposure to 15 ppm, direct impairment of nasal mucociliary function and cessation 

37 of ciliary activity were observed in the anterior region of the nose. Lesions in this area were 

38 characterized by separation of epithelial cells and intravascular margination and local tissue 

39 infiltration by neutrophils and monocytes. The investigators characterized the lesions as 

40 Aminimal effects,@ but indicated that the lesions were followed by severe degenerative changes. 

41 In what appears to be the same group of animals, Swenberg et al. (1983) characterized the 

42 lesions as acute degeneration of the respiratory epithelium with edema and congestion... evident 

43 at the end of one day of exposure. Less severe changes were found in rats exposed to 6 ppm for 

44 6 hours, and no epithelial lesions were detected in rats exposed to 2 or 0.5 ppm for 6 hours. 

45 Repeated exposures resulted in more extensive changes in the anterior nasal passages. The 

46 investigators considered inhibition of mucociliary function a more sensitive indicator of toxicity 

47 than epithelial lesions. 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 34 of 71

1 

2 In a second study (Morgan et al. 1986b), rats were exposed to 0, 2, or 15 ppm for 10, 20, 

3 45, or 90 minutes or 6 hours with recovery groups examined 1 hour after the 90-minute and 6-

4 hour exposures. There was no evidence of impaired mucociliary function in rats exposed to 2 

5 ppm for 90 minutes or 6 hours. A 90-minute or 6-hour exposure to 15 ppm followed by a 1-hour 

6 recovery period resulted in extensive recovery of both ciliary activity and mucus flow. Recovery 

7 was almost complete in the group exposed to 15 ppm for 90 minutes, whereas recovery was 

8 Aconsiderable but incomplete@ in the group exposed for 6 hours. 

9 

10 Groups of 48 male F-344 rats inhaled 0 (filtered air), 0.7, 2, or 6 ppm for 6 hours/day, 5 

11 days/week for up to three weeks (Andersen et al. 2008). Atmospheres were generated by 

thermal depolymerization of paraformaldehyde into 8 m3 12 steel and glass chambers. Atmospheres 

13 were monitored by infrared analysis (measured concentrations of 1, 0.6, 1.8, 5.0, and 14 ppm). 

14 Sacrifices (n = 8 for each group) took place after 6 hours of exposure, after 18 hours of exposure, 

15 at the end of six days of exposure, 18 hours after the sixth exposure, and at the end of 15 days of 

16 exposure. Minimal inflammatory infiltrates were frequently noted in controls and all treated 

17 groups, with consistent increases evident only in the 6 ppm group. Neither cell proliferation nor 

18 histopathology was observed at 0.6 ppm at any time point. Immediately following exposure on 

19 day 1, minimal inflammatory cell infiltrate of the maxilloturbinate was present in 6 of 8 rats that 

20 inhaled 1.8 ppm and in all rats that inhaled 5.0 ppm. At day 1 recovery, epithelial hyperplasia 

21 was observed in 0, 1, 3, and 8 rats in the control through 5.0 ppm groups, respectively. 

22 Following 15 days of exposure, rats in the 1.8 ppm and 5.0 ppm groups exhibited epithelial 

23 hyperplasia (2 of 8 and 7 of 8, respectively), but all rats failed to exhibit squamous metaplasia. 

24 Squamous metaplasia had been observed in 7 of 8 rats in the 5.0 ppm group at the end of the first 

25 week of exposure. Cell proliferation, evaluated only at days 5 and 15 was observed only in the 

26 5.0 ppm group. 

27 

28 In the above study (Andersen et al. 2008), an additional group of 8 rats inhaled 15 ppm; 

29 sacrifice took place following the 6-hour exposure. Gene expression in rat nasal epithelium was 

30 evaluated and compared with that of the groups above. Both temporal and concentration31 dependent transitions in genomic signatures were observed between 0.6 and 5.0 ppm. These 

32 concentration affected primarily genes associated with extracellular componenets and plasma 

33 membrane. The number of genes altered at 15 ppm (evaluated after only a single exposure) was 

34 18-fold greater than those altered at 5.0 ppm. 

35 

36 Dubreuil et al. (1976) observed slight irritation in rats continuously exposed to 1.6 ppm 

37 for up to two months. Minimal adverse effects occurred at 4.6 ppm, and clear signs of nasal 

38 irritation were observed at 8.1 ppm. 

39 

40 3.2.3. Mice 

41 

42 Kane and Alarie (1977) evaluated sensory irritation in male Swiss-Webster mice. 

43 Percent decreases in respiratory rate were measured in groups of four mice inhaling 0.52 to 10 

44 ppm formaldehyde for 10 minutes. From the data, a 50% decrease in respiratory rate, the RD50, 

45 was calculated at 3.1 ppm. Chang et al. (1981) conducted a similar study with B6C3F1 mice. 

46 The RD50 values in mice and rats were 4.9 and 31.7 ppm, respectively. The authors of the latter 

47 study point out that the ability of mice to depress their respiratory rate in response to irritants 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 35 of 71

1 results in minimization of the inhaled dose and may contribute to differences in respiratory tract 

2 toxicity between mice and rats. 

3 

4 A series of immune function and host resistance parameters ere examined in female B6C3F1 

5 mice following inhalation exposure to 15 ppm of formaldehyde for 6 hours/day, 5 days/week for 

6 3 weeks (Dean et al. 1984). There were no deaths, and no significant differences in body weight 

7 between the control and exposed group were observed. Lymphoid organ weight, bone marrow 

8 cellularity, and hematology parameters were unchanged in formaldehyde-exposed mice. The 

9 percentage of T and B lymphocytes and their proliferative responses to mitogens were not 

10 significantly altered. Antibody plaque-forming cell response following antigen challenge was 

11 unchanged. Macrophage function was normal although some evidence of enhanced hydrogen 

12 peroxide production associated with elevated bactericidal activity was observed in resident 

13 macrophages. Resistance to challenge with the bacteria Listeria monocytogenes was 

14 significantly enhanced, while resistance to tumor challenge remained unchanged. 

15 

16 3.2.4. Guinea Pigs

17 

18 The airway reactivity of guinea pigs to formaldehyde was assessed in several studies. 

19 Amdur (1960) measured pulmonary mechanics in groups of 4 to 18 guinea pigs exposed to 0.05, 

20 0.31, 0.58, 1.22, 3.6, 11.0, or 49 ppm for 1 hour. Preexposure values served as control values. 

21 An increase in resistance and a decrease in compliance, suggestive of bronchoconstriction, 

22 became statistically significant at 0.31 ppm. Decreases in respiratory rate and minute volume 

23 became statistically significant at 11 ppm. Delivery of formaldehyde directly to the trachea via a 

24 cannula increased the response to formaldehyde. In both cases, the resistance change was 

25 reversible in an hour after the exposure ended. 

26 

27 Inhalation of 6 or 10 ppm, 6 or 8 hours/day, for 5 consecutive days failed to elicit 

28 pulmonary hypersensitivity or produce antibodies in guinea pigs, although two of four animals 

29 that had inhaled 10 ppm for 8 hours over 5 days developed skin sensitivity (Lee et al. 1984). 

30 Pulmonary sensitivity, both immediate and delayed, was assessed by measurement of bronchial 

31 reactivity in response to a formaldehyde challenge. Dermal sensitivity was assessed with a 

32 topical challenge, and antibodies were assessed with formaldehyde-specific antigens. 

33 Respiratory rates of animals inhaling 10 ppm for 6 hours were measured over the course of the 

34 first day. Respiratory rates first decreased by 45% within the first hours of exposure and 

35 remained depressed during he following 5 hours of exposure. The pattern of respiration changed 

36 over the course of the exposure, with the first hour resembling that of animals exposed to a 

37 sensory irritant and the second hour characteristic of animals with tracheal cannulation, i.e., 

38 indicating the formaldehyde had reached the lower respiratory tract. Antibodies to formaldehyde 

39 were observed only in guinea pigs administered the material by injection. 

40 

41 In a another study, Swiecichowski et al. (1993) investigated the changes in pulmonary 

42 resistance and airway reactivity to intravenous acetylcholine in guinea pigs exposed to selected 

43 concentrations of formaldehyde. Groups of 5 to 7 male Hartley guinea pigs were exposed to 0, 

44 0.86, 3.4, 9.4, or 31.1 ppm for 2 hours or to 0, 0.11, 0.31, 0.59, or 1.05 ppm for 8 hours. 

45 Baseline reactivities were measured prior to exposure and up to 24 hours postexposure. Tracheal 

46 histology was also examined immediately after exposure and for up to 96 hours after exposure to 

47 3.4 ppm for 8 hours. Specific pulmonary resistance to infused acetylcholine increased by 31% 
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1 after exposure to 9.4 ppm for 2 hours, but not at the lower exposures. A similar increase was 

2 observed following an 8-hour exposure to 1.0 ppm. Microscopic examination of the trachea 

3 revealed no changes in the number of ciliated cells of the epithelium or in inflammatory cell 

4 infiltration into the lamina propria of the epithelium. 

5 

6 3.3. Neurotoxicity

7 

8 No information on neurotoxicity in animals was located. 

9 

10 3.4. Developmental/Reproductive Toxicity

11 

12 Inhalation, oral gavage, dietary, and drinking water studies have been used to study the 

13 effects of formaldehyde on reproduction and development. Study results published prior to 1982 

14 were reviewed by the Federal Panel on Formaldehyde (1982). Many of the studies suffered from 

15 an unreported or inadequate number of animals in treated dose groups. Details in the studies 

16 were often conflicting. Dietary studies with dogs and rats, gavage studies with mice, and 

17 drinking water studies with rats, the latter with hexamethylenetetramine (which is metabolized to 

18 formaldehyde in vivo), were also conducted. Although formaldehyde was not teratogenic in 

19 these studies, the panel concluded that additional, well-conducted studies should be performed. 

20 In a multi-generation study with rats administered 1% hexamethylenetetramine in the drinking 

21 water (Della Porta et al. 1970), there was no effect of treatment on survival or body weight of 

22 any generation. 

23 

24 Saillenfait et al. (1989) exposed Sprague-Dawley rats to 0, 5, 10, 20, or 40 ppm for 6 

25 hours/day from day 6 to 20 of gestation. On day 21 of gestation the fetuses were examined. 

26 There were no effects on embryo or fetal lethality and no teratogenic effects. The concentration 

27 of 40 ppm was maternally toxic as reflected by a significant reduction in dam body weight. 

28 Concentrations of 20 and 40 ppm were fetotoxic as reflected by reduced fetal weights, 

29 characterized as slight at 20 ppm and 20% at 40 ppm. 

30 

31 Morgan (1990) exposed 25 mated female Sprague-Dawley rats whole-body to 1.9, 4.9, or 

32 9.5 ppm formaldehyde for 6 hours/day from day 6 through day 15 of gestation. Both an air and a 

33 room control group were included in the study. Dams were weighed and sacrificed, and 

34 examined for reproductive indices; fetuses were weighed and examined for malformations. A 

35 significant decrease in maternal food consumption and weight gain was observed in the 10 ppm 

36 group. Pregnancy rate, number of corpora lutea, implantation sites, live fetuses, dead fetuses and 

37 resorptions, and fetal weight, sex ratio, and preimplantation and postimplantation losses were 

38 unaffected by treatment. Incidences of litters and fetuses with major malformations, minor 

39 external visceral anomalies, and minor skeletal anomalies were unaffected by treatment. 

40 Incidences of reduced ossification of the pubic and ischial bones in the 5 and 10 ppm groups 

41 were significantly increased when compared to the air control group but not when compared to 

42 the room control group. This effect appeared to be related to the larger litter sizes in the higher 

43 exposure groups. 

44 

45 3.5. Genotoxicity

46 
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1 The genotoxicity of formaldehyde has been reviewed by many groups including NRC 

2 1980, WHO (1989), Feron et al. (1991), ATSDR (1999), and IARC (2006). According to IARC 

3 (2006), formaldehyde Ademonstrates positive effects in a large number of in vitro tests for 

4 genotoxicity, including bacterial mutation, DNA strand breaks, chromosomal aberrations, and 

5 sister chromatid exchange. Studies in humans showed inconsistent results with regard to 

6 cytogenetic changes (micronuclei, chromosomal aberrations, and sister chromatid exchange).” 

7 Formaldehyde induced DNA-protein cross-links in vitro in human bronchial epithelial cells, 

8 fibroblasts, and lymphocytes. Studies in formaldehyde-exposed workers revealed increased 

9 DNA-protein cross-links, consistent with results of inhalation studies with rats and monkeys. 

10 

11 In a dominant lethal test with mice, intraperitoneal injections of males with 16, 20, 32, or 

12 40 mg/kg did not affect spermatogenesis or fertility, i.e., no dominant lethal mutations (Epstein 

13 et al. 1972). According to WHO (1989) formaldehyde is mutagenic in different test systems, 

14 especially at high concentrations. However, evidence that formaldehyde may induce mutations 

15 in vivo is lacking.?? 

16 

17 Formaldehyde readily reacts with a variety of cellular nucleophiles including DNA. 

18 Reaction products with DNA include adducts and DNA-protein cross-links in vitro (WHO 

19 1989). In inhalation studies of rats exposed to formaldehyde, formaldehyde induces the 

20 formation of DNA -protein cross-links in the nasal respiratory mucosa in vivo (Casanova21 Schmitz and Heck 1983; Casanova-Schmitz et al. 1984). The concentration-response curve is 

22 sublinear below 6 ppm, but linear above. DNA-protein cross-links were not found at other sites. 

23 

24 3.6. Chronic Toxicity/Carcinogenicity

25 

26 Studies of intermediate duration as well as chronic toxicity/carcinogenicity studies are 

27 summarized in Table 5. Subchronic studies show that precursor carcinogenic effects - 

28 pathologic lesions of the nasal mucosa occur if concentrations are sufficiently high. Generally 

29 no nasal lesions occurred in 13-week studies at concentrations of 1-4 ppm for 6-8 hours/day. 

30 Concentrations $10 ppm for at least 13 weeks caused lower respiratory tract damage as 

31 evidenced by nasal, laryngeal and tracheal lesions (Rusch et al. 1983; Maronpot et al. 1986; 

32 Woutersen et al. 1987; Feron et al. 1988; Wilmer et al. 1989). Respiratory tract lesions were 

33 always greater in rats than in mice and were generally absent in hamsters. Only the chronic 

34 studies are discussed in the following text. 

35 

36 Several studies addressed carcinogenicity in rodents at low levels of exposure. In the 

37 earliest such study (Swenberg et al. 1980; Kerns et al. 1983) groups of 120 male and 120 female 

38 Fischer 344 rats and groups of 120 male and 120 female B6C3F1 mice inhaled measured 

39 concentrations of 0, 2.0, 5.6, or 14.3 ppm for 6 hours/day, 5 days/week for 24 months. Some 

40 animals were sacrificed at 6, 12, and 18 months. Rats exposed to all concentrations had a 

41 concentration-dependent yellow discoloration of the fur. Clinical signs were limited to the 14.3 

42 ppm group and included dyspnea and emaciation. At the end of 24 months, body weights of 

43 male and female rats in the 5.6 and 14.3 ppm groups were decreased (p<0.05); body weight 

44 recovery took place during a 3-month postexposure non-treatment period. Concentration45 dependent observations of rhinitis, epithelial dysplasia, and squamous metaplasia occurred in all 

46 exposure groups of rats. Squamous cell carcinomas were observed in the nasal cavities of 51 of 

47 117 male rats (44%) and 52 of 115 female rats (45%) exposed to 14.3 ppm and in one male (of 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 38 of 71

1 119) and one female (of 116) rat exposed to 5.6 ppm (both approximately 1%). At 24 months, 

2 the adjusted incidence rates of squamous cell carcinomas in male and female rats in the 14.3 ppm 

3 exposure group were 67 and 87%. The nasal lesions were described as Asquamous metaplasia 

4 with zones of squamous epithelial hyperplasia and increased keratin production that appeared to 

5 precede areas of squamous papillary hyperplasia with foci of cellular atypia.@ Carcinomas 

6 invaded the nasal turbinates. In many animals in this exposure group, the excessive 

7 accumulation of keratin and inflammatory exudate within the nasal cavity caused severe dyspnea 

8 and death. Polyploid adenomas of the nasal mucosa were seen in rats at all doses in a significant 

9 dose-related trend. At study termination, squamous cell carcinomas were found in 2 of 106 male 

10 mice exposed to 14.3 ppm (2%) and in none of the female mice (0/109) exposed to 14.3 ppm. 

11 Mouse survival was not affected by exposure. 
TABLE 5. Summary of Subchronic and Chronic/Carcinogenicity Studies in Laboratory Animals 

Species 

Concentration 

(ppm) 

Exposure 

Duration Effect 

Monkey (male cynomolgus) 

0, 0.19, 0.98, 2.95 22 h/d, 

7 d/w, 26 wk 

No effect at 0.19 or 0.98 ppm; hoarseness, congestion and squamous cell metaplasia in the nasal turbinates at 2.95 ppm 

Rat (male SpragueDawley) 0, 15 6 h/d, 5 d/wk, 

lifetime 

Controls: epithelial or squamous hyperplasia of the nasal mucosa, 0/99 tumors; 15 ppm: squamous hyperplasia and metaplasia; nasal cavity tumors: 38/100 squamous cell carcinomas, 1/100 fibrosarcoma, 1/100 mixed carcinoma 

Rat (male and female Wistar) 

0, 1, 9.7, 20 6 h/d 

5 d/wk, 13 wks 

1 ppm: minimal focal hyperplasia in the nose 9.7 ppm: moderate squamous metaplasia, nasal respiratory epithelium 

19.8 ppm: growth retardation, squamous metaplasia, squamous cell carcinomas 

(4/44 vs 0/45 controls), carcinoma in situ, adenomas 

Rat (male Wistar) 1, 2 

2,4 

8 h/d, 5 d/wk, 13 wks 8 x 30-min/d, 30-min break, 13 wks 

Continuous, 8 hours: 1, 2 ppm: no histopathology of the nose Interrupted, 4 hours: 2 ppm: rhinitis (considered incidental); 4 ppm: squamous metaplasia and hyperplasia, nasal turbinates, increased cell turnover 

Rat (male and female Fischer 344) 

0, 0.19, 0.98, 2.95 22 h/d, 

7 d/w, 26 wks 

No effect at 0.19 or 0.98 ppm; squamous metaplasia in the nasal turbinates, decreased body weight, and decreased liver weight at 2.95 ppm 

Rat (male Wistar) 0, 0.1, 1, 10 12 months No adverse effects at 0.1 and 1 ppm; growth retardation, reduced urine 

production, and rhinitis accompanied by squamous metaplasia of the nasal respiratory epithelium at 10 ppm 

Rat (male Fischer 344) 

0, 0.3, 2.0, 3.3, 15 6 h/d, 

5 d/wk, 24-28 months 

Dose-related incidences of rhinitis and nasal hyperplasia 15 ppm: 88% mortality; squamous cell carcinomas, 14/27 vs 0/27 controls surviving past 12 months 

Rat (male Fischer344) 0, 0.3, 2.1, 14.9 6 h/d, 5 d/wk, 

28 months 

Inflammatory cell infiltration, erosion, or edema observed in all groups including controls; concentration dependent nasal epithelial cell hyperplasia with squamous cell metaplasia at all concentrations; 15 ppm: squamous cell 

carcinomas, papillomas in 8/32 by 24 months 

Rat (male Fischer 344) 

0, 0.7, 2, 6, 10, 15 ppm 

6 h/d, 5 d/wk, 24 months 

0.7, 2 ppm: no squamous cell carcinomas 6, 10, 15 ppm: tumor incidences of 1, 22, and 47%, respectively 

Rat (male and female Fischer 344) 

0, 2, 5.6, 14.3 6 h/d, 

5 d/wk, 24 months 

Rat: 2 ppm: no clinical signs, no carcinomas 

5.6 ppm: rhinitis, increased mortality (males), nasal squamous metaplasia, 

squamous carcinomas (2/153 vs 0/156 controls) 14.3 ppm: dyspnea, emaciation, increased mortality, nasal squamous carcinomas (94/140 vs 0/156 controls) 

Rat (male Wistar) 0, 0.1, 1, 10 6 h/d, 

5 d/wk, 28 months 

No effect on nasal respiratory epithelium at 0.1 or 1 ppm; degenerative inflammatory, and hyperplastic changes at 10 ppm; nasal squamous cell carcinomas in 0/26, 1/26, 1/28, and 1/26 rats, respectively 

Mouse (male and female B6C3F1) 

0, 2, 4, 10, 20, 40 6 h/d, 

5 d/wk 13 wks 

2, 4 ppm: no histopathology of the nasal epithelium; 10 ppm: nasal lesions; 20 ppm: nasal, laryngeal, and tracheal lesions; 40 ppm: ataxia, body weight depression, inflammation and metaplasia of the 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 40 of 71

TABLE 5. Summary of Subchronic and Chronic/Carcinogenicity Studies in Laboratory Animals 

nasal cavity, larynx, trachea, and lungs, 80% mortality 

Mouse (male and female B6C3F1) 

0, 2, 5.6, 14.3 6 h/d, 

5 d/wk, 24 months 

2 ppm: no noteworthy lesions 5.6, 14.3 ppm: squamous cell carcinomas, 2/116 males 

Hamster (male and female golden Syrian) 

0, 0.19, 0.98, 2.95 ppm 

22 h/d, 7 d/w, 26 wk 

No effect at any concentration (no increase in squamous metaplasia in the nasal cavity of treated hamsters) 

Hamster (male Syrian golden) 

0, 10 5 h/d, 

5 times/wk, lifetime 

No increase in rhinitis; hyperplastic and metaplastic areas in nasal epithelium in 5% of hamsters exposed to 10 ppm; no tumors in treated or control group 

Studies are arranged by species followed by length of study. 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 41 of 71

1 Sellakumar et al. (1985; see also Albert et al. 1982) exposed groups of 100 male Sprague2 Dawley rats to 15 ppm for a lifetime. Two additional groups were included in the experiment: a 

3 group exposed to air only and a group exposed to 15 ppm formaldehyde and 10 ppm hydrogen 

4 chloride (HCl). HCl was administered to see if tumor response was enhanced by an additional 

5 irritant effect or by the combination of the two chemicals to form bis-(chloromethyl)ether, a 

6 known carcinogen. Squamous cell carcinomas of the anterior nasal cavity were induced in 

7 38/100 rats that received formaldehyde alone. Concurrent administration of HCl had no effect 

8 on the incidences of nasal cancers. In addition to rhinitis, hyperplasia and squamous metaplasia 

9 of the nasal mucosa, larynx and trachea were observed in all formaldehyde exposed group. 

10 Exposure to HCl alone resulted in only hyperplasia. 

11 

12 Tobe et al. (1985) conducted a 28-month study with male F-344 rats. Groups of 32 rats 

13 were exposed 6 hours/day, 5 days/week to 0, 0.3, 2.0, 3.3, or 15 ppm in aqueous methanol. 

14 Another group was exposed to the methanol only. Exposure to 15 ppm ended at 24 months at 

15 which point the mortality was 88%. Squamous cell carcinomas were observed in 14/27 rats in 

16 the 15 ppm group surviving past 12 months (controls, 0/27). No polyploid adenomas were 

17 observed. Incidences of rhinitis and hyperplasia were dose-related. 

18 

19 Using male Wistar rats, Woutersen et al. (1989) observed nasal squamous cell 

20 carcinomas in only 1/26, 1/28, and 1/26 exposed to 0.1, 1.0, or 10 ppm, respectively, for 6 

21 hours/day, 5 days/week for 28 months. There were no carcinomas in 26 control rats. Physical 

22 damage to the nasal mucosa (electrocoagulation) increased the response in a group subsequently 

23 exposed to 10 ppm group (15/58 compared with 1/54 in controls treated with 

24 electrocoagulation). 

25 

26 Male F-344 rats inhaled 0.3, 2, or 15 ppm for 6 hours/day, 5 days/week for 28 months 

27 (Kamata et al. 1997). Clinical signs of irritation were observed in the 15 ppm group. No nasal 

28 tumors were observed in the groups that inhaled 0.3 or 2 ppm. By 14 months, nasal tumors were 

29 macroscopically evident in the in the 15-ppm group, and this group had early deaths. By 24 

30 months, 8/32 rats had squamous cell papillomas and carcinomas. 

31 

32 Dalbey (1982) exposed male Syrian golden hamsters to 10 ppm formaldehyde 5 

hours/day, 5 times/week, throughout their lifetimes. Beginning with the 20th 33 week, survival time 

34 was reduced in the exposed group compared with unexposed controls. No tumors were observed 

35 in the respiratory tract of either the control or exposed group. Only a minimal increase in 

36 hyperplastic and metaplastic areas was observed in the nasal epithelium of 5% of the exposed 

37 group. 

38 

39 As noted in Section 2.6, the U.S. EPA (2003) in their Weight-of-Evidence 

40 characterization classifies formaldehyde as B1, probable human carcinogen. This classification 

41 is based on limited evidence in humans and sufficient evidence in animals. IARC (2006) 

42 concluded there is sufficient evidence in humans for the carcinogenicity of formaldehyde. 

43 

44 3.7. Summary

45 

46 Lethal concentrations were available for the rat and mouse. LC50 values for the rat 

47 ranged from 820 ppm for 30 minutes (Skog 1950) to 250-482 ppm for 4 hours (Carpenter et al. 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 42 of 71

1 1949; Nagorny et al. 1979). For the mouse, the value was similar to the rat when the duration 

2 was shorter (Nagorny et al. 1979), whereas the Lt50 (similar to the LC50) was 320 ppm for 100 

3 minutes (Bitron and Aharonson1978). Mice survived a 4-day repeat exposure to 140 ppm with 

4 little signs of distress (Horton et al. 1963). 

5 

6 Few studies at sublethal concentrations were of acute duration. Murphy et al. (1964) 

7 reported that 35 ppm for 18 hours was a sublethal concentration for the rat. Rats exposed to 15, 

8 20 or 30 ppm for 6 hours showed eye and nose irritation, inhibition of the mucociliary clearance 

9 mechanism, and damage of the nasal mucosa which extended to the trachea at the higher 

10 exposures (Chang et al. 1983; Tobe et al. 1985; Morgan et al. 1986a). There was no evidence of 

11 damage to the anterior respiratory epithelium after exposures to 2 ppm for up to 6 hours 

12 (Morgan et al. 1986b). Repeated exposures to 1 or 2 ppm for 6 hours/day also produced no 

13 histopathology in rats (Woutersen et al. 1987). It should be noted that rats are obligate nose 

14 breathers. Horton et al. (1963) observed no substantial distress in mice during a 4-day repeat 

15 exposure to 140 ppm (of 2 hours duration). The RD50 in mice is 3.1 ppm (Kane and Alarie 

16 (1977). 

17 

18 Guinea pigs are the only species to react with bronchoconstriction during exposure to low 

19 concentrations. A concentration of 0.3 ppm produced bronchoconstriction (Amdur 1960). 

20 

21 Formaldehyde has been evaluated for potential teratogenicity in several test systems. 

22 Inhalation studies with rats, although lacking in detail, indicate no teratogenic response. 

23 Inhalation exposure of pregnant rats to 20 or 40 ppm on days 6-20 of gestation reduced fetal 

24 body weight but failed to cause malformations (Saillenfait 1989). No teratogenic responses were 

25 observed in dogs or mice treated orally. The reviewed studies do not show any evidence of the 

26 embryo being unusually sensitive to formaldehyde, and there is no information that indicates 

27 formaldehyde is teratogenic to rodents when administered by a number of routes. 

28 

29 A 13-week repeat exposure to 2 or 4 ppm did not result in pathologic changes in the nasal 

30 epithelium of mice (Maronpot et al. 1986). However, repeat exposures to 10, 20, or 30 ppm 

31 produced squamous metaplasia and inflammation. The 40 ppm exposure was lethal to most mice 

32 during the 13-week exposure. Subchronic exposures were carcinogenic to the rat (Woutersen et 

33 al. 1987). 

34 

35 Chronic studies have been carried out with rats, mice, and hamsters. In these studies, 

36 formaldehyde-induced effects were restricted to non-neoplastic and neoplastic lesions in the 

37 anterior regions of the nasal epithelium. Non-neoplastic lesions in rats such as metaplasia were 

38 found at concentrations as low as 2 ppm (Kamata et al. 1997). Neoplastic lesions - squamous 

39 cell carcinomas, squamous cell papillomas, or polyploid adenomas - were observed in rats 

40 exposed to 5.6 ppm and in mice exposed to 14.3 ppm (Kerns et al. 1983). Neoplastic lesions 

41 were not found in hamsters exposed to 10 ppm (Dalbey 1982). 

42 

43 Studies with several species of animals confirm that the upper respiratory tract is a 

44 critical target for inhaled formaldehyde. These studies describe exposure-response relationships 

45 for upper respiratory tract irritation and epithelial damage. Inhaled formaldehyde damages 

46 epithelial tissue in specific regions of the upper respiratory tract in rats, mice, and monkeys. 

47 Lesions consist of hyperplasia and squamous cell metaplasia. Lung damage occurs at higher 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 43 of 71

1 concentrations than those affecting only the upper respiratory tract. Mice and hamsters are less 

2 susceptible to formaldehyde-induced upper respiratory tract epithelial damage than rats. Rats 

3 and monkeys may be equally susceptible to epithelial damage, but display damage in different 

4 regions of the respiratory tract. 

5 

6 4. SPECIAL CONSIDERATIONS

7 4.1. Metabolism and Disposition

8 

9 Inhaled formaldehyde, being highly water soluble, is rapidly and almost completely 

10 absorbed from the respiratory tract. Studies with mongrel dogs exposed to 122-235 ppm of 

11 vapor showed that the retention of vapor is nearly 100%, with most of the absorption in the 

12 upper respiratory tract (Egle 1972; ATSDR 1999). Gastric absorption is also high, but dermal 

13 absorption is quite low. Although all tissues are capable of metabolizing formaldehyde, rapid 

14 local metabolism in the tissues of the respiratory tract results in little or no formaldehyde 

15 reaching the blood. Given the high absorption and metabolism in the tissues of the respiratory 

16 tract, storage or distribution to other tissues in unlikely. 

17 

18 Heck et al. (1985) measured the blood level of formaldehyde in six volunteers 

19 immediately following inhalation of 1.9 ppm for 40 minutes and compared the results to pre20 exposure values. Although individual differences in blood concentrations were noted both pre21 and post-exposure, differences in the mean values were not statistically significant following 

22 exposure (control value, 2.61 Fg/g; postexposure, 2.77 Fg/g). Similar results were found by 

23 Heck et al. (1985) following exposure of eight male F-344 rats to 0 or 14.4 ppm for 2 hours and 

24 sacrificed immediately after. Blood levels in the control and exposed groups were 2.24 and 2.25 

25 Fg/g, respectively. After intravenous injection of monkeys, formaldehyde is rapidly eliminated 

26 from the blood with a half-life of about 1.5 minutes (McMartin et al. 1982). 

27 

28 In the cell, the initial reaction of formaldehyde is with glutathione to form a hemiacetal. 

29 The hemiacetal is then metabolized to formate, primarily by formaldehyde dehydrogenase, 

30 although other aldehyde dehydrogenases are capable of metabolizing formaldehyde (ATSDR 

31 1999). This enzyme is present in all animal tissues. The actual endproduct of the dehydrogenase 

32 reaction is S-formylglutathione which slowly hydrolyzes to formate. Formate can undergo three 

33 reactions: oxidation to carbon dioxide and water, elimination in the urine as a sodium salt, or 

34 entrance into the metabolic one-carbon cycle. Formaldehyde may also enter the one-carbon pool 

35 directly. Formaldehyde also reacts with protein and single-strand DNA. 

36 

37 4.2. Mechanism of Toxicity

38 

39 Formaldehyde is a primary irritant that is extensively scrubbed in the anterior nasal 

40 passages. The mechanism of action of primary irritants involves activation of sensory nerve 

41 fibers which relay to the trigeminal nerve to reflexively induce bronchoconstriction through the 

42 vagus nerve. This mechanism of action has been observed in guinea pigs (Amdur 1960), but has 

43 not been observed at the low concentrations used in clinical studies with healthy subjects and 

44 asthmatics. 

45 

46 Formaldehyde is a highly cytotoxic respiratory tract irritant. The exact mechanism of 

47 formaldehyde=s irritant, corrosive, and cytotoxic effects is unknown. Aldehydes as a group are 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 44 of 71

1 highly reactive chemicals. The highly electronegative oxygen atom and less electronegative 

2 carbon atoms convey a substantial dipole moment. The electrophilic carbonyl atom reacts easily 

3 with nucleophilic sites on cell membranes and in body tissue fluids. Formaldehyde also 

4 combines readily with free, unprotonated amino groups of amino acids to yield hydroxymethyl 

5 amino acid derivatives and a proton (H+). This action may be responsible for its germicidal 

6 properties. Higher concentrations will precipitate protein (ATSDR 1999). 

7 

8 The precursor of tumor formation for respiratory irritants is persistent tissue damage 

9 followed by sustained cell proliferation. Induction of nasal squamous carcinomas in rats by 

10 formaldehyde requires long-term exposure to concentrations of 10-20 ppm that result in 

11 epithelial degeneration and cell death accompanied by rhinitis, followed by regenerative 

12 hyperplasia and metaplasia, changes associated with increased cell proliferation 

13 (Feron et al. 2001). Studies of nasal epithelial lesions and cell proliferation in formaldehyde14 exposed rats demonstrated a good correlation of cellular injury with cell proliferation and 

15 neoplasia. At concentrations of 10 and 15 ppm there is a 4- to 10-fold increase in cell 

16 proliferation in rat nasal tissue (Monticello et al. 1996). Formaldehyde is weakly genotoxic, 

17 inducing DNA cross-links in the nasal respiratory epithelium of rats and monkeys (Casanova and 

18 Heck 1991). At 10 ppm, the major pathway for detoxification in the rat is saturated. And above 

19 10 ppm there is a 7-fold greater level of formation of DNA-protein cross-links per ppm of 

20 exposure than what occurs at lower concentrations. Areas of DNA-protein cross links are 

21 correlated with regional sites of formaldehyde-induced epithelial damage in the nose of rats. 

22 Inhibition of mucociliary function, epithelial degeneration, inflammation, squamous metaplasia, 

23 and increased cell proliferation in the nasal tissue all correlate with the site-specific uptake and 

24 cancer pattern observed in experimental studies (Paustenbach et al. 1997). 

25 

26 4.3. Structure-Activity Relationships

27 

28 In their study of the irritancy of six aldehydes, Sim and Pattle (1957) reported that 

29 acrolein and crotonaldehyde were highly irritant, and acetaldehyde, propionaldehyde, 

30 butyraldehyde, and isobutryaldehyde were almost nonirritant. The irritancy of formaldehyde 

31 was intermediate between that of the highly irritant and nonirritant groups. Pattle and 

32 Cullumbine (1956) reported formaldehyde toxicity to be between the unsaturated aldehydes and 

33 acetaldehyde. U.S. EPA (2003) notes that when inhaled, acetaldehyde causes cancers in the nose 

34 and trachea of hamsters and nasal cancers in rats. 

35 

36 Kane and Alarie (1977) compared the irritancy of formaldehyde and acrolein. The 

37 respective RD50 values were 3.1 and 1.7 ppm, demonstrating that formaldehyde is approximately 

38 half as irritating as acrolein. 

39 

40 4.4. Other Relevant Information

41 

42 Dermal exposure to formaldehyde produces allergic contact dermatitis. This is a delayed 

43 hypersensitivity reaction in which only minute quantities of a material are necessary to elicit an 

44 overt reaction. Allergic contact dermatitis is preceded by sensitization to the allergen. 

45 Subsequent exposures elicit clinical effects (Cohen and Rice 2001). 

46 

47 4.4.1. Species Variability
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1 

2 The carcinogenic response to formaldehyde is species specific. Formaldehyde was 

3 carcinogenic to F-344 rats and Wistar rats, but not hamsters. Wistar rats were much less 

4 responsive than F-344 or Sprague-Dawley rats. Mice were much less susceptible than F-344 

5 rats. Both the rat and monkey reacted to subchronic exposure with squamous metaplasia (Rusch 

6 et al. 1983). There are differences in the deposition of formaldehyde in the nasal regions of the 

7 rat and monkey, due to anatomical differences which influence air-flow patterns. In addition, 

8 monkeys develop much lower amounts of DNA-protein crosslinks than rats after exposure to 

9 formaldehyde (Casanova et al. 1991). For mice, differences in the carcinogenic response appear 

10 due to differences in dose. Mice respond to formaldehyde with decreased minute volume and 

11 therefore have less formaldehyde available for deposition in the nasal epithelium than rats 

12 (Chang et al. 1983). 

13 

14 Nasal airflow patterns appear to play a dominant role in determining olfactory lesions 

15 (Morgan and Monticello 1990). To estimate local formaldehyde dose in rat and monkey nasal 

16 passages and in the human respiratory tract, researchers at the CIIT developed and applied three17 dimensional nasal airflow models and computational fluid dynamics modeling (Bush et al. 1998; 

18 Frederick et al. 1998; Kimball et al. 2001; Conolly et al. 2003; 2004). Additional key elements 

19 of their approach were (1) association of the flux of formaldehyde into the nasal mucosa with 

20 formation of DNA-protein cross-links and with cell death and cell proliferation, and (2) use of a 

21 two-stage clonal growth model to link DNA-protein cross-links and cell proliferation with tumor 

22 formation. Based on this computer modeling maximum likelihood estimates of cancer risk are 

23 de minimis at relevant human exposures. 

24 

25 4.4.2. Susceptible Populations

26 

27 Several studies indicate that there is wide variation in subjective response to irritation. 

28 Response of subjects exposed to 1.6 ppm ranged from no discomfort to discomfort (Andersen 

29 and Molhave 1977). Subjects were excluded from the study of Bender et al. (1983) if they did 

30 not respond to 1.3 or 2.2 ppm. Green et al. (1987) reported that during exposure of 38 exercising 

31 healthy and asthmatic subjects to 3 ppm, scores for odor, nose/throat irritation, and eye irritation 

32 ranged from none to severe. Slightly less than a third of the subjects scored odor and eye and 

33 nose/throat irritation as moderate or above and approximately 18% of the subjects reported no 

34 odor perception. Up to 3 ppm, exercising asthmatics were not more susceptible to the irritant 

35 effects of formaldehyde than exercising healthy subjects. 

36 

37 A small proportion of the population may develop formaldehyde asthma as a result of 

38 occupational exposure. Of a total of 230 patients who had been exposed to formaldehyde and 

39 suffered from asthma-like respiratory symptoms, 12 were considered a result of specific 

40 sensitization to asthma (Nordman et al. 1985). Exposures ranged from 1 month to 19 years. 

41 Diagnosis was made on the basis of bronchial reactivity to formaldehyde at a challenge 

42 concentration of 2 ppm. In another study, 13 patients who had been chronically exposed to 

43 formaldehyde in the home or workplace and had asthmatic-like symptoms at the site of exposure, 

44 were tested with a challenge dose of formaldehyde or room air (Reed and Frigas 1984). One to 

45 several concentrations were administered: 0.1, 1.0, and 3 ppm. Reactivity was measured as a 

46 decline in FEV1 of greater than 20%; a dose-response to formaldehyde and a lack of response to 

47 room air were also considered in the positive response. These patients did not response to the 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 46 of 71

1 formaldehyde bronchial challenges. Furthermore, it has been difficult to demonstrate antibodies 

2 to formaldehyde in individuals affected by asthma (Hendrick et al. 1982). 

3 

4 4.4.3. Concentration-Exposure Duration Relationship

5 

6 The slight to moderate irritation that accompanies low concentrations of formaldehyde is 

7 concentration rather than concentration x time dependent. Based on a review of several studies 

8 including the subchronic study of Rusch et al. (1983), the Industrial Health Foundation expert 

9 panel concluded that irritant effects of formaldehyde are concentration rather than concentration 

10 x time dependent. They noted that nasal irritation did not occur below 0.98 ppm for three animal 

11 species, even after 22 hours of exposure, and that no lower respiratory tract effects were 

12 observed at 2.95 ppm, i.e., squamous metaplasia was confined to the nasal epithelium. 

13 

14 A number of studies indicate that adaptation takes place during continuous exposure. For 

15 example, Weber-Tschopp et al. (1977) demonstrated that continuous exposure was subjectively 

16 less irritating than discontinuous exposures to identical concentrations. Longer-term animal 

17 studies also show a concentration effect. For example, in a 26-week inhalation study with rats, 

18 monkeys and hamsters (Rusch et al. 1983), no nasal irritation or lower respiratory effects 

19 occurred at or below 0.98 ppm, whereas, nasal lesions (squamous metaplasia) was observed in 

20 rats and monkeys at 2.95 ppm. 

21 

22 Exposure duration has little effect on pulmonary function changes. In the clinical study 

23 of Sauder et al. (1986), the maximal pulmonary response in healthy subjects inhaling 3 ppm for 3 

24 hours (a 2% decrease in FEV1 and a 7% decrease in FEF25-75%) occurred during the first 30 

25 minutes of exposure and was no longer detectable between 60 and 180 minutes. 

26 

27 However, for a carcinogenic effect, exposure must be of sufficient duration. A 13-week 

28 exposure at 10 ppm produced non-neoplastic changes in the nasal mucosa of rats (Woutersen et 

29 al. 1987; Feron et al. 1988), whereas a 13-week exposure at 20 ppm caused squamous cell 

30 carcinoma, carcinoma in situ, and polyploid adenomas in rats (Feron et al. 1988). A 4- or 8-

31 week exposure at 20 ppm failed to produce nasal cancers in rats (Feron et al. 1988). 

32 

33 Conolly et al. (2002) presented a dose-response analysis for formaldehyde-induced 

34 respiratory tract cytotoxicity. Regenerative cellular proliferation data (secondary to cytotoxicity) 

35 from F-344 rats inhaling 0, 0.7, 2.0, 6.0, 10, or 15 ppm 6 hours/day, 5 days/week for up to 2 

36 years (Monticello et al. 1996) was extrapolated to humans (human flux model) to predict the 

37 extent and intensity of the cytotoxic response throughout the human respiratory tract. The dose38 response to regenerative cellular proliferation was J-shaped, with the rates of regenerative 

39 cellular proliferation at 0.7 and 2.0 ppm not statistically different from control. Both the J40 shaped and hockey-stick-shaped curves were fitted to the raw data to predict human dose 

41 response for regenerative cellular proliferation. A computational fluid dynamics model of air 

42 flow and gas transport in the human nasal airways was linked to a typical path model of the 

43 human lung to provide site-specific flux. Three working levels (respiratory rates) were 

44 considered. Using the most vigorous working level, the lowest concentrations of formaldehyde 

45 predicted to exert any cytotoxic effects in humans were 1.0 and 0.6 ppm for the J-shaped and 

46 hockey-stick-shaped curves, respectively. 

47 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 47 of 71

1 For the endpoint of lethality, a time-scaled concentration-response probably occurs. 

2 However, the diverse lethality data, including the LC50 values of Skog (1950), Carpenter et al. 

3 1949), Bitron and Aharonson (1978), and Nagorny et al. (1979) do not show a good relationship. 

4 

5 4.4.4. Concurrent Exposure Issues

6 

7 Particulate matter may enhance the irritant effects of chemicals. Green et al. (1989) 

8 tested the acute response of healthy nonsmoking subjects inhaling both 3.0 ppm formaldehyde 

and 0.5 mg/m3 9 respirable activated carbon aerosol (see Section 2.2.2 for results of exposure to 

10 3.0 ppm formaldehyde alone). Synergistic increases in cough, but not in other irritant respiratory 

11 tract symptoms were observed. Small (<5%) synergistic decreases in FVC and FEV3 were also 

12 seen. The authors could draw no conclusions concerning the clinical significance of these 

13 effects. 

14 

15 5. DATA ANALYSIS FOR AEGL-1

16 5.1. Summary of Human Data Relevant to AEGL-1

17 

18 A number of controlled exposure studies have been conducted. These 22 clinical 

19 exposure studies with controlled atmospheres and involving over 500 subjects provide the most 

20 scientific evidence for dose-response effects. The most sensitive endpoint in these studies is eye 

21 and upper respiratory tract irritation. These studies show that irritation ranges from none to mild 

22 to moderate at concentrations up to 1 ppm. Below 1 ppm many studies show no dose-response 

23 relationship. Above 1 ppm, definite symptoms of discomfort are reported. However, even at 3 

24 ppm, the majority of subjects reported only mild-moderate eye and upper respiratory tract 

25 irritation (Green et al. 1987; 1989; Kulle et al. 1987; Sauder et al. 1986; 1987; Weber-Tschopp et 

26 al. 1977). Of the 180 subjects tested in these latter studies, only one reported severe eye 

27 irritation at 3 ppm (Sauder et al. 1987). Occupational studies report symptoms at lower levels 

28 than in clinical studies, but the occupational studies have concomitant exposures to other 

29 chemicals and particulates which increases irritancy. 

30 

31 Individuals may differ greatly in their response to the irritancy of formaldehyde. Several 

32 of the studies were designed to include presumably sensitive individuals such as asthmatics. At 

33 concentrations up to 3 ppm, asthmatics engaged in moderate exercise suffered no decrements in 

34 several pulmonary function parameters (Sheppard et al. 1984; Green et al. 1987). This and 

35 additional studies with asthmatics indicate that at #3 ppm, formaldehyde is scrubbed in the upper 

36 respiratory passages. In evaluating eye irritation, Bender et al. (1983) excluded nonsusceptible 

37 individuals, i.e., individuals that did not report eye irritation at 1.3 or 2.2 ppm were excluded 

38 from the study. The sensitive subjects in the Bender et al. (1983) reported the same irritant 

39 response (none to slight) during exposures to clean air and to formaldehyde concentrations 

40 #0.9 ppm. 

41 

42 5.2. Summary of Animal Data Relevant to AEGL-1

43 

44 Several animal studies addressed low concentrations and damage to the respiratory 

45 epithelium. A concentration of 2 ppm for 6 hours did not damage the anterior respiratory 

46 epithelium in obligate nose-breathing rats (Morgan et al. 1986b). A 13-week repeat exposure to 

47 2 or 4 ppm did not result in pathologic changes in the nasal epithelium of mice (Maronpot et al. 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 48 of 71

1 1986). Repeated exposures to 1 or 2 ppm for 6 hours/day filed to induce lesions in rats 

2 (Woutersen et al. 1987). Concentrations of 2 or 4 ppm did not damage the respiratory epithelium 

3 in mice exposed for 13 weeks (Maronpot et al. 1986) or rats exposed to 3 ppm for 22 hours/day, 

4 7 days/week, for 26 weeks (Rusch et al. 1983). Rodents have higher respiratory rates than 

5 humans, which increases the dose delivered to the target tissues. 

6 

7 5.3. Derivation of AEGL-1

8 

9 Rather than a weight-of-evidence approach, the AEGL-1 was based on a NOAEL for eye 

10 irritation in a single study with sensitive subjects (Bender et al. 1983). In this study, groups of 5 

11 to 28 healthy subjects were exposed eye-only for 6 minutes to 0, 0.35, 0.56, 0.7, 0.9, or 1.0 ppm. 

12 The subjects had been selected for their response to formaldehyde at 1.3 or 2.2 ppm, i.e., 

13 subjects that did not report eye irritation during previous exposures to 1.3 or 2.2 ppm were 

14 excluded from the study. At 0.35 to 0.9 ppm, the subjects= subjective eye irritation responses 

15 ranged from none to slight, the same as their responses to clean air. The 0.9 ppm concentration 

16 was selected as the basis for the AEGL-1. No intraspecies uncertainty factor was applied as no 

17 additional sensitive populations were identified [there were no significant decrements in 

18 pulmonary function parameters in exercising asthmatic subjects at 2 or 3 ppm, and asthmatic 

19 subjects reported <moderate eye irritation, the same as healthy subjects, at these concentrations 

20 (Green et al. 1987; Kulle et al. 1987; Sauder et al. 1987)]. Because several studies show there is 

21 adaptation to irritation at this low concentration, the 0.9 ppm concentration was applied across 

22 all exposure durations (Table 6). 

23 

24 The 0.90 ppm value is supported by the fact that animal studies show there is no damage 

25 to the respiratory epithelium during single (Morgan et al. 1986b) or repeated exposures to 1 or 2 

26 ppm (Rusch et al. 1983; Maronpot et al.1986; Woutersen et al. 1987). Derivations of AEGL 

27 values are in Appendix C and a category graph of human and animal toxicity data in relation to 

28 AEGL values is in Appendix D. 

29 

TABLE 6. AEGL-1 Values for Formaldehyde 

10-min 30-min 1-h 4-h 8-h 

0.90 ppm 

(1.1 mg/m3

) 

0.90 ppm 

(1.1 mg/m3) 

0.90 ppm 

(1.1 mg/m3) 

0.90 ppm 

(1.1 mg/m3) 

0.90 ppm 

(1.1 mg/m3) 

30 

31 

32 6. DATA ANALYSIS FOR AEGL-2

33 6.1. Summary of Human Data Relevant to AEGL-2

34 

35 Only a few studies with controlled exposures addressed effects defined by the AEGL-2. 

36 Stephens et al. (1961) reported that 5 ppm delivered via goggles produced severe eye irritation , 

37 whereas, Douglas (1974) reported eye irritation for 1 of 5 subjects at 8 ppm and for 5 of 6 

38 subjects at 13 ppm during short exposures. Delivery to the eye was also via goggles. During 

39 100% mouth breathing, airway resistance was increased at both concentrations. The decrement 

40 was less than 50% at 8 ppm and 50-108% at 13 ppm. Lacrimation was mild and adaptation 

41 occurred during a 30-minute exposure to 13.8 ppm (Sim and Pattle 1957). Two healthy 

42 investigators considered the lacrimation and eye, nose, and throat irritation during several short 

43 exposures to 20 ppm objectionable (Barnes and Speicher 1942). Average concentrations in 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 49 of 71

1 occupational situations have ranged up to 38 ppm (IARC 2006). Exposure durations and 

2 concomitant exposures to other chemicals or particles were unknown. 

3 

4 6.2. Summary of Animal Data Relevant to AEGL-2

5 

6 Few animal acute studies addressed effects that meet the definition of the AEGL-2. 

7 Several studies reported on exposures of rats to concentrations as high as 15 ppm for 6 hours 

8 (Chang et al. 1983; Morgan et al. 1986a; 1986b). These exposures inhibited mucociliary 

9 clearance and resulted in histopathologic lesions of the respiratory epithelium, but little effect on 

10 the olfactory epithelium. When exposure was discontinued, extensive recovery took place. 

11 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 50 of 71

1 6.3. Derivation of AEGL-2

2 

3 The AEGL-2 was based on the clinical study of Sim and Pattle (1957). Twelve healthy 

4 male subjects inhaled 13.8 ppm for 30 minutes. Initially, the exposure caused considerable nose 

5 and eye irritation. Mild lacrimation continued for some period of time. The eye irritation was 

6 not considered severe, and adaptation occurred in about 10 minutes. Mild lacrimation at 13.8 

7 ppm (rounded to 14 ppm) with adaptation was considered the threshold concentration for the 

8 inability to escape. The lacrimation experienced by Barnes and Speicher (1942) at 20 ppm 

9 during short exposures might impair the ability to escape. The 14 ppm concentration may also 

10 be close to the threshold for an increase in airways resistance (Douglas 1974). No intraspecies 

11 uncertainty factor was applied to the 14 ppm concentration because application of an uncertainty 

12 factor of $3 would lower the value to close to a no-effect concentration in several studies with 

13 exercising asthmatics. Because the endpoint is eye and nose irritation to which adaptation 

14 occurs, the same value was used across all exposure durations (Table 7). 

15 

TABLE 7. AEGL-2 Values for Formaldehyde 

10-min 30-min 1-h 4-h 8-h 

14 ppm 

(17 mg/m3

) 

14 ppm 

(17 mg/m3) 

14 ppm 

(17 mg/m3) 

14 ppm 

(17 mg/m3) 

14 ppm 

(17 mg/m3) 

16 

17 

18 7. DATA ANALYSIS FOR AEGL-3

19 7.1. Summary of Human Data Relevant to AEGL-3

20 

21 No human data relevant to development of AEGL-3 values were located. 

22 

23 7.2. Summary of Animal Data Relevant to AEGL-3

24 

25 Lethal concentrations were available for the rat and mouse. LC50 values for the rat 

26 ranged from 820 ppm for 30 minutes (Skog 1950) to 250-482 ppm for 4 hours (Carpenter et al. 

27 1949; Nagorny et al. 1979). For the mouse, the Lt50 (similar to the LC50) was 320 ppm for 100 

28 minutes (Bitron and Aharonson 1978). These assorted studies did not show a good 

29 concentration-response relationship. 

30 

31 Few studies at sublethal concentrations were of acute duration. Mice survived a 2-hour, 

32 4-day repeat exposure to 140 ppm with little signs of distress (Horton et al. 1963). Murphy et al. 

33 (1964) reported that 35 ppm for 18 hours was a sublethal concentration for the rat. Rats exposed 

34 to 15, 20 or 30 ppm for 6 hours showed eye and nose irritation, inhibition of the mucociliary 

35 clearance mechanism, and damage of the nasal mucosa which extended to the trachea at the 

36 higher exposures (Chang et al. 1983; Tobe et al. 1985; Morgan et al. 1986a). Pregnant rats 

37 inhaling 20 or 40 ppm on days 6-20 of gestation suffered no mortalities, but delivered fetuses of 

38 reduced body weight (Saillenfait 1989). Mice did not survive a 13-week, 5 hour/day, exposure 

39 to 40 ppm (Maronpot et al. 1986). In chronic studies, mice survived 5 hour/day exposures to 14 

40 ppm (Swenberg et al. 1983). 

41 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 51 of 71

1 7.3. Derivation of AEGL-3

2 

3 The AEGL-3 values were based on the highest non-lethal value for the rat (350 ppm) 

4 during a 4-hour exposure (Nagorny et al. 1979). The value was adjusted by interspecies and 

5 intraspecies uncertainty factors of 3 each for a total of 10. These uncertainty factors, applied to 

6 irritants, are protective of sensitive populations. Furthermore, application of larger uncertainty 

7 factors, e.g., a total of 30, would reduce the value to the level of the AEGL-2. No data on time8 scaling were found. Therefore, the default value of n = 3 when scaling to shorter exposure 

9 periods (NRC 2001) was applied (Table 8). 

10 

11 The 8-hour value was set equal to the 4-hour value because formaldehyde is well 

12 scrubbed in the nasal passages. Furthermore, application of the default of n = 1 when scaling to 

13 longer time periods would result in an 8-hour value of 18 ppm, similar to the 8-hour AEGL-2. 

14 The 8-hour value is supported by sublethal concentrations in additional animal studies. Rats 

15 were exposed to the sublethal concentration of 35 ppm for 18 hours in the study of Murphy et al. 

16 (1964), and no deaths were attributable to effects of formaldehyde on the lungs during chronic 

17 exposures of mice to 15 ppm (Swenberg et al. 1983). 

18 

TABLE 8. AEGL-3 Values for Formaldehyde 

10-min 30-min 1-h 4-h 8-h 

100 ppm 

(123 mg/m3

) 

70 ppm 

(86 mg/m3) 

56 ppm 

(69 mg/m3) 

35 ppm 

(43 mg/m3) 

35 ppm 

(43 mg/m3) 

19 

20 

21 8. SUMMARY OF AEGLS

22 8.1. AEGL Values and Toxicity Endpoints 

23 

24 AEGL values are summarized in Table 9. Derivation summary tables are in Appendix E. 

25 

TABLE 9. Summary of AEGL Values 

Exposure Duration

Classification 10-min 30-min 1-h 4-h 8-h

AEGL-1 

(Nondisabling) 

0.90 ppm 

(1.1mg/m3

) 

0.90 ppm 

(1.1mg/m3) 

0.90 ppm 

(11.mg/m3) 

0.90 ppm 

(1.1mg/m3) 

0.90 ppm 

(1.1mg/m3) 

AEGL-2 

(Disabling) 

14 ppm 

(17 mg/m3

) 

14 ppm 

(17 mg/m3) 

14 ppm 

(17 mg/m3) 

14 ppm 

(17 mg/m3) 

14 ppm 

(17 mg/m3) 

AEGL-3 

(Lethal) 

100 ppm 

(123 mg/m3

) 

70 ppm 

(86 mg/m3) 

56 ppm 

(69 mg/m3) 

35 ppm 

(43 mg/m3) 

35 ppm 

(43 mg/m3) 

26 

27 

28 8.2. Comparison with Other Standards and Guidelines 

29 

30 Standards and guidance levels for workplace and community exposures are listed in 

31 Table 10. Emergency Response Planning Guidelines (ERPGs) are similar to AEGLs, but are set 

32 for only 1-hour exposures. The ERPG-1 of 1 ppm is based on human exposure data including 

33 the studies of Weber-Tschopp et al. (1977), Kulle et al. (1987), and Sauder et al. (1987). At the 

34 exposure of 1 ppm, it is felt that nearly all individuals would experience no greater health effects 

35 than odor or mild sensory irritation. The ERPG-2 of 10 ppm is based on the studies of Kulle et 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 52 of 71

1 al. 1987 and Sim and Pattle (1957). Concentrations greater than this might impair the ability to 

2 escape. The ERPG-3 of 25 ppm is based on acute exposure data in animals (Carpenter et al. 

3 1946, Skog 1950) and human data cited in Patty=s Industrial Hygiene and Toxicology (Morandi 

4 and Maberti. 2001). 

5 

6 The NIOSH IDLH of 20 ppm is based on a report that exposure to 10 to 20 ppm produces 

7 almost immediate eye irritation and a sharp burning sensation of the nose and throat which may 

8 be associated with sneezing, difficulty in taking a deep breath, and coughing; recovery is prompt 

9 from these transient effects (personal observations reported in Morandi and Maberti 2001 ). 

10 NIOSH standards carry carcinogen notations. NIOSH (1976) notes that their recommended 

11 standard is not designed to protect an individual already sensitized to formaldehyde. 

12 

13 The NRC (1994) SMAC of 0.4 ppm is based on the prevention of mucosal irritation. In 

14 setting this value, the NRC considered complaints of workers and residents in mobile homes. It 

15 should be noted that exposure to 0.4 ppm was not irritating in most of the clinical studies and 

16 that the exposures in mobile homes and factories were to a mixture of chemicals. 

17 

18 The NRC (2007) 1-hour EEGL of 2 ppm was based on a range of 1-3 ppm in multiple 

19 controlled human studies which allowed for up to moderate irritation with reversible symptoms. 

20 

21 Noisel et al. (2007; IRSST 2006) addressed the impact of lowering the occupational 

22 standard for exposure to formaldehyde in Quebec, Canada. They assessed the exposure-response 

23 relationship from a pooled analysis of published controlled human studies on the incidence of the 

24 most sensitive effects related to acute formaldehyde exposure (irritation of the eyes, nose, and 

25 throat). The exposure-irritating effect relationship compiled from concentration ranges and by 

26 degree of severity was best described by quadratic regression. The authors concluded that 

27 workers exposed to formaldehyde concentrations <0.75 ppm should not experience moderate or 

28 severe irritating effects to the eyes, nose, or throat that may be attributed to formaldehyde. 

29 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 53 of 71

TABLE 10. Extant Standards and Guidelines for Formaldehyde 

Exposure Duration

Guideline 10 min 30 min 1 h 4 h 8 h 

AEGL-1 0.90 ppm 0.90 ppm 0.90 ppm 0.90 ppm 0.90 ppm 

AEGL-2 14 ppm 14 ppm 14 ppm 14 ppm 14 ppm 

AEGL-3 100 ppm 70 ppm 56 ppm 35 ppm 35 ppm 

ERPG-1 (AIHA)a 1 ppm 

ERPG-2 (AIHA) 10 ppm 

ERPG-3 (AIHA) 25 ppm 

SMAC 

(NRC)b

 0.4 ppm 

EEGL 

(NRC)c

 2 ppm 

PEL-TWA 

PEL-STEL 

(OSHA)d

 0.75 ppm 

2 ppm 

(15 minute) 

IDLH (NIOSH)e 20 ppm* 

REL-TWA 

REL-STEL 

(NIOSH)f

 0.016 ppm* 

0.1 ppm 

(15 minute) 

TLV-Ceiling 

(ACGIH)g

 0.3 ppm* 

MAK 

Peak Limit 

(Germany)h

 0.3 ppm* 

1 ppm 

MAC 

Peak Limit 

(The Netherlands)i

 1 ppm 

2 ppm 

1 *potential occupational carcinogen 

2 a 3 ERPG (Emergency Response Planning Guidelines, American Industrial Hygiene Association (AIHA 2004) 

4 The ERPG-1 is the maximum airborne concentration below which it is believed nearly all individuals could be 

5 exposed for up to one hour without experiencing other than mild, transient adverse health effects or without 

6 perceiving a clearly defined objectionable odor. 

7 The ERPG-2 is the maximum airborne concentration below which it is believed nearly all individuals could be 

8 exposed for up to one hour without experiencing or developing irreversible or other serious health effects or 

9 symptoms that could impair an individual=s ability to take protection action. 

10 The ERPG-3 is the maximum airborne concentration below which it is believed nearly all individuals could be 

11 exposed for up to one hour without experiencing or developing life-threatening health effects. 

12 b 13 SMAC (Spacecraft Maximum Allowable Concentration) (NRC 1994) 

14 SMACs provide guidance on chemical exposures during normal operations of spacecraft as well as emergency 

15 situations. The one-hour SMAC is a concentration of airborne substance that will not compromise the 

16 performance of specific tasks by astronauts during emergency conditions or cause serious or permanent toxic 

17 effects. Such exposure may cause reversible effects such as skin or eye irritation, but they are not expected to 

18 impair judgment or interfere with proper responses to emergencies. 

19 c 20 EEGL (Emergency and Continuous Exposure Levels for Chemicals in Submarines) (NRC 2007) 

21 EEGLs provide guidance on chemical exposures during normal operations of submarines. The one-hour EEGL 

22 is a concentration that would allow up to moderate irritation in some individuals, but would not interfere with 

23 critical duties. These exposures are for healthy adults. 

24 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 54 of 71

d 1 OSHA PEL-TWA (Occupational Safety and Health Administration, Permissible Exposure Limits - Time 

2 Weighted Average) (NIOSH 1997) is defined analogous to the ACGIH-TLV-TWA, but is for exposures of no 

3 more than 10 hours/day, 40 hours/week. The OSHA PEL-STEL (Permissible Exposure Limits - Short Term 

4 Exposure Limit) is defined analogous to the ACGIH-TLV-STEL. 

5 e 6 IDLH (Immediately Dangerous to Life and Health, National Institute of Occupational Safety and Health)

7 (NIOSH 1997) represents the maximum concentration from which one could escape within 30 minutes without 

8 any escape-impairing symptoms, or any irreversible health effects. 

9 f 10 NIOSH REL-TWA (National Institute of Occupational Safety and Health, Recommended Exposure Limits - 

11 Time Weighted Average) (NIOSH 1997) is defined analogous to the ACGIH-TLV-TWA. The NIOSH REL12 STEL (Recommended Exposure Limits - Short Term Exposure Limit) is defined analogous to the ACGIH TLV13 STEL. 

14 g 15 ACGIH TLV-TWA (American Conference of Governmental Industrial Hygienists, Threshold Limit Value - 

16 Time Weighted Average) (ACGIH 2004) is the time-weighted average concentration for a normal 8-hour 

17 workday and a 40-hour workweek, to which nearly all workers may be repeatedly exposed, day after day, 

18 without adverse effect. 

19 

20 hMAK (Maximale Arbeitsplatzkonzentration [Maximum Workplace Concentration]) List of MAK and BAT 

21 Values 2007 (Deutsche Forschungsgemeinschaft [German Research Association] 2007) is defined analogous to 

22 the ACGIH-TLV-TWA. In the case of formaldehyde a momentary value of 1 ppm should not be exceeded. 

23 The MAK Spitzenbegrenzung (Peak Limit [give category]) constitutes the maximum average concentration to 

24 which workers can be exposed for a period up to 30 minutes with no more than 2 exposure periods per work 

25 shift; total exposure may not exceed 8-hour MAK. 

26 

27 iMAC (Maximaal Aanvaarde Concentratie [Maximal Accepted Concentration]) (SDU Uitgevers [under the 

28 auspices of the Ministry of Social Affairs and Employment], The Hague, The Netherlands 2000) is defined 

29 analogous to the ACGIH-TLV-TWA. The peak limit is defined analogous to the ACGIH ceiling.

30 

31 8.3. Data Adequacy and Research Needs

32 

33 Formaldehyde has a robust data set of controlled human exposures. Data from 22 well34 conducted clinical studies involving over 500 subjects form a reliable basis for setting AEGL-1 

35 and AEGL-2 values. The data base for lethality involves relatively old animal studies that lack 

36 details of methodology as well as clear results. However, the data, with support from repeat37 exposure studies with animals, can be used to set non-lethal values for humans. 

38 

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35 Monticello, T.M., K.T. Morgan, J.I. Everitt, and J.A. Popp. 1989. Effects of formaldehyde gas on the respiratory 

36 tract of rhesus monkeys. Amer. J. Pathol. 134:515-527. 

37 

38 Monticello, T.M., J.A. Swenberg, E.A. Gross, J.R. Leiniger, J.S. Kimball, S. Seilkop, T.B. Starr, J.E. Gibson, and 

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41 

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44 

45 Morgan, K.T. and T.M. Monticello. 1990. Airflow, gas deposition, and lesion distribution in the nasal passages. 

46 Environ. Health Persp. 85:209-218. 

47 

48 Morgan, K.T., D.L. Patterson and E.A. Gross. 1986a. Responses of the nasal mucociliary apparatus of F-344 rats to 

49 formaldehyde gas. Toxicol. Appl. Pharmacol. 82:1-13. 

50 

51 Morgan, K.T., E.A. Gross and D.L. Patterson. 1986b. Distribution, progression , and recovery of acute 

52 formaldehyde-induced inhibition of nasal mucociliary function in F-344 rats. Toxicol. Appl. Pharmacol. 

53 86:448-456. 

54 

55 Murphy, S.D., H.V. Davis and V.L. Zaratzian. 1964. Biochemical effects in rats from irritating air contaminants. 

56 Toxicol. Appl. Pharmacol. 6:520-528. 

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2 formaldehyde. Gig. Tr. Prof. Zabol. 1:27-30. 

3 

4 NIOSH. 1976. Criteria for a Recommended Standard: Occupational Exposure to Formaldehyde. Cincinnati, OH: 

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6 DHEW Publication No. 77-126. 

7 

8 NIOSH. 1997. NIOSH Pocket Guide to Chemical Hazards. U.S. Department of Health and Human Services. June, 

9 1997. 

10 

11 Noisel, N., M. Bouchard,and G. Carrier. 2007. Evaluation of the health impact of lowering the formaldehyde 

12 occupational exposure limit for Quebec workers. Regul. Toxicol. Pharmacol. 48:118-127. 

13 

14 Nordman, H., H. Keshinen, and M. Tuppurainen. 1985. Formaldehyde asthma - rare or overlooked? J. Aller. Clin. 

15 Immunol. 75:91-99. 

16 

17 NRC (National Research Council). 1980. Formaldehyde - An Assessment of Its Health Effects. Washington, DC: 

18 National Academy Press. 

19 

20 NRC (National Research Council). 1981. Formaldehyde and Other Aldehydes. Washington, DC: National 

21 Academy Press. 

22 

23 NRC (National Research Council). 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne 

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25 

26 NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure 

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28 

29 NRC (National Research Council). 2007. Emergency and Continuous Exposure Guideline Levels for Selected 

30 Submarine Contaminants. Washington, DC: National Academy Press. 

31 

32 O=Neil, M.J., A. Smith, and P.E. Heckelman. 2001. The Merck Index. Whitehouse Station, NJ: Merck & Co., Inc. 

33 

34 OSHA (Occupational Safety and Health Administration). 1996. Occupational Exposure to Formaldehyde. OSHA 

35 Fact Sheet No. 97-27. Washington, DC: U.S. Department of Labor. 

36 

37 Paustenbach, D., Y. Alarie, T. Kulle, N. Schacter, R. Smith, J. Swenberg, H. Witchi, and S.B. Horowitz. 1997. A 

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39 Health 50:217-263. 

40 

41 Pazdrak, K., P. Gorski, A. Krasowiak and U. Ruta. 1993. Changes in nasal lavage fluid due to formaldehyde 

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43 

44 Pettersson, S. and T. Rehn. 1977. Hyg. Miljo 10:35-37. 

45 

46 Pross, H.F., J.H. Day, R.H. Clark, and R.E.M. Lee. 1987. Immunological studies of subjects with asthma exposed 

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49 

50 Reed, C.E. and E. Frigas. 1984. Does formaldehyde cause allergic respiratory disease? pp. 379-386 in Gammage, 

51 R.B. et al. eds. Indoor Air and Human Health. Chelsea, MI: Lewis Publishers, Inc. 

52 

53 Ritchie, I.M. and R.G. Lehnen. 1987. Formaldehyde-related health complaints of residents living in mobile and 

54 conventional homes. Am. J. Public Health 77:323-328. 

55 

56 Rusch, G.M., J.J. Clary, W.E. Rinehart, and H.F. Bolte. 1983. A 26-week inhalation toxicity study with 

57 formaldehyde in the monkey, rat, and hamster. Toxicol. Appl. Pharmacol. 68:329-343. 
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2 Saillenfait, A.M., P. Bonnet, and J. deCeaurriz. 1989. The effects of maternally inhaled formaldehyde on 

3 embryonal and foetal development in rats. Food Chem. Toxicol. 27:545-548. 

4 

5 Salem, H. and H. Cullumbine. 1960. Inhalation toxicities of some aldehydes. Toxicol. Appl. Pharmacol. 2:183-

6 187. 

7 

8 Sauder, L.R., C.D. Chatham, D.J. Green, and T.J. Kulle. 1986. Acute pulmonary response to formaldehyde 

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10 

11 Sauder, L.R., D.J. Green, M.D. Chatham, and T.J. Kulle. 1987. Acute pulmonary response of asthmatics to 3.0 ppm 

12 formaldehyde. Toxicol. Ind. Health 3:569-577. 

13 

14 Schachter, E.N., T.J. Witek, T. Tosun, G.J. Beck and B.P. Leaderer. 1985. Respiratory effects of exposure to 2.0 

15 ppm of formaldehyde in asthmatic subjects. Am. Rev. Respir. Dis. 131:A170. 

16 

17 Schachter, E.N., T.J. Witek, T. Tosun, B.P. Leaderer, and G.J. Beck. 1986. A study of respiratory effects from 

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19 

20 SDU Uitgevers. 2000. Nationale MAC List: 2000. The Hague, The Netherlands: Under the Auspices of the 

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22 

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24 hydrogen chloride in rats. Toxicol. Appl. Pharmacol. 81:401-406. 

25 

26 Sheppard, D., W..L. Eschenbacher and J. Epstein. 1984. Lack of bronchomotor response to up to 3 ppm 

27 formaldehyde in subjects with asthma. Environ. Res. 35:133-139. 

28 

29 Shuck, E.A., E.R. Stephens, and J.T. Middleton. 1966. Eye irritation response at low concentrations of irritants. 

30 Arch. Environ. Health 13:570-575. 

31 

32 Sim, V.M. and R.E. Pattle. 1957. Effect of possible smog irritants on human subjects. J. Amer. Med. Assoc. 

33 165:1908-1913. 

34 

35 Skog, E. 1950. A toxicological investigation of lower aliphatic aldehydes. I. Toxicity of formaldehyde, 

36 acetaldehyde, propionaldehyde, and butyraldehyde, as well as of acrolein and crotonaldehyde. Acta 

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38 

39 Starr, T.B., J.E. Gibson, C.S. Barrow, C.J. Boreiko, H.d=A. Heck, R.J. Levine, K.T. Morgan, and J.A. Swenberg. 

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43 

44 Starr, T.B. 1990. Workshop on indoor air quality. Quantitative cancer risk estimation for formaldehyde. Risk 

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46 

47 Stephens, E.R., E.R. Darley, O.C. Taylor, and W.E. Scott. 1961. Photochemical reaction products in air pollution. 

48 Int. J. Air Water Pollut. 4:79-100. 

49 

50 Swenberg, J.A., W.D. Kerns, R.J. Mitchell, R.E. Gralla, and K.C. Pavkov. 1980. Induction of squamous cell 

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52 3402. 

53 

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56 
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2 hyperreactivity in vivo and ex vivo in guinea pigs. Environ. Res. 61:185-199. 

3 

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6 

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8 Washington, DC: American Chemical Society. 

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10 U.S. EPA (U.S. Environmental Protection Agency). 1982. Exposure Assessment for Formaldehyde. Washington, 

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12 

13 U.S. EPA (U.S. Environmental protection Agency). 1992. Reference Guide to Odor Thresholds for Hazardous Air 

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15 

16 U.S. EPA (U.S. Environmental Protection Agency). 2003. Integrated Risk Information System, online data base: 

17 www.epa.gov/iris/subst/0419.htm. 

18 

19 van Doorn, R., M. Ruijten, and T. van Harreveld. 2002. Guidance for the application of odor in chemical 

20 emergency response. (In press). 

21 

22 Ward, J.B.J., J.A. Hokanson, E.R. Smith, et al. 1984. Sperm count, morphology and fluorescent body frequency in 

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24 

25 Weber, A., C. Jermini, and E. Grandjean. 1976. Irritating effects on man of air pollution due to cigarette smoke. 

26 Amer. J. Publ. Health 66:672-676. 

27 

28 Weber-Tschopp, A., T. Fischer, and E. Grandjean. 1977. Irritating effects of formaldehyde on men. Int. Arch. 

29 Occup. Environ. Health 39:207-218. 

30 

31 WHO (World Health Organization). 1989. Environmental Health Criteria 89: Formaldehyde. Geneva: World 

32 Health Organization. 

33 

34 Wilmer, J.W.G.M., R.A. Woutersen, L.M. Appleman, W.R. Leeman, and V.J. Feron. 1989. Subchronic (13-week) 

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36 exposures. Toxicol. Lett. 47:287-293. 

37 

38 Witek, T.J., E.N. Schacter, T. Tosun, B.P. Leaderer, and G.J. Beck. 1986. Controlled human studies on the 

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40 12:129-135. 

41 

42 Witek, T.J., E.N. Schacter, T. Tosun, G.J. Beck, and B.P. Leaderer. 1987. An evaluation of respiratory effects 

43 following exposure to 2.0 ppm formaldehyde in asthmatics: lung function, symptoms, and airway reactivity. 

44 Arch. Environ. Health 42:230-237. 

45 

46 Woutersen, R.A., L.M. Appleman, J.W.G.M. Wilmer, H.E. Falke, and V.J. Feron. 1987. Subchronic (13-week) 

47 inhalation toxicity study of formaldehyde in rats. J. Appl. Toxicol. 7:43-49. 

48 

49 Woutersen, R.A., van Garderen-Hoetmer, A. Bruijntjes, J.P., et al. 1989. Nasal tumors in rats after severe injury to 

50 the nasal mucosa and prolonged exposure to 10 ppm formaldehyde. J. Appl. Toxicol. 9:39-46.
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 63 of 71

1 

2 APPENDIX A: Level of Distinct Odor Awareness 

3 

4 The LOA derivation follows the guidance given by van Doorn et al. (2002). 

5 

6 The odor detection threshold (OT50) for formaldehyde reported by Berglund et al. (1987) is 

7 0.145 ppm. 

8 

9 The concentration C leading to an odor intensity (I) of distinct odor detection (I=3) is derived 

10 using the Fechner function: 

11 

12 I = kw x log 8 /OT50) + 0.5 

13 

14 For the Fechner coefficient, the default of kw = 2.33 was used due to the lack of chemical15 specific data: 

16 

17 3 = 2.33 x log C /0.145) + 0.5 which can be rearranged to 

18 log C /0.145) = (3 - 0.5) / 2.33 = 1.266 and results in 

C = (101.266 19 ) x 0.145 = 2.675 ppm 

20 

21 The resulting concentration is multiplied by an empirical field correction factor of 1.33. 

22 

23 LOA = C x 1.33 = 2.675 ppm x 1.33 = 3.6 ppm 

24 

25 The LOA for formaldehyde is 3.6 ppm. 

26 

27 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 64 of 71

1 

2 APPENDIX B: Carcinogenicity Assessment 

3 

4 The U.S. EPA (2003) in its Integrated Risk Information System (IRIS) has calculated dose 

5 levels for cancer risk levels of 1 in 10,000, 1 in 100,000, and 1 in 1,000,000 individuals. The 

6 calculations are based on the study of Kerns et al. (1983) with Fischer 344 rats (see Section 3.6 

7 for discussion of this study). The concentration over a lifetime of 70 years that would result in a 

risk level of 1 in 10,000, a virtually safe dose, is 8 Fg/m3 8 (6.5 ppb). 

9 

10 To convert a 70-year exposure to a 24-hour exposure, multiply by the number of days in 70 

11 years (25,600): 

12 

13 24-hour exposure = dose x 25,600 

= 8 Fg/m3 14 x 25,600 

= 205 mg/m3 15 

16 

17 To account for uncertainty regarding the variability in the stage of the cancer at which 

18 formaldehyde or its metabolites may act, a multistage factor of 6 is applied(Crump and Howe 

19 1984: 

20 

205 mg/m3/6 = 34.17 mg/m3 21 (28 ppm) 

22 

23 Therefore, based upon the potential carcinogenicity on formaldehyde, an acceptable 24-hour 

exposure would be 34 mg/m3 24 . If the exposure is limited to a fraction of a 24-hour period, the 

25 values are adjusted accordingly: 

26 

24-hour exposure = 34 mg/m3 27 (28 ppm) 

8-hour exposure = 103 mg/m3 28 (83 ppm) 

4-hour exposure = 205 mg/m3 29 (167 ppm) 

1-hour exposure = 820 mg/m3 30 (667 ppm) 

30-min exposure = 1640 mg/m3 31 (1333 ppm) 

10-min exposure = 4920 mg/m3 32 (6052 ppm) 

33 

34 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 65 of 71

1 

2 APPENDIX C: Derivation of AEGL Values 

3 

4 Derivation of AEGL-1

5 

6 Key Study: Bender et al. 1981 

7 

8 Toxicity endpoint: 0.9 ppm: NOAEL for eye irritation in sensitive subjects 

9 

10 Time scaling: not applied; there is adaptation to the slight irritation defined by the 

11 AEGL-1 

12 

13 Uncertainty factors: 1 - the subjects had been selected for their eye sensitivity to slightly 

14 higher concentrations of formaldehyde 

15 

16 Modifying factor: none applied 

17 

18 Calculations: none; 0.90 ppm used across all exposure durations 

19 

20 10-minute AEGL-1: 0.90 ppm 

21 30-minute AEGL-1: 0.90 ppm 

22 1-hour AEGL-1: 0.90 ppm 

23 4-hour AEGL-1: 0.90 ppm 

24 8-hour AEGL-1: 0.90 ppm 

25 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 66 of 71

1 

2 Derivation of AEGL-2

3 

4 Key Study: Sim and Pattle 1957 

5 

6 Toxicity endpoints: 14 ppm for 30 minutes 

7 

8 Time scaling none applied; there was adaptation to the eye and mild nose irritation 

9 

10 Uncertainty factors: none applied; application of an uncertainty factor would lower the 

11 value to a no-effect level in exercising asthmatics 

12 

13 Modifying factor: none applied 

14 

15 Calculations: none; 14 ppm used across all exposure durations 

16 

17 10-minute AEGL-2: 14 ppm 

18 30-minute AEGL-2: 14 ppm 

19 1-hour AEGL-2: 14 ppm 

20 4-hour AEGL-2: 14 ppm 

21 8-hour AEGL-2: 14 ppm 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 67 of 71

1 

2 Derivation of AEGL-3

3 

4 Key Study: Nagorny et al. 1979 

5 

6 Toxicity endpoint: 350 ppm for 4 hours: highest non-lethal value in the rat 

7 

8 Time scaling default value of 3 when extrapolating to shorter exposure durations 

9 (NRC 2001) 

10 

11 Uncertainty factors: interspecies and intraspecies of 3 each for a total of 10; these factors 

12 have been protective of sensitive subjects exposed to irritants 

13 

14 Modifying factor: none applied 

15 

Calculations: C3 16 x t = k 

(350 ppm/10)3

 x 240 minutes = 10290000 ppm3 17 $minutes 

18 

19 10-minute AEGL-3: 100 ppm 

20 30-minute AEGL-3: 70 ppm 

21 1-hour AEGL-3: 56 ppm 

22 4-hour AEGL-3: 35 ppm 

23 8-hour AEGL-3: 35 ppm 

24 

25 The 8-hour AEGL-3 was set equal to the 4-hour value because formaldehyde is well-scrubbed in 

26 the nasal passages. 

27 

28 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 68 of 71

1 

2 APPENDIX D: Category Graph of Toxicity Data and AEGL Values

3 

4 

0.1 

1.0 

10.0 

100.0 

1000.0 

10000.0 

ppm

0 60 120 180 240 300 360 420 480 

Minutes

Human - No Effect

Human - Discomfort

Human - Disabling

Animal - No Effect

Animal - Discomfort

Animal - Disabling

Animal - Some Lethality

Animal - Lethal

AEGL

AEGL-3

AEGL-1

AEGL-2

5 

6 

7 

8 

9 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 69 of 71

APPENDIX E: Derivation Summary for Formaldehyde AEGLs

ACUTE EXPOSURE GUIDELINE LEVELS FOR 

FORMALDEHYDE (CAS Reg. No. 50-00-0) 

DERIVATION SUMMARY

AEGL-1 VALUES

10-min 30-min 1-h 4-h 8-h 

0.90 ppm 0.90 ppm 0.90 ppm 0.90 ppm 0.90 ppm 

Key Reference: Bender, J.R., L.S. Mullin, G.J. Grapel, and W.E. Wilson. 1983. Eye irritation response of 

humans to formaldehyde. Am. Ind. Hyg. Assoc. J. 44:463-465. 

Test Species/Strain/Number: Humans, sensitive subjects/groups of 5-28; subjects whose eyes were not sensitive 

to 1.3 or 2.2 ppm were excluded from the study 

Exposure Route/Concentrations/Durations: Eye exposure/ 0, 0.35, 0.56, 0.7, 0.9, 1.0 for 6 minutes 

Effects: 

0.35-0.90 ppm: responses same as those to clean air 

 1.0 ppm: slight irritation, adaptation with time 

Endpoint/Concentration/Rationale: NOAEL for irritation/0.90 ppm 

Uncertainty Factors/Rationale: 

Total uncertainty factor: 1 

Interspecies: not applicable 

Intraspecies: 1 - subjects whose eyes were sensitive to formaldehyde were used 

Modifying Factor: not applied 

Animal to Human Dosimetric Adjustment: not applied 

Time Scaling: not applied; there was no irritation; in other cases, there is adaptation to the slight irritation that 

defines the AEGL-1 

Data Adequacy: There over 22 clinical studies involving 500 subjects that show that concentrations <1 ppm are 

generally non-irritating. 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 70 of 71

AEGL-2 VALUES

10-min 30-min 1-h 4-h 8-h 

14 ppm 14 ppm 14 ppm 14 ppm 14 ppm 

Key Reference: Sim, V.M. and R.E. Pattle. 1957. Effect of possible smog irritants on human subjects. J. 

Amer. Med. Assoc. 165:1908-1913. 

Test Species/Strain/Number: Humans/male/12 

Exposure Route/Concentrations/Durations: Inhalation/14 ppm/30 minutes 

Effects: Initial nose and eye irritation with mild lacrimation; adaptation in 10 minutes 

Endpoint/Concentration/Rationale: mild irritation at 14 ppm for 30 minutes meets the definition of the AEGL-2 

Uncertainty Factors/Rationale: 

Total uncertainty factor: 1 

Interspecies: not relevant 

Intraspecies: 1 - application of an uncertainty factor would lower the value to a no-effect level in exercising 

asthmatics 

Modifying Factor: not applied 

Animal to Human Dosimetric Adjustment: not relevant 

Time Scaling: not applied; there was adaptation to the irritation in 10 minutes 

Data Adequacy: The abundance of clinical studies at lower concentrations and involving over 500 subjects 

support the 14 ppm concentration as a reasonable value. 
FORMALDEHYDE NAC/Interim 1: 07/2008; Page 71 of 71

AEGL-3 VALUES

10-min 30-min 1-h 4-h 8-h 

100 ppm 70 ppm 56 ppm 35 ppm 35 ppm 

Key Reference: Nagorny, P.A., Zh.A. Sudakova and S.M. Schablenko. 1979. On the general toxic and 

allergic action of formaldehyde. Gig. Tr. Prof. Zabol. 1:27-30. 

Test Species/Strain/Number: rat/not given/groups of 6-12 

Exposure Route/Concentrations/Durations: Inhalation/not given/4 hours 

Effects: 228-350 ppm, no deaths; #732 ppm, some lethality; >732 ppm, 100% lethal 

Endpoint/Concentration/Rationale: highest non-lethal value, 350 ppm for 4 hours, meets definition of AEGL-3 

Uncertainty Factors/Rationale: 

Total uncertainty factor: 10 

Interspecies: 3 - rodents with higher respiratory rates than humans have greater uptake 

Intraspecies: 3 - applied to irritants; protective of the sensitive population 

Modifying Factor: none applied 

Animal to Human Dosimetric Adjustment: not applied 

Time Scaling: default values of 3 and 1 when extrapolating to shorter and longer exposure durations, 

respectively 

Data Adequacy: The lethality studies are old and lack details of methodology and results. Longer-duration and 

repeat-exposure studies (Horton et al. 1963; Murphy et al. 1964; Tobe et al. 1985) support the 4 and 8-hour 

values.