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1.0 - Toxicology Comments 

1.1 - Toxicology Comments from the Formaldehyde Council 

Comment 1. Reliance on the Horvath et al. (JAMA 259(5): 701-707, 1988) study for the noncancer inhalation endpoint for formaldehyde inhalation non-cancer risk assessments. 

The Formaldehyde Council suggested using the published paper of Noisel et al. (Regulatory 

Toxicology and Pharmacology 48: 118-127, 2007). This study, in the Council's opinion, "is 

based on human exposure rather than controlled human chamber studies and can be used to 

derive a No-Observed-Adverse-Effect-Level (NOAEL) for the non-cancer inhalation endpoint 

for formaldehyde." The Council also commented that it understood, the Agency may not be able 

to use the Noisel et al. data because it was from controlled, human intentional exposure studies, 

which would be subject to review by the Agency’s Human Studies Review Board. If the Agency 

continued with the use of the Horvath et al. data, the Council suggested that the Agency consider 

the comments on the Horvath et al. paper by Paustenbach et al. (J. Tox. Environ. Health 50(3): 

217-263, 1997). In this review, the examination of the Horvath study by a panel assembled by 

the Formaldehyde Institute recommended that the study should have stated “10 years of exposure 

to 0.4 ppm formaldehyde produced no permanent respiratory impairment or chronic respiratory 

effects.” 

Agency Response: As noted in the June 24, 2008 Report of the Antimicrobials Division’s 

Toxicity Endpoint Selection Committee on Formaldehyde/Paraformaldehyde (available in EPA’s 

public docket (EPA-HQ-OPP-2008-0121) at www.regulations.gov): 

The original endpoint of 100 ppb was selected from the published report of Horvath et al. 

[JAMA 259, no. 5: 701-707, 1988], who reported nasal and respiratory effects in 109 workers 

occupationally exposed to formaldehyde. The 100 ppb value was selected as a NOAEL for use in 

occupational risk assessments, while for the general population, a value of 10 ppb was selected. 

The general population value was derived by applying a 10-fold uncertainty factor to the 

NOAEL value of 100 ppb to account for intraspecies variation in response in accordance with 

Agency policy. 

The Agency acknowledges that the Noisel et al. publication contained both observational human 

exposure data as well as data compiled from intentional exposure of human subjects under 

controlled conditions. However, the observational data alone was insufficient to support a 

NOAEL determination. And, as the commenter correctly noted, the ethics and technical merits 

of the intentional human exposure portion of the study would need to be presented to and 

reviewed by the Agency's Human Studies Review Board before they could be relied upon by the 

Office of Pesticide Programs (OPP). 

The irritant effects of formaldehyde have been reported in other studies below the 0.75 ppm 

concentration recommended by Noisel et al. as a “safe” level. Further, the Noisel et al. 

recommendation is for worker populations only and not residential populations, where risk 

mitigation is not feasible. The ADTC also considered the mission of the EPA to be health 

protective, and that in the absence of an Agency-wide peer-reviewed level of concern (NOAEL) 
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for non-cancer inhalation effects of formaldehyde, that selection of the 0.1 ppm level of concern 

is considered health-protective. Further justification is provided in the following discussion. 

The irritant effects of formaldehyde, including both eye and nasal irritation as well as respiratory 

symptoms (irritation, changes in pulmonary function), can be considered to be composed of both 

physiological and adverse responses. The Occupational Safety and Health Administration 

(OSHA) in 2002 noted in its formaldehyde fact sheet (found at: 

http://www.osha.gov/OshDoc/data_General_Facts/formaldehyde-factsheet.pdf) that “Airborne concentrations 

of formaldehyde above 0.1 ppm can cause irritation of the respiratory tract. The severity of 

irritation worsens as concentrations increase.” The American Conference of Governmental 

Industrial Hygienists (ACGIH) in its 2001 TLV document on formaldehyde recommended a 

threshold limit value (TLV) of 0.3 ppm for formaldehyde, noting that 10-20% of the worker 

population is “reported to be responsive to low ambient concentrations (< 0.25 ppm) of the 

chemical...” and that the 0.3 ppm value “may not eliminate all worker complaints of sensory 

irritation associated with exposure to this chemical.” The 0.3 ppm value recommended by 

ACGIH is considered a LOAEL. Holmstrom et al. (Acta Otolaryngol (Stockh) 1989; 107:120-

129) observed higher mean nasal histological scores in formaldehyde-exposed workers at 0.3 

mg/m3 (0.24 ppm), supporting the ACGIH LOAEL of 0.3 ppm. 

In the review by Paustenbach et al. noted by the Formaldehyde Council, the Industrial Health 

Foundation (IHF) was asked by the Formaldehyde Institute to evaluate the rationale for the 

ACGIH TLV of 0.3 ppm. The IHF panel’s objective was “to identify an airborne concentration 

of formaldehyde to which it is believed that nearly all workers may be repeatedly exposed day 

after day without adverse health effects.” As part of the their review, the IHF commented on the 

conclusions of the Horvath et al. study and stated that this study should have stated “10 years of 

exposure to 0.4 ppm formaldehyde produced no permanent respiratory impairment or chronic 

respiratory effects.” 

This conclusion within the review of the data available at the time was but one conclusion of the 

Paustenbach et al. review. The IHF panel as part of its overall conclusions noted that “if 

concentrations of formaldehyde are kept below 0.1 ppm in the indoor environment (where 

exposure can occur 24 h/d) this should prevent irritation in virtually all persons.” Therefore, for 

the reasons stated above, the Agency believes the 100 ppb level is an appropriate NOAEL for 

non-cancer inhalation effects of formaldehyde at this time 

The OPP is aware, however, of ongoing efforts by the EPA’s National Center for Environmental 

Assessment (NCEA) within the Office of Research and Development (ORD) to develop an 

inhalation reference concentration, or RfC for formaldehyde. OPP will continue to coordinate its 

efforts with ORD and other program offices to refine the non-cancer inhalation assessment as 

necessary. 

Comment 2: The Formaldehyde Council commented on the Agency’s use of a 10x uncertainty 

factor (UF) to assess risks from residential exposure. 

The Council comments that “in the case of formaldehyde, the nature of the health effect does not 

suggest that there are particularly susceptible subpopulations which would warrant the 

application of the 10x intraspecies UF." 
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Agency Response: The 1999 ATSDR Toxicological Review of formaldehyde (ATSDR, 1999) 

noted two studies as "...providing suggestive evidence that children may be more sensitive to the 

irritant effects of formaldehyde." These studies were not intentional exposure studies. The 

ATSDR review went on to note that "additional research is necessary to confirm or discard the 

hypothesis that children may be more susceptible than adults to the irritant effects of 

formaldehyde..." 

Largely based on the ATSDR report cited above, the Agency concluded that it is appropriate to 

remain with the NOAEL value selected from the 1988 Horvath et al. publication. The Agency 

further believes application of the 10-fold uncertainty factor for risk assessments to the general 

population is appropriate minimally until issues surrounding increased sensitivity in children is 

satisfactorily resolved. 

1.2 - Toxicology Comments from Landis International 

Comments were also received from Richard H. Collier, PhD, Vice President, Regulatory Affairs 

on the formaldehyde risk assessment. These comments and the Agency’s response follow: 

Comment 3: The Agency was asked to consider estimating carcinogenic worker risks for 

formaldehyde exposures using the CIIT model rather than the IRIS model. 

Agency Response: The Agency appreciates this comment particularly given the varied options 

for conduct of a carcinogenic risk assessment. Much of the history surrounding development of 

the current cancer unit risk for formaldehyde is detailed in the Reregistration Eligibility Decision 

(RED) document. However, the Agency has presented worker risks using both the CIIT model 

and the IRIS model. That discussion is presented below. 

“Based of the on going development of the science to predict carcinogenic potential of 

formaldehyde within EPA, OPP has decided to present the formaldehyde cancer risks for 

the pesticidal uses using both the existing 1991 IRIS cancer unit risk of 1.3 E-5 per 

(μg/m3

) and the CIIT biologically-based dose-response (BBDR) model until any new 

cancer estimates are fully peer reviewed. OPP also acknowledges the wide range in 

cancer risks using these approaches and will coordinate with other offices in EPA on the 

outcome of the upcoming peer review process on the carcinogenicity of formaldehyde. 

The formaldehyde IRIS assessment is scheduled to begin internal review in May 2008 

and is scheduled to start external peer review in January 2009. Because formaldehyde air 

concentrations approach those associated with ocular and respiratory tract irritation, the 

risk mitigation measures to be implemented in the meantime for the pesticidal uses will 

be based on mitigating the non-cancer effects at a limit of 0.01 ppm. It is believed that 

this level will reduce exposures sufficiently such that the cancer risks would not be of 

concern. The EPA process of regulating pesticides allows for reevaluation at any time if 

new information from the peer review process of the carcinogenic potential of 

formaldehyde warrants.” 
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Comment 4: Landis International also stated that they believe “...that an incorrect endpoint for 

the cancer unit risk was used for the IRIS model. In the past, EPA has used 1.3 x 10-5 per 

(μg/m3) for the cancer unit risk for formaldehyde; however, in late 1991, the EPA revised this 

number to 2.7 x 10-7 per (μg/m3

).” 

Agency Response: The value quoted by Landis International, 2.7 x 10-7 per (μg/m3

), was derived 

in 1991 within an internal OPP Draft document entitled Formaldehyde Risk Assessment Update

by the Office of Toxic Substances (now the Office of Pollution Prevention and Toxics). This 

draft was never finalized nor was it ever published as an Agency position on the carcinogenicity 

of formaldehyde. This analysis also preceded the model development undertaken by CIIT and 

others in subsequent years. As stated above, the Agency is still in the process of developing an 

updated carcinogenicity unit risk. For these reasons, the OPP presented the cancer risk estimates 

for pesticidal uses of formaldehyde as a range using both the existing IRIS value and the CIIT 

model value. 

Comment 5: Landis International also commented on the use of the Horvath et al. (1988) study 

for selection of the inhalation non-cancer endpoint for use in occupational and residential risk 

assessments. The comment is similar to that made by the Formaldehyde Council. 

Agency Response: The response to this comment is the same as that found above for the 

Formaldehyde Council (see Comment 1). 

2.0 - Occupational and Residential Exposure (ORE) Comments 

2.1 - ORE Comments from the Formaldehyde Council 

The following is a response to the ORE aspects of the comments that were submitted by the 

Formaldehyde Council in a letter dated May 28, 2008, as a follow-up to a meeting held on April 

16, 2008, regarding the formaldehyde RED. 

Comment 6: Accounting for ambient formaldehyde levels in human breath studies. 

This comment is in reference to a study by Moser et al. during which 179 exhaled chemicals, 

including formaldehyde, were measured in 344 human volunteers exposed to uncontaminated 

ambient air at a health fair. This study indicated that the exhaled formaldehyde levels ranged 

from 1.2 ppb to 73 ppb with a median of 4.3 ppb. Although the study indicated that the 

“background VOC concentration was negligible”, the study did not list the background levels. 

Because currently available ambient air data from sources such as the EPA Building Assessment 

Survey and Evaluation (BASE) Study and the Formaldehyde Council indicate that the average 

formaldehyde level inside an office building is 13 to 14 ppb, the Agency asked the 

Formaldehyde Council to find out exactly what levels of formaldehyde were present in the 

ambient air at the time of the study. In response to this question, the Formaldehyde Council 

contacted one of the study authors and provided the following text from the article to support 

their claim that it is evident that Moser et al. were careful to avoid spurious breath level analysis 

due to ambient formaldehyde: 
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“Parallel evaluation of room air was performed to unveil possible interactions with 

exogenous parameters able to spoil measurements like, for example, cleaning substances, 

medication and hemodynamic variables.” 

 

Agency Response: The above information does not clarify what was the ambient level of 

formaldehyde at the time of the study. It is also unclear if the study was conducted in Innsbruck, 

Austria or Milwaukee, Wisconsin. Although it is possible that this study was conducted in 

Austria and that the ambient level of formaldehyde in the building was less than 14 ppb, this 

information is not listed in the either the Moser article or in the Formaldehyde Council’s 

comment and therefore remains an unknown. It would also be useful to have the results 

stratified by smoking status since formaldehyde is a component of cigarette smoke and 14% 

percent of the study participants were smokers. 

2.2 - ORE Comments from Landis International 

The following is a response to the ORE aspects of the comments that were submitted by 

Landis International on behalf of the registrant Champion Technologies in a letter dated July 18, 

2008, as a follow-up to a mitigation meeting held on May 28, 2008. 

Comment 7: There is no need to lower the re-entry interval for unprotected individuals from 

0.75 ppm to 0.1 ppm. 

This comment is in reference to the recommendation in the ORE chapter that treated areas such 

as poultry houses be ventilated prior to re-entry until the air concentration reaches the EPA level 

of concern of 100 ppb for occupational exposures. This level is less than the rentry limit of 0.75 

ppm (i.e., 750 ppb) that is currently on the formaldehyde labels. In their comments, Champion 

Technologies contend that ambient levels of formaldehyde exceed 100 ppb in egg hatcheries, 

poultry/swine confinement buildings and mushroom houses where formaldehyde is not used and 

therefore a standard of 100 ppb is not achievable in these facilities. They also provide an 

argument that the level of concern should be 750 ppb instead of 100 ppb based upon Noisel et 

al., 2007. 

Agency Response: The issue of which level of concern is appropriate (100 or 750 ppb) is 

discussed in the Toxicology Comments section of this document (see Comment 1). During 

mitigation discussions for the RED it was decided that the re-entry restriction should be based on 

time rather than a target concentration because of the difficulties of measuring down to 100 ppb 

using currently available equipment and because ambient levels in some environments might 

exceed 100 ppb due to non-pesticidal sources of formaldehyde. Because the ORE assessment 

indicated that ventilation for three hours at the rate of four air changes per hour would reduce the 

air concentration to 100 ppb, it was decided that the re-entry restriction should be for three hours. 

It should also be noted that if 750 ppb were chosen as the target concentration, the required 

ventilation time would only be slightly reduced to 2.5 hours due to the exponential nature of 

contaminate decay in a ventilated space. 
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2.3 - ORE Comments from ChemDAQ Incorporated 

The following is a response to the comments that were submitted by ChemDAQ in a letter dated 

July 23, 2008. ChemDAQ is a manufacturer of gas monitoring systems for occupational safety 

in health care settings and currently markets systems for ethylene oxide, hydrogen peroxide and 

ozone. 

Comment 8: The RED should include other occupations that present a high risk to 

formaldehyde.

ChemDAQ contends that the RED should include other occupations such as morticians, funeral 

workers and health care laboratory workers because these occupations involve the use of 

formalin as a tissue preservative and present a high risk of formaldehyde exposure. 

Agency Response: The uses of formalin as a tissue preservative were not included in the RED 

because they are not covered by FIFRA and the products used for these purposes do not require 

EPA registration. These products are under the jurisdiction of the FDA and the workers 

exposures are regulated by OSHA. 

Comment 9: Continuous monitors should be used to assess and manage formaldehyde 

exposure. 

ChemDAQ notes that the exposure assessment in the RED appears to be entirely based on 

exposure models with almost a complete lack of experimental data. They recommend that 

continuous exposure monitors be used to collect experimental data to supplement the conclusions 

from the models and to ensure that workers are not exposed to harmful levels of formaldehyde. 

Agency Response: The EPA concurs that the model results should be supplemented by 

experimental data as discussed in the following statement from page 27 of the ORE assessment: 

“Since the actual exposure at a particular worksite would depend on worksite specific factors 

such as the type and condition of the closed system transfer system and the design and 

maintenance status of the ventilation systems, workplace specific monitoring is 

recommended to verify that exposures are acceptable.”