EXECUTIVE SUMMARY

Dimethoxane is registered for use as a pr eservative for industrial adhesives, paints, emulsions, coatings, and specialty industrial products which incl ude pigment slurries, dyestuffs, inks, thickeners, gums and lignosulfonate. Dimet hoxane is also registered for use in textile chemicals and finishes, leather pr ocessing liquors and di stillation fuels. There is currently one product registered.

The RED for Dimethoxane was completed in 1996 and all of the above uses were found to be eligible for registration provided that the labels were modified to include precautionary language regarding skin sensitization and a label statemen t about the use of dimethoxane in food contact adhesives and coatings. In 2009, the registra nt requested a label amendment to include preservation of household, industr ial and institutional wa ter based products. The human health aspects of this request were evaluated in D 356732 (EPA, 2009) and it was determined that a 90 day inhalation study and a dermal sensitization study would be needed to support these uses.

Dimethoxane has a fairly high vapor pressure of 0.111 mm Hg @ 25 C a nd it rapidly hydrolyzes to acetaldehyde. Based upon the use patterns, phys ical/chemical properties and hazard data, the following exposures will need to be assessed:

• Occupational dermal and inhalation exposure to dimethoxane and inhalation exposure to acetaldehyde during the open pour application of dimethoxane during paint preservation.

• Occupational and residential dermal and inhalation exposure to dimethoxane and inhalation exposure to acetal dehyde during the use of dime thoxane treated paints.

• Residential dermal and incidental oral exposures to textiles treated with textile chemicals

and finishes that have been preserved with dimethoxane.

• Residential dermal and incidental oral e xposures to leather products treated with processing liquors that have been preserved with dimethoxane.

To assess the above exposures, the following toxi cological and exposure da ta will be needed:

• Dermal sensitization threshold quantification study to quantify the dermal sensitization potential in humans

• 90 Day inhalation toxicity study in rats

• Indoor exposure studies (derma l and inhalation) during materi al preservation, and indoor painting.

• Leaching studies on textiles treated with di methoxane preserved textile chemicals and

finishes.

• Leaching studies on leather produc ts treated with dimethoxane preserved leather liquors.

• Product use information

Page 2 of 221.0 BACKGROUND

1.1 Chemical Identity

The chemical identity of dimethoxane listed in Table 1.

Table 1 - Chemical Identity of Dimethoxane

Chemical Name 2,6-dimethyl-m-dioxane-4-ol acetate

Common Name Dimethoxane

PC Code 001001 CAS Registry Number 828-00-2

Case No. 3064 Empirical Formula C 8 O 4 H 14 Structure

1.2 Chemical and Physical Properties

The physical and chemical properties of dimethoxa ne that are relevant for human health risk

assessment are listed in Table 2. It should be noted that dimet hoxane has a relatively high vapor pressure of 0.111 mm Hg at 23 C.

Table 2 - Physical and Chemic al Properties of Dimethoxane

Property Value Reference

Molecular Weight 174.2

Physical State Liquid EPA, 1996

Density 1.060 – 1.075 @ 25 C EPA, 1996
Solubility >2 gm/ml @ 25 C in methanol, hexane and

water EPA, 1996

Octanol/Water Partition Coefficient N/A - Hydrolyzes in water

Vapor Pressure 0.111 mm Hg @ 23 C MRID 416782-05

Henry’s Law Constant 1.24 x 10 -7 atm-m 3 /mole @ 25 C Estimated using EPI Suite

Page 3 of 222.0 USE INFORMATION

2.1 Formulation Types and Percent Active Ingredient

According to OPPIN, as of 9/7/2010, there is one end use product, Bioban DXN (464-682, approved 4/21/2010) that contains dimethoxane ( 87.0%) as the active ingr edient (ai). This product is formulated as a liquid.

2.2 Summary of Registered Uses

According to product information (Dow Chem ical, 2002), Bioban DXN is a biocide for the protection of water based industr ial products, processes and syst ems against microbial growth and spoilage. Upon addition to aqueous syst ems, Bioban DXN undergoes hydrolysis to its microbiological active components a cetaldehyde, aldol and acetic acid. It functions over a wide Ph range of 3 to 8 and it is not e ffective in systems with a Ph over 9.

Dimethoxane is registered for use as a pr eservative for industrial adhesives, paints, emulsions, coatings, and specialty industrial products which incl ude pigment slurries, dyestuffs, inks, thickeners, gums and lignosulfonate. Dimet hoxane is also registered for use in textile chemicals and finishes, leather pr ocessing liquors and distillation fuels. The product application rate for all these uses ranges from 0.01% to 0.2% by weight. Given that the product contains 87.0% dimethoxane, the application rates in term s of active ingredient range from 0.0087% to

0.174%.

The RED for Dimethoxane was completed in 1996 and all of the above uses were found to be eligible for registration provided that the labels were modified to include precautionary language regarding skin sensitization and a label statemen t about the use of dimethoxane in food contact adhesives and coatings. In 2009, the registra nt requested a label amendment to include preservation of household, industr ial and institutional wa ter based products. The human health aspects of this request were evaluated in D 356732 (EPA, 2009) and it was determined that a 90 day inhalation study and a dermal sensitization st udy would be needed to support these uses. These requirements were re -iterated in D371458/D371587 (EPA, 2010) which was written in response to waiver requests

2.3 Summary of Use Data

According to the Specialty Biocides North America Report 2004-2005 (Kline, 2006), dimethoxane (listed as Bioban DXN) is used in paints and coati ngs with a market share of 2 percent by volume and 1 percent by value and in adhesives with a market share of 6 percent by volume and 5 percent by value.

Page 4 of 223.0 TOXICOLOGY

The toxicological database for the dimethoxane registration review case is comprised of studies that were available to the Agency wh en the RED was written in 1996 and additional

studies that were submitted after the RED. The additional studies include the following:

• Unscheduled DNA Synthesis – Rat Hepatocyte, MRID 457183-01

• Micronucleus Test – Mouse Bone Marrow Erythrocyte, MRID 457195-01

Both these studies were reviewed and found to be acceptable. The micronucleaus test

indicated that dimethoxane does not cause a ch ange in the frequency of micronuclei in mouse bone marrow erythrocytes. The unscheduled DNA Synthesis test indicated that dimethoxane does not cause unscheduled DNA synthesis.

3.1 Acute Toxicity

A complete database of acute toxicity data was available to the Agency at the time the RED was written. A summary of the fi ndings, which are detailed in the RED, is included in Table 3. These findings indicate that dime thoxane is of low to moderate acute toxicity by all routes of exposure and that dimethoxane is a strong sensitizer.

Table 3 - Acute Toxicity Values for Dimethoxane. Test (species) Result Toxicity Category
81-1 Oral Toxicity (rat) LD50 >2000 mg/kg III 81-2 Dermal Toxicity (rabbit) LD50 > 2000 mg/kg III 81-3 Inhalation Toxicity (rat) LC50 > 4.0 mg/L III 81-4 Eye Irritation (rabbit) Mild Irritation III 81-5 Skin Irritation (rabbit) Slight Irritation IV 81-6 Dermal sensitization (guinea pig) Strong sensitizer N/A

3.2 Subchronic and Chronic Toxicity

The most recent hazard assessment for dimet hoxane is included in D356732 (EPA, 2009) and a summary of this assessment is included below:

Dermal Toxicity

90 Day Dermal Toxicity Study: During a dermal toxicity study (MRID #406502-01) doses of 0, 100, 300, or 1000 mg/kg/day of dimethoxane were a pplied to the skin of rats for 6 hrs/day, 5 days/week, for three months. The test material was administered undiluted and the test site was covered with gauze. The gauze was removed af ter six hours and the test site was cleaned with water. There were signs of dermal irritation in females during the first three weeks of treatment, however, the irritation subsided af ter the use of water to clean the dosing site was discontinued and during the last month of the study irritation (eschar formation and superficial necrosis) were observed only on one male and two females in the 1000 mg/kg/day dose group. Systemic effects were also observed at 300 and 1000 mg/ kg/day and included decreased body weight gain

Page 5 of 22and hepatic lesions. The lesions consisted of minimal or sli ght necrosis, inflammation or hemorrhage. T he NOAEL for systemic effects was 100 mg/kg/day.

Subchronic Oral Toxicity

NTP 16-day oral gavage study: The National Toxicology Progr am (NTP) conducted a 16-day study, during which groups of five rats and five mice of each sex were administered 0, 125, 250, 500, 1,000, or 2,000 mg/kg dimethoxane in corn oil pe r day. The rats were 6 weeks old and mice were 8 weeks old when placed in the study. Deaths occurred in rats and in male mice that received 2,000 mg/kg. Body weights of rats and mice were similar to those of vehicle controls. Compound-related clinical signs were not seen in surviving rats. Hemorrhage and necrosis of the

stomach were observed in rats in the 2,000 mg/kg group which died be fore the end of the studies. Lesions of the forestomach, including inflammation, hyperplasia, hyperkeratosis, and ulceration, occurred in rats that received 250-2,000 mg/kg. Mice that received 500-2,000 mg/kg

dimethoxane had lesions of the forestomach including erosion, ulceration, hyperplasia, and hyperkeratosis. Forestomach lesions were not seen at 125 or 250 mg/kg.

NTP 13-week oral gavage study: The NTP conducted a 13-week rat and mice gavage study with commercial grade dimethoxane (80% pure, none of these impurities exceeded 3%) in corn oil. Groups of 10 rats and 10 mice of each sex were administered levels of 0, 31, 62, 125, 250, or 500 mg/kg/day by gavage. No compound-related de aths occurred in rats. The final mean body weights of rats that received 500 mg/kg were 17% lower than that of vehicle controls for males and 5% lower for females. Ulceration, inflamma tion, and acanthosis with hyperkeratosis of the stratified squamous epithelium of the forestomach were seen in rats that received 500 mg/kg.

Forestomach lesions were not seen in males that received 31 mg/kg or in females that received 31, 62, or 125 mg/kg.

All mice lived to the end of the studies and final mean body we ights of dosed and vehicle control

mice were similar. Minimal-to- mild acanthosis and hyperkeratosis of th e squamous epithelium of the forestomach were seen in 4/10 high dose male and 1/10 high dose female mice.

Because of the forestomach lesions observed in rats and mice and reduced body weight observed for male rats, doses selected for the 2-year studies were 0, 62.5, or 125 mg/kg dimethoxane in corn oil, given by gavage 5 days per week to groups of 60 male rats ; 0, 125, or 250 mg/kg to groups of 60 female rats; and 0, 250, or 500 mg/kg to groups of 58 or 60 mice of each sex. Ten animals per sex and species from each dose group were killed 15 months after initiation of the studies to determine toxicity, pre-neoplast ic lesions, and early induced neoplasia.

Chronic Oral Toxicity and Carcinogenicity

NTP 15-month oral gavage study: The NTP conducted a 15-month rat and mice gavage study with commercial grade dimethoxane in corn oil. Groups of 60 male rats were administered 0, 62.5, or 125 mg/kg/day and groups of 60 female rats were administered at levels of 0, 125, or 250 mg/kg/day. Groups of 58 or 60 mice of each se x were administered at levels of 0, 250, and 500 mg/kg/day. Minimal diffuse acanthosis and hype rplasia of the forestomach were seen in 7/10 female rats at 250 mg/kg, 7/10 males at 125 mg/kg, and 1/9 male and 1/9 female vehicle

controls. Acanthosis of the forestomach was seen in 7/10 male and 6/10 female mice at 500

Page 6 of 22mg/kg. Harderian gland adenomas were seen in one high dose male and one high dose female mouse. A harderian gland adenocarcinoma was seen in a second high dose female mouse. No compound-related effects were observed for clinical chemical or hematologic values or for organ weights for rats or mice. The NOAEL was 125 mg/kg/day.

NTP two-year cancer study: The NTP conducted carcinogenicity st udies on rats and mice with commercial grade dimethoxane (80% pure). The male rats were give n 0, 62.5, or 125 mg/kg/day and the female rats were given 0, 125 or 250 mg /kg/day dimethoxane in corn oil by gavage for two years. Acanthosis and hyperk eratosis were increased in th e forestomach of high dose rats. The male and female mice were given 0, 250, or 500 mg/kg/day by gavage for two years. Acanthosis, hyperkeratosis, focal hyperplasia, an d chronic inflammation were increased in the forestomach of dosed mice. Mean body weights of dosed and vehicle c ontrol rats and mice of each sex were generally similar. No significant differences in survival were observed between any groups of rats or mice.

There was no evidence of carcinogenic activity of dimethoxane for male rats receiving 62.5 or 125 mg/kg or for female rats receiving 125 or 250 mg/kg per day. There was equivocal evidence of carcinogenic activity of dimethoxa ne for male mice, as indicated by an increased incidence of forestomach neoplasms. There was no evidence of carcinogenic activity for female mice receiving 250 or 500 mg/kg per day. Acanthosis and hyperkeratosis o ccurred at increased incidences in the forestomach of high dose ra ts. Inflammation, acanthosis with hyperkeratosis, and focal hyperplasia occurred at increased in cidences in the forestomach of dosed mice.

Developmental Toxicity

MRID # 411514- 01 - Dimethoxane (92.0% a.i.) was admini stered to groups of 24-26 pregnant female rats by gavage on gestation days 6- 15 inclusive at dose levels of 0, 60, 300, and 900 mg/kg/day. Excessive salivation a nd was noted in all high dose fema les at one or more intervals during treatment. Food consumption was decrea sed in high dose females and body weight gain was significantly decreased. There were no ad verse effects noted on pregnancy incidence or number of females with live pups at any dose le vel; cesarean section obs ervations were also

unremarkable. Filamentous tail was observe d in one high dose pup. One mid dose pup was observed with abnormal origin and course of the ri ght subclavian artery o ff the aortic arch; this same pup was observed to be edematous and pale in color. Tortuous ureter was also observed among the dose groups but were within historical control incidence and did not demonstrate a dose-response. Several skeletal variations were observed in the mid- and high-dose pups in this study which were slightly increased over control, and included incomplete ossification of several bones; however, these increases were not statistically significant. Based on the results of this study, the Maternal NOAEL is determined to be 300 mg/kg/day, and the Maternal LOAEL is determined to be 900 mg/kg/day, based on reduc ed body weight gain and food consumption, and excessive salivation. The Developmental NOAEL is considered to be 900 mg/kg/day.

Page 7 of 22Reproductive Toxicity

There are no reproductive toxicity studies available for dimethoxane.

Mutagenicity

The following summary is obtained from TR-35 4, “Toxicology and Carcinogenesis Studies of Dimethoxane (Commercial Grade) in F344/N Rats and B6C2F1 Mice.”

Dimethoxane was mutagenic in strain TA100 of S. typhimurium in the presence but not the absence of exogenous metabolic activation; it was not mutagenic in strains TA98, TA1535, or

TA1537 with or without activation. Dimethoxane induced sister chromatid exchanges and

chromosomal aberrations in Chinese hamster ova ry (CHO) cells both with or without exogenous

metabolic activation. Dimethoxane induced sex-li nked recessive lethal mutations in Drosophila when administered by abdomina l injection to adult males; no induction of reciprocal

translocations was observed in adult males after injection of dimethoxane.

In studies submitted to and reviewed by th e Agency, dimethoxane was found to be nonmutagenic in the Ames Salmonella assay in five tester strains. In the CHO assay, dimethoxane was clastogenic at concentrati ons of 100 and 150 μg/ml under condi tions of metabolic activation, but was non-clastogenic under c onditions of non-activation.

3.3 Metabolites and Degradates of Toxicological Concern

As discussed in the Product Chemistry, Environmental Fate and Ecotoxicity Data Summary (EPA, 2010), the available da ta indicate that the major r oute of degradation is abiotic hydrolysis aided by microbial mediated degradation. Further, the data indicate that dimethoxane is highly unstable in water with over 50% of the compound hydrol yzed in 2 hours. Dimethoxane is purported to react with water to form acetic acid and a transient intermediate, dioxinol. The

dioxinol then breaks down into acetaldehyde and aldol (i.e. 3-hydroxybutanal ). The breakdown

into acetic acid and dioxinol is completed in 14 hours.

3.4 Toxicological Endpoints Used for Risk Assessment

A summary of the endpoints that could be used for risk a ssessment was included in D356732 (EPA, 2009) and these endpoints are listed in Tabl e 4. Endpoints are not available to assess

dermal sensitization effects or effects from inhalation exposures.

Page 8 of 22Table 4. Summary of Doses and Endpoints Se lected for Dimethoxane Risk Assessments.

Exposure

Scenario Dose Used in

Risk Assessment Level of Concern for

the MOE Study and Toxicological Effects

Incidental Oral - Short

and Intermediate Term (1-30 days) NOAEL=125 mg/kg/day Residential/Occupational

MOE = 100 A NTP fifteen-month rat study

LOAEL = 250 mg/kg/day

Based on diffuse acanthosis and hyperplasia in the forestomach

Dermal – All Durations NOAEL= 100 mg/kg/day Residential/Occupational

MOE = 100 A 90-Day Dermal Toxicity – Rats

LOAEL = 300 mg/kg/day based on hepatocellular alterations

Dermal Sensitization B No study available (data gap); this risk assessment IS required for specific dermal exposure concern. The chemical is a strong dermal sensitizer.

Inhalation C – All

Durations No study available (data gap); this risk assessment IS required.

Cancer (all routes) Suggestive evidence of carcinogenicity to humans; quantitative risk assessment not required. A. Includes 10x for inter-species variatio n, and 10X for intra-species variation. B. Dimethoxane is a strong dermal sensitizer and a dermal sensitization study that can be used to identify a

threshold for dermal sensitizati on risk assessment is needed. C. A data gap exists for a 90-day inhala tion toxicity study in rats was identifie d by the OPP Hazard Identification Assessment Review Committee (2000). This study is required due to the significant vapor pressure (0.111 mm Hg at 23°C). Inhalation is considered as an important route of exposure.

Toxicity Data Needs

Several toxicology studies will be needed to co mplete registration review. These studies are

listed in Section 10.

4.0 DIETARY ASSESSMENT

Dietary Exposure

Dimethoxane is not registered for any direct or indirect f ood uses, nor does it have any FDA approvals for such uses. The label contains the following statement which was required by the

RED:

“THE PRODUCT HAS NOT BEEN CLEARED UNDER THE FEDERAL, FOOD, DRUG,

AND COSMETIC ACT FOR USE IN THE MANU FACTURE OF COATINGS THAT MAY

COME IN CONTACT WITH FOOD.”

Drinking Water Exposure

There is a potential for drinking water exposur e from the material preservative uses. The Agency expects that the environmental fate data th at are being required will be useful to evaluate

Page 9 of 22this potential. Therefore, the need for a drinking water assessment will be determined after the

environmental fate data ar e received and reviewed.

5.0 OCCUPATIONAL/RESIDENTIAL EXPOSURE

At the time of the RED, it was determined th at there were no toxicological endpoints of concern due to low toxicity and minor effect s and therefore no assessment was required for occupational or residential risk s. It was also determined incorrectly that there would be minimal post application exposure due to the chem ical properties (low va por pressure, etc.) and small amounts contained in treated products such as paints. Because dimethoxane actually has a fairly high vapor pressure of 0.11 mm Hg at 25 C, this determination needs to be reconsidered. It will also be necessary to evaluate the e xposures from acetaldehyde which is a degradate of dimethoxane. Based on these factors and the use patterns, physical/c hemical properties and hazard data, the following exposur es will need to be assessed:

• Occupational dermal and inhalation exposure to dimethoxane from the open pour application of dimethoxane during paint preservation.

• Occupational inhalation exposure to acetal dehyde released from dimethoxane during paint preservation.

• Occupational and residential de rmal and inhalation exposure to dimethoxane from the use of dimethoxane treated paints.

• Occupational and residential inhalation e xposure to acetaldehyde from the use of dimethoxane treated paints.

• Residential dermal and incidental oral exposures to textiles treated with textile chemicals

and finishes that have been preserved with dimethoxane.

• Residential dermal and incidental oral e xposures to leather products treated with processing liquors that have been preserved with dimethoxane.

Exposure Studies Needed for Registration Review

A listing of the exposure studies that will be needed for registration review is included in Section 10 and detailed justifica tions are included in Appendix A.

6.0 AGGREGATE AND CUMULATIVE EXPOSURE

In examining aggregate exposure, EPA take s into account the available and reliable information concerning exposures to pesticide re sidues in food and drinking water, as well as non-occupational pesticide exposures. An aggr egate risk assessment may be needed for

dimethoxane if it is determined that a dr inking water exposure could occur based on the

environmental fate data.

Section 408(b)(2)(D)(v) of FFD CA requires that, when consid ering whether to establish, modify, or revoke a tolerance, the Agency consider "available information” concerning the cumulative effects of a particular pesticide's re sidues and "other substances that have a common mechanism of toxicity.” EPA has not yet determined whether dimethoxane has a common

Page 10 of 22mechanism with other compounds; consequently, a cumulative assessment will not be performed

at this time.

7.0 INCIDENTS

There are no incidents reported for dimethoxane in the OPP incident database. There is one report in the literature (Shmunes and Kempton, 1980) of allergic contact dermatitis resulting

from the use of dimethoxane in a textile spin finish.

8.0 TOLERANCES

There are no tolerances or exemptions from tolerances for dimethoxane. As mentioned in Section 4.0, dimethoxane is not approved for use as an indirect food additive.

9.0 ENDOCRINE DISRUPTION EFFECTS

As required under FFDCA section 408(p), EP A has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (inc luding pesticide active and other ingredients) may have an effect in humans or wildlife si milar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two-tiered ap proach to making the statutorily required

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrog en, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go th rough Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stag e of the EDSP where EPA will determine which, if any, of th e Tier 2 tests are necessary base d on the available data. Tier 2 testing is designed to identify a ny adverse endocrine related eff ects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T effect.

Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticid e active ingredients and 9 inert ingredients.

This list of chemicals was selected based on th e potential for human exposure through pathways such as food and water, residen tial activity, and certain post-applic ation agricultural scenarios.

This list should not be construed as a lis t of known or likely e ndocrine disruptors.

Dimethoxane is not among the group of 58 pesticid e active ingredients on the initial list to be

screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide chemicals. Accordingly, EPA anticipates issuin g future EDSP test orders/data call-ins for all pesticide active ingredients.

For further information on the status of the ED SP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery, pleas e visit our website: http://www.epa.gov/endo/.

Page 11 of 2210.0 ANTICIPATED DATA NEEDS

To assess the exposures listed in Section 4 (die tary) and Section 5 (occupational/residential) the toxicological and exposure studies listed in Tables 5 and 6 will be needed. Detailed justifications for these studies are provided in Appendix A.

Table 5 – Human Toxicology Studies Needed for Dimethoxane Registration Review

Study Needed Guideline Rationale

Dermal Sensitization Threshold Quantification N/A This study is needed to identify a threshold for dermal sensitization risk

assessment for dimethoxane in treated ma terials such as paints, textiles and leather products. 90 Day Inhalation - rat 870.3465 This study is needed to assess occupational inhalation risk from openpouring of liquids during materials preservation and the occupational and residential inhalation risks during the use of dimethoxane treated paints.

Table 6 –Exposure Studies Needed for Dimethoxane Registration Review

Study Needed Guideline Rationale Indoor Exposure (Open Mixing/Loading Liquids) 875.1200 (Dermal) 875.1400 (Inhalation) 875.1600 (Data Reporting/Calculations) Exposure may occur during open pour

addition of dimethoxane * during material preservation and fuel treatment. Indoor Exposure (Interior Painting) 875.1200 (Dermal) 875.1400 (Inhalation) 875.1600 (Data Reporting/Calculations) Exposures to paint aerosols and vapors of

dimethoxane and to va pors of acetaldehyde may occur during interior applications of dimethoxane treated paints. Leaching Study on Textiles No Guideline Derm al and incidental oral exposures may occur from wearing and mouthing clothing,

towels and blankets made from textiles treated with dimethoxane preserved textile

chemicals and finishes. Leaching Study on Leather No Guideline Derm al and incidental oral exposures may occur from wearing and mouthing leather products treated with dimethoxane preserved liquors.

Product Use Information 875.1700 Use information can be used to evaluate exposures and assist in the planning of exposure studies. *If the labels are amended to require closed mixing and loading, then the exposure studies will not be needed for the open loading/mixing scenario.

Page 12 of 2211.0 REFERENCES

Dow Chemical, 2002. Product Information for BIOBAN DXN, Form No. 253-01219-10/10/02.

EPA, 1996. Dimethoxane Reregistration Eligibility Decision (RED), May 1996, http://www.epa.gov/pesticides/reregistration/status.htm

EPA, 2009. Dimethoxane: Hazard Assessment for the Proposed New Use as an Antimicrobial in Preservation of Household, Industrial and In stitutional Water Base Products. D356732, May 7,

2009

EPA, 2010. Summary of Product Chemistry, Envir onmental Fate, and Ecotoxicity Data for the Dimethoxane Registration Review D ecision Document. D382303, October, 2010.

Kline, 2006. Specialty Biocides Nort h America 2004-2005, Kline and Company, Inc.

Shmunes and Kempton, 1980. Allergic Contact De rmatitis to Dimethoxane in a Spin Finish, Contact Dermatitis: 6 (6), pp 421-424, October, 1980.

Page 13 of 22Page 14 of 22 This page intentionally left blank.Appendix A – Justification for theToxicology and Exposure Studies Needed forRegistration Review of DimethoxanePage 15 of 22Appendix A, Table 1 - Toxicology Study JustificationsGuidelineStudy TitlePractical Utility of the Data870.346590-Day InhalationToxicity Study(Rat)1) What is the value of the study?The Agency currently does not have a repeateddose inhalation toxicity study for dimethoxaneand is therefore required to extrapolate from a repeated dose oraltoxicity study to assess the risksof inhalation exposure. Since the effects of a chemical can varygreatly with respect to route ofadministration, the use of a route specific study will greatly increase the accuracy of the riskassessment.2) How would the data be used?The study will be used to assess risks from inhalation exposures to dimethoxane that occur duringopen pour addition of liquids during materials preservation and painting withpaint treated withdimethoxane. The study will be used to determine inhalation specific endpoints that will be usedto assess the inhalation exposures and it will eliminate the uncertainty that exists when oralstudies are used to assess inhalation exposures.3) How could the data affect the risk assessment?The study will allow the selectionof a route specific endpoint which may be different than theroute extrapolated endpoint that would otherwisebe used. It is possible that the databaseuncertainty factor that is associated with using route to route extrapolation can be reduced orremoved, resulting in a lower level ofconcern for the uncertainty factor.4) What is triggering the need for this data?The potential inhalation exposuresthat might occur during openpour addition of liquids duringmaterial preservation and painting with dimethoxanetreated paints are thetrigger for requiring aninhalation risk assessment which in turnrequires an inhalation toxicity study.Page 16 of 22Appendix A, Table 1 - Toxicology Study JustificationsGuidelineStudy TitlePractical Utility of the DataN/ADermalSensitizationThresholdQuantification1) What is the value of the study?This study is needed to quantify the dermal sensitization effects that have been observed in theacute animal study (MRID 419367-03) where dimethoxanewas found to be a strong sensitizer inguinea pigs.2) How would the data be used?The data would be used to identify a threshold for the dermal sensitization of dimethoxane.Specifically the data would be usedto identify a safe threshold level for the elicitation phase ofsensitization which is protective of induction asrecommended by the FIFRA SAP (See note 1).This level would then be used to assess the risk of dermal sensitization from exposure todimethoxane.3) How could the data affect the risk assessment?Currently it is not possible to assess the risksof sensitization from exposure to dimethoxanebecause the acute animal study doesnot provide a threshold level.4) What is triggering the need for this data?The need for this data is triggered by residential dermal exposures from the paint preservationuse, the positive result for dermalsensitization seen in the acutestudy and the literature report ofdermal sensitization in a textileworker exposed to spinning fluids treated with dimethoxane.Note 1 - Transmittal of Minutes of the FIFRA Scientific Advisory Panel Meeting Held May 4-6,2004: A Consultation on DermalSensitization Issues for Exposures toPesticides, Memorandum of 1 July 2004.Page 17 of 22Appendix A, Table 2 - Exposure Study JustificationsGuidelineStudy TitlePractical Utility of the Data875.1200875.1400875.1600Applicator Indoor Exposure(Open Pour Liquids)DermalInhalationData Reporting1) What is the value of the study?Dermal and inhalation exposures to dimethoxane and inhalation exposures toacetaldehyde are expected during the open pouraddition of liquids during materialspreservation. In addition, dermal and inhalation exposures from open pouring of liquidsare evident in exposure studies in the Pesticide Handlers Exposure Database (PHED).The existing Chemical Manufacturer Association (CMA) data baseand PHED for thesescenarios are limited in scope for QA/QC andthe number of replicates (i.e., number oftimes a worker is monitored for a specific activity). EPA presented the need foradditional handler exposure datato the January 2007 Science Advisory Panel (SAP) aswell as to the April 2007 Human Studies Review Board (HSRB) and both groups agreedthat additional data are warranted.2) How would the data be used?The data would be used to assess dermal and inhalation exposures that result from theopen pour addition of liquids during materials preservation.3) How could the data affect the risk assessment?The exposure data would be used to assess the risks to occupational workers anddetermine if mitigation measures, such as closed system loading, are needed to reducethese risks.4)What is triggering the need for this data?The need for the exposure study is based on the potential for exposure from the open pouraddition of liquids during the materialspreservation uses listed on the label.Page 18 of 22Appendix A, Table 2 - Exposure Study JustificationsGuidelineStudy TitlePractical Utility of the Data875.1200875.1400875.1600Applicator Indoor Exposure(Brush/Roller Painting)DermalInhalationData Reporting1) What is the value of the study?Dermal and inhalation exposures to dimethoxane and inhalation exposures toacetaldehyde are expected during interiorbrush/roller application of dimethoxanepreserved paints. There are no studies available to assess these exposures.2) How would the data be used?The exposure data would be used to assess dimethoxane and acetaldehyde exposures thatresult from brush/roller application of dimethoxane preserved paints.3) How could the data affect the risk assessment?Current there are no dataavailable to assess the exposure of dimethoxane andacetaldehyde resulting from the use of dimethoxane in paints and therefore the risks fromthis use are unknown. The exposure data would be used to assess these risks anddetermine if mitigation is needed to reduce these risks.4) What is triggering the need for this data?Dimethoxane is labeled for use asa preservative in “Paints”.Page 19 of 22Appendix A, Table 2 - Exposure Study JustificationsGuidelineStudy TitlePractical Utility of the DataN/ATextile Leaching Study1) What is the value of the study?Dermal and incidental oral exposures to dimethoxane are expectedduring use of clothingand linens made from textiles that are treatedwith textile chemicals and finishes that arepreserved with dimethoxane. There are noleaching studies available to assess theseexposures.2) How would the data be used?The leaching data would be used to assess dimethoxane exposures that result from the useof clothing and blankets treated with textile finishes and chemicals that have beenpreserved with dimethoxane.3) How could the data affect the risk assessment?Currently there are no leaching data availableto assess the dermal and incidental oralexposure of dimethoxane resulting from the use of dimethoxane in textile chemicals andfinishes and thus the risksfrom this use are unknown.4) What is triggering the need for this data?Dimethoxane is labeled for use as a preservativein “Textile Chemicals and Finishes”.Page 20 of 22Appendix A, Table 2 - Exposure Study JustificationsGuidelineStudy TitlePractical Utility of the DataN/ALeather Leaching Study1) What is the value of the study?Dermal and incidental oral exposures to dimethoxane are expectedduring use of leathergoods made from leather that is processed with leather processing liquors that arepreserved with dimethoxane. There are noleaching studies available to assess theseexposures.2) How would the data be used?The leaching data would be used to assess dimethoxane exposures that result from the useof leather processed with leather processing liquors that arepreserved with dimethoxane.3) How could the data affect the risk assessment?Currently there are no leaching data availableto assess the dermal and incidental oralexposure of dimethoxane resulting from theuse of dimethoxane in leather processingliquors and thus the risks from these exposures are unknown.4) What is triggering the need for this data?Dimethoxane is labeled for use as a preservative in “Leather Processing Liquors”.Page 21 of 22Page 22 of 22Appendix A, Table 2 - Exposure Study JustificationsGuidelineStudy TitlePractical Utility of the Data875.1700Product Use Information1) Whatis the value of the study?Product use information is a description of howthe product is actuallyapplied; it is not afield study. A description of how this productis used would provide for a comprehensiverealistic assessment of its potential applications.2) How would the data be used?The product use information will be used to define and characterize the exposurescenarios that will be assessed in the risk assessment.3) How could the data affect the risk assessment?A complete description of product use would ensure that the risk assessment is inclusiveof the types of exposures occurring during use and that these exposures are accuratelyassessed.4)What is triggering the need for this data?The need for a risk assessment under Registration Review in turn necessitates that the riskassessor understand how the product is used.