Page 2 of 8 EXECUTIVE SUMMARY

The Antimicrobial s Division ( AD ) Registration Review Team has evaluated the status
of the human health assessments for diethylene glycol monomethyl ether ( DGME ) ( case 5010 , PC Code 0 42204 ) for the purpose of registration re view

. DGME is an antimicrobial pesticide that is used for non

- food uses a s an additive in jet fuel , diesel fuel, marine fuel, and fuel oil. DGME control s fungi and bacteri a in hydrocarbon systems that can reduce fuel performance

. DGME is also a deicer tha t lowers the freezing point of fuel

thus prevent ing fuel ice from forming . Fuel ice may form when airplanes fly at higher

elevations

. DGME has a use classification as a material preservative (Category VII) and only has o ne registered label

, and no toleran ces or exemptions from the requirement of a

tolerance

. There are inert uses. However, the inert use s are not covered in this

assessment

.

DGME is formulated as a liquid ready to use product and is sold as a 99.7% active ingredient in tanks, drums, and to tes. The only potential exposure to DGME is through closed mixing and loading into fuel delivery systems. The l abel prohibits open pouring

. Closed mixing and loading systems typically use automatic metering pumps using hoses and various connecting devices to facilitate transfer from drums, totes, holding tanks, etc.

The purpose of this review is to examine a nd characterize the existing hazard and exposure databases for DGME and to determine whether new data and risk assessments are expected to be needed

.

DGME was first registered as a pesticide in June 2002

. A R eregistration E ligibility

D ecision (RED) document h as not been issued for DGME since this chemical was registered after November 1, 1984. The primary source of information for this assessment

was registration records for the only registered product (EPA Reg

. 324

- 32) and applicable Agency risk assessment memoranda pertaining to this registration.

Based on this review of the Agency data , existing risk assessments, reviews and the existing use pa ttern (e.g., mixing/loading using a closed delivery systems fuel systems)

, the Agency does not expect that data or additional risk assessments will be needed to

assess occupationa l

, residential, dietary, and drinking water exposures. In addition, t he Agen cy does not anticipate the need for additional toxicity , exposure, and chemistry

studies to assess the hazard s of DGME

.Page 3 of 8

Section 1. Chemical Identity

Table 1 Chemical Identity

Common

Name Diethylene Glycol Monomethyl Ether

( DGME ) Synomyms Ethano l, 2

- (2

- methoxyethoxy) Methyl

Carbitol

PC Code 042204 CAS registry

number 111

- 77

- 3

Registration

Review Case

No. 5010

Structure

Section 2. Toxicology

The Agency has reviewed the existing toxicity assessments and toxicity data f or DGME

. The Agency reviewed the historical t oxicological database supporting the original registration of DGME . Based on the use patt ern ( material preservative for fuels )

and application methods ( used only in closed systems ) , the Agency expects that only a Tier 1 toxicity data set will be needed

.

Acute Toxicity

For registration review, t he Agency will rely on the existing acute toxicity database developed during registration. According to Agency documentation (D273299)

, DGME

has an acute oral toxicity category of I V based on a n oral LD50 of 5,050 mg/kg for rats.

An acute dermal toxicit y category of IV was based on a dermal LD50 of 5,050 mg/kg

from a dermal rabbit study

. DGME was not identified as a dermal or eye irritant or a dermal sensitizer in rabbits. An inhalation toxicity category of III was assigned based on

the results of a rat inhalation open literature study (D273299) i n which n o toxicity was

identified at the maximum air concentration of 216 ppm (1.06 mg/L).

Mutagenicity

The Agency does not anticipate the need for additional mutagenicity data based on review of the existing mutagenicity data submitted during registra tion of DGME ( D273300)

. In the database of mutagenicity studies, n o evidence of gene mutation was identified in an acceptable in vitro bacterial reverse gene mutation (Ames) assay ( MRID

453251

- 02 )

. T his study was considered as acceptable

. Another accept able study, MRID

453251

- 03, indicated that no chromosomal aberrations were seen in an in vitro mammalian cytogenetics chromosomal aberration study . No statistically significant

increases of chromosomal aberrations were seen with and without metabolic activ ation inPage 4 of 8

Chinese hamster ovary CHO

- K1 cell cultures. Finally, n o statistically significant

increase s of micronucleated erthrocytes were seen in an acceptable in vi vo mammalian

cytogen e tics bone marrow micronucleus assay in mice (MRID 453251

- 04)

.

Subchron ic Toxicity

Dermal

For the initial registration, EPA reviewed a published DGME subchronic dermal toxicity study (Hobson et al., 1986: Fund. Appli. Toxicol. 6: 339

- 348) (D2 6 1013).

Hobson et al. performed a 13

- week dermal study in which male guinea pigs received

DGME dermal dose s of 0, 40, 200, or 1000 mg/kg/day for 5 days/week and 6 hours/day. Body weight, selected organ weights, hematology, clinical chemistry, urinalysis, and gross and histopathologic examinations were observed in this study

. A NOAEL o f 40 mg/kg/day was determined based on elevation of urinary calcium, alteration in spleen weight, and change s in t he mean corpuscular hemoglobin concentration ( MCHC ) at dose levels of 200 mg/kg/day and above (D261013)

.

Inhalation

A 90

- day inhalation st udy in male Fisher 344 rats submitted in registration (Miller et

al . 1985 , MRID 44655801 ) identified no effects on body w eights, organ weights, gross pathology, histopathology, hematology or serum concentrations up to 216 ppm ( 1.06 mg/liter ) . This concent ration was the maximum attainable concentration and was more than 60% of the theoretical maximum vapor pressure (U.S. EPA 2002)

. This study was not used to generate inhalation toxicity endpoints for short

- and intermediate effects for the occupational ass essment, since it did not identify a dose response, but t he study was used for establishing an acute inhalation category

.

Developmental Toxicity

EPA reviewed rat and rabbit developmental studies on DiGME (D621013)

. According to th is review, Yamano et a l. (1993), administered DiGME to Wistar rats at dose levels of 0, 200, 600, and 1800 mg/kg/day during days 7

- 17 of gestation. At 600 mg/kg

, decreased fetal body weight and adverse effect on the fetal thymus were noted in

the absence of maternal effects. In another rat study by Hardin et al. (1986), Sprague Dawley rats were dosed at 0, 720, and 2165 mg/kg. Skeletal abnomalities (reduced cranium, reduced skeletal ossification, and rudimentary ribs) and visceral abnormalities (dilated renal pelvis) were obse rved at 720 mg/kg at a dose that was not maternally toxic. Scortichini et al (1986) dosed pregnant New Zealand rabbits dermally at 0, 50, 250 and 750 mg/kg during days 6

- 18 of gestation. No developmental effects were observed but maternal effects (reduced body weight) were noticed at the highest dose level.

Summary of Toxicity Data

Based on the review of the registration submissions

, the acute toxicity and mutagenicity data appear to be satisfied (D273299 and D273300). According to the EPA registratio n submission ( D2 6 1013 )

, the subchronic dermal study an d the dermalPage 5 of 8

developmental data appear ed to s atisf y the subchronic and developmental data requirements

. Traditionally, the Agency requires a 90

- day inhalation toxicity study to
assess inhalation toxici ty endpoints , but the study was not needed based on the use

pattern and the label restriction for engineering controls (e.g. closed mixing/loading) that

will minimize inhalation exposure

. Additionally, t he Agency also indicated some concern based on the de velopmental effects and that a 2

- generation reproductive study may be

needed

. However, the 2

- generation reproductive study w ill not be needed since DGME is only used for non

- food uses. N ew uses or new registrations in the future could potentially trigger the need for these toxicity data considerations in the future

.

Section 3. Dietary Assessment

Currently, there is only one registered label for the active ingredient, and no tolerances or exemptions from the requirement of a tolerance. N 

### o residue da ta are needed and no dietary exposures of concern are anticipated based on the use pattern
of DGME

.

Section 4. Aggregate and Cumulative Exposure

In examining aggregate exposure, EPA takes into account the available and reliable information concerning e xposures to pesticide residues in food and drinking water, and

non

- occupational pesticide exposures

. Dietary (food and drinking water) exposures of concern are not anticipated for DGME

. An aggregate risk assessment for DGME is not

needed since there is no dietary or residential exposure for the active ingredient

. Therefore, an aggregate assessment is not needed.

Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider "avail able information” concerning the cumulative effects of a particular pesticide's residues and "other substances that have a common mechanism of toxicity.” EPA has not yet determined

whether DGME ha s a common mechanism with other compounds , consequently a

cu mulative assessment will not be performed at this time

.

Section 5. Occupational /Residential Exposure

An occupational and/or residential exposure assessment is required for an active ingredient if (1) certain toxicological criteria are triggered and (2) there is potential exposure to handlers (mixers, loaders, applicators, etc.) during use or to persons entering treated sites after application is complete. There are no potential residential exposures and minimal exposures to persons entering treated sit es so a residential risk assessment is

not needed.

DGME is an antimicrobial pesticide used on indoor nonfood uses as a fuel additive in occupational settings only

. The label prohibits mixing or loading of DGME with any fuel unless it is done through close d delivery systems. These systems typically use automatic metering pumps using hoses and various connecting devices to facilitate transfer from drums, totes, holding tanks, etc

. According to data from the supplier, the closed system process begins at “pic kup” from the supplier. The additive, in bulk, is loaded into thePage 6 of 8

railroad tank cars or tank trucks through closed piping or hose systems. The bulk is delivered at a gasoline terminal where it is transferred through closed mixing to a holding

tank. When an order is made additive is metered into the fuel of a tank truck at a rate of

0.1

- 0.15% by weight, as it is loaded (US EPA, 2002)

.

An occupational assessment was conducted in 1999 (D261014) and the calculated MOEs were acceptable for handler s (e.g., c losed mixing/loading worker exposure)

. Potential for p ostapplication exposure s (e.g., exposure to persons entering treated sites after application is completed) is expected to be minimal based on the engineering

controls

. EPA expects dermal and inhalation handler exposures will likely be minimized using a closed delivery system

. In addition, the label specif ies that the appropriate personal protective equipment ( PPE ) [ e.g. chemical resistant gloves , long sleeved shirt, socks, shoes, and pants] will be used for handling exposures such as connecting hoses or maintenance of the closed system

. B ecause of the safety requirements (PPE) and engineering controls specified on the label, a n additional occupational risk assessment is anticipated as not needed

. N o addi tional exposure data are needed for the closed mixing

fuel additive use. Product use data was already provided in the original submission, so it is not anticipated as needed

.

Section 6. Anticipated Data Needs

The Antimicrobial Division (AD) does not an ticipate the need for any additional

human health data needs for D GME at the current time

. New uses or new registrations in the future could potentially trigger the need for these toxicity data considerations in the future, however.

Section 7. Tolerance s

There are no tolerance s or exemption s from the requirement of tolerance for DGME

.

Section 8. Endocrine Disruption

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certa in substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP emplo ys a two

- tiered approach 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 estrogen, androgen, or thyroid (E, A, or T) hormonal syst ems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine related effects 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 is sued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inertPage 7 of 8

ingredients. This list of chemicals was selected based on the potential for human exposure through pathways such as food and wat er, residential activity, and certain post

application agricultural scenarios. This list should not be construed as a list of known or likely endocrine disruptors.

DGME is not among the group of 58 pesticide 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 issuing future EDSP test orders/data

call

- ins for all pesticide active ingredients

.

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

Section 9. Human Incident Data

There have been no human incidents reported in an y of the OPP databases associated with exposure to DGME as a fuel additive.

Section 10 . Overall Conclusions

The Agency reviewed the hazard and exposure databases for DGME and anticipates

that no additional studies will be needed for registration revie w

. The Agency does not expect to conduct any additional r isk assessment s for this chemical since this use was already assessed in registration . EPA also expect s the exposure to be minimal based on engineering controls typically used for fuel additive use

. New uses or new registrations could potentially trigger the need for additional risk assessments and toxicity data considerations in the future, however.

Section 11 . Reference s

US EPA, 2002. Memorandum from F. Sanders, Antimicrobials Division Director to M.

M u l key, Office of Pesticide Programs Director. Subject: 12

- Month Time Limited Registration of Diethylene Glycol Monomethyl Ether

. Antimicrobials Division (AD)

, Office of Pesticide Programs (OPP)

. June 2002.

D261013. Memorandum from T. McMahon, Seni or Toxicologist, Risk Assessment Science Support Branch (RASSB) to D. Edwards, Branch Chief, Regulatory Management Branch 1 (RMB1) . Subject: Diethylene Glycol Monomethyl Ether (DGME) . Review of Literature Data in Support of Jet Fuel De

- Icer Use. Antimicro bials

Division (AD) , Office of Pesticide Programs (OPP) . November 1999.

D261014. Memorandum from S. Mostaghimi, Environmental Engineer, Risk Assessment Science Support Branch (RASSB) to W.Dang, Team Leader, Risk Assessment Science Support Branch (RASSB). Occupational Exposure Assessment Estimates of Diethylene Glycol Monomethyl Ether. Antimicrobials Division (AD)

, Office of Pesticide Programs (OPP) . December 1999.Page 8 of 8

D273299. Memorandum from C. Jiang, Chemist, RASSB to M.Swindell, Team Leader,

RMB1. Subject: Acute Toxicity Reviews. Phillips Fuel Additive. Antimicrobials Division (AD), Office of Pesticide Programs (OPP). April 2001.

D273300. Memorandum from S. Malish, Toxicologist, RASSB to M.Swindell, Team Leader, RMB1. Subject: Toxicity Reviews of Mutagenic ity Studies. Phillips Fuel Additive. Antimicrobials Division (AD), Office of Pesticide Programs (OPP). August

2001.