Page 2 of 7 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 pub lished 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 th e 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 Paus tenbach et al. (J. Tox. Environ. Health 50(3): 217-263, 1997). In this review, th e 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 resp iratory 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 Form aldehyde/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], w ho reported nasal and respirat ory 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 ge neral population, a value of 10 ppb was selected. The general population value was derived by appl ying a 10-fold uncertainty factor to the NOAEL value of 100 ppb to account for intraspecies variation in respons e 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 corre ctly noted, the ethics and technical merits of the intentional human exposur e 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 formal dehyde have been reported in ot her 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 abse nce of an Agency-wide peer-revi ewed level of concern (NOAEL)Page 3 of 7 for non-cancer inhalation effects of formaldehyde, that selection of the 0.1 ppm level of concern is considered health-pro tective. Further justification is provided in the following discussion.

The irritant effects of formalde hyde, 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 Occ upational Safety and H ealth Administration (OSHA) in 2002 noted in its formaldehyde fact sheet (found at:

http://www.osha.gov/OshDoc/data_Genera l_Facts/formaldehyde-factsheet.pdf ) that “Airborne concentrations of formaldehyde above 0.1 ppm can cause irritation of the respirat ory 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 form aldehyde, noting that 10-20% of the worker population is “reported to be responsive to lo w 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 expos ure to this chemical.” Th e 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 sc ores in formaldehyde-exposed workers at 0.3 mg/m 3 (0.24 ppm), supporting the ACGI H 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 In stitute to evaluate the rationale for the ACGIH TLV of 0.3 ppm. The IHF panel’s objective was “to identi fy an airborne concentration of formaldehyde to which it is believed that ne arly all workers may be repeatedly exposed day after day without adverse health effects.” As pa rt 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 pe rmanent respiratory impairment or chronic respiratory effects.”

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

Paustenbach et al. review. Th e IHF panel as part of its overall conclusions noted that “if concentrations of formaldehyde are kept belo w 0.1 ppm in the indoor environment (where exposure can occur 24 h/d) this should prevent irri tation in virtually all pe rsons.” Therefore, for the reasons stated above, the Agency believe s 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 Res earch and Development (ORD) to develop an

inhalation reference concen tration, or RfC for formaldehyde. O PP 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 formal dehyde, the nature of the health effect does not suggest that there are partic ularly susceptible subpopulati ons which would warrant the application of the 10x intraspecies UF."Page 4 of 7 Agency Response: The 1999 ATSDR Toxicological Revi ew of formaldehyde (ATSDR, 1999) noted two studies as "...providing suggestive eviden ce that children may be more sensitive to the irritant effects of formaldehyde." These studie s were not intentional ex posure studies. The

ATSDR review went on to note that "additional research is necessa ry 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 th e 1988 Horvath et al. publication. The Agency further believes application of th e 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 fr om 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 es timating carcinogenic worker risks for formaldehyde exposures using the CIIT m odel 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 de tailed in the Reregistra tion Eligibility Decision (RED) document. However, the Agency has pres ented worker risks using both the CIIT model

and the IRIS model. That di scussion is presented below.

“Based of the on going development of the sc ience 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 cance r unit risk of 1.3 E-5 per (μg/m 3 ) and the CIIT biologically-based dos e-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 co ordinate with other offices in EPA on the outcome of the upcoming peer review proce ss on the carcinogenicity of formaldehyde. The formaldehyde IRIS assessment is schedul ed to begin internal review in May 2008 and is scheduled to start external peer revi ew in January 2009. Because formaldehyde air concentrations approach those associated w ith ocular and respir atory 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 su ch that the cancer risks would not be of concern. The EPA process of regulating pesticid es allows for reevaluation at any time if new information from the peer review pr ocess of the carcinogenic potential of formaldehyde warrants.”Page 5 of 7 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/m 3 ) for the cancer unit risk for formaldehyde; however, in late 1991, the EPA revised this

number to 2.7 x 10 -7 per (μg/m 3 ).”

Agency Response : The value quoted by Landis International, 2.7 x 10 -7 per (μg/m 3 ), was derived

in 1991 within an internal OPP Draft documen t entitled Formaldehyde Risk Assessment Update by the Office of Toxic Substances (now the Office of Pollution Pr evention and Toxics). This draft was never finalized nor was it ever publishe d 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 stil l in the process of developing an updated carcinogenicity unit risk. For these reasons, the OPP presen ted the cancer risk estimates for pesticidal uses of formaldehyde as a range using both the existing IR IS value and the CIIT

model value.

Comment 5 : Landis International also commented on th e use of the Horvath et al. (1988) study for selection of the inhalation non-cancer endpoin t 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 Reside ntial 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 Mo ser 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 indi cated that the exhaled fo rmaldehyde 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 fr om 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 le vels of formaldehyde were present in the ambient air at the time of the study. In res ponse to this question, the Formaldehyde Council contacted one of the study aut hors and provided the following te xt from the article to support

their claim that it is evident that Moser et al. we re careful to avoid spurio us breath level analysis due to ambient formaldehyde:Page 6 of 7 “Parallel evaluation of room air was perf ormed to unveil possible interactions with exogenous parameters able to spoil measuremen ts 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 al so 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 formalde hyde in the building was less than 14 ppb, this

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

comment and therefore remains an unknown. It w ould 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 Technologi es 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-ent ry interval for unprotected individuals from 0.75 ppm to 0.1 ppm.

This comment is in reference to the recommenda tion in the ORE chapter that treated areas such as poultry houses be ventilated prior to re-entry until the air concentratio n reaches the EPA level of concern of 100 ppb for occupational exposures. Th is level is less than the rentry limit of 0.75 ppm (i.e., 750 ppb) that is currently on the form aldehyde labels. In their comments, Champion Technologies contend that ambient levels of formaldehyde exceed 100 ppb in egg hatcheries, poultry/swine confinement build ings and mushroom houses where formaldehyde is not used and therefore a standard of 100 ppb is not achievable in these facil ities. They also provide an argument that the level of c oncern should be 750 ppb instead of 100 ppb based upon Noisel et al., 2007.

Agency Response: The issue of which level of concer n is appropriate (100 or 750 ppb) is discussed in the Toxicology Co mments section of this docum ent (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 con centration 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 ventila tion for three hours at the rate of f our air changes per hour would reduce the air concentration to 100 ppb, it was d ecided that the re-entry restrict ion should be for three hours. It should also be noted that if 750 ppb were c hosen as the target c oncentration, the required ventilation time would only be sl ightly reduced to 2.5 hours due to the exponential nature of contaminate decay in a ventilated space.Page 7 of 7 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 ga s monitoring systems for occupational safety in health care settings and currently markets systems for et hylene oxide, hydrogen peroxide and

ozone.

Comment 8: The RED should include other occupa tions 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 be cause these occupations involve the use of formalin as a tissue preservative and pres ent a high risk of formaldehyde exposure.

Agency Response: The uses of formalin as a tissue pr eservative 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 produc ts 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 exposur e 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 us ed 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 depe nd 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 sy stems, workplace specific monitoring is recommended to verify that exposures are acceptable.”