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From: Saved by Windows Internet Explorer 7 <Saved by Windows Internet Explorer 7> Date: Fri, 3 Jul 2009 16:27:17 -0400 Subject: Substance: tetraethylene glycol ethyl ether / 3,6,9,12-tetraoxatetradecan-1-ol / 3,6,9,12-tetraoxatetradecan-1-ol / 5650-20-4 / PCA Services, Inc. / Durham / United States of America Content-Type: multipart/related; boundary="

_ 005

_ 6875707670716565696866736977697675767965696578807274687

_ "; type="multipart/alternative" Thread-Topic: Substance: tetraethylene glycol ethyl ether / 3,6,9,12-tetraoxatetradecan-1-ol / 3,6,9,12-tetraoxatetradecan-1-ol / 5650-20-4 / PCA Services, Inc. / Durham / United States of America Thread-Index: AcrBZmtzGiZ4S2zISDiG2x2/JRhq9w== X-MS-Has-Attach: yes X-MS-TNEF-Correlator: MIME-Version: 1.0

Printing Date 2009-07-03 16:26:34 EDT
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Confidentiality

N ame tetraethylene glycol ethyl etherLegal entity owner PCA Services, Inc. / Durham / United States of America Substance: tetraethylene glycol ethyl ether UUID IUC5-178944e7-91bd-422a-a252-50f5b47ca82b Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-06-14 10:47:38 EDT Remarks 0 Related Information 0.1 Templates 0.2 Categories 0.3 Mixtures 1 General Information 1.1 Identification Substance identification Chemical name tetraethylene glycol ethyl ether Legal entity PCA Services
, Inc . / Durham / United States of America Reference substance Reference substance 3,6,9,12

- tetraoxatetradecan

- 1

- ol / 3,6,9,12

- tetraoxatetradecan

- 1

- ol / 5650

- 20

- 4

EC number EC name 227-090-6 3,6,9,12-tetraoxatetradecan-1-ol CAS number CAS name 5650-20-4 IUPAC name 3,6,9,12-tetraoxatetradecan-1-ol

Type of substance Composition mono constituent substance Origin organic 1.2 Composition 1.3 Identifiers 1.4 Analytical information 1.5 Joint submission 1.6 Sponsors 1.7 Suppliers 1.8 Recipients 1.9 Product and process oriented research and development 2 Classification and Labelling 2.1 GHS 2.2 DSD - DPD 3 Manufacture, use and exposure 3.1 Technological process 3.2 Estimated quantities 3.3 Sites3.4 Form in the supply chain 3.5 Identified uses and exposure scenarios 3.6 Uses advised against 3.7 Waste from production and use 3.8 Exposure estimates 3.9 Biocidal information 3.10 Application for authorisation of uses 4 Physical and chemical properties 4.1 Appearance/ p hysical state/colour Appearance/ p hysical state/colour.002 UUID IUC5-f24606b9-1f08-408d-b54d-19222488b810 Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-06-14 10:56:06 EDT Remarks

Administrative Data Purpose flag weight of evidence ( ) robust study summary ( ) used for classification ( ) used for MSDS Study result type other: visual appearance and specification Reliablility 2 (reliable with restrictions) Rationale for reliability N o study reviewed. Manufacturer's data

Data source Reference Reference type company data Author Year Title Pennzoil product data sheet for Pennzoil brake fluid Bibliographic

source Available online at http://www. p ennzoil.com/documents/Super%20HD%20Dot%203and4%20Bra ke%20Fluid. p df Testing laboratory Report no.

Owner company Company study

no. Report date

Materials and methods Test materials Test material equivalent to submission substance identity

no Test material identity Identifier Common name

Identity DOT 4 Brake fluidDetails on test material Data come from DOT 3 and DOT 4 specifications for brake fluid. Substance is available commercially only as a component in brake fluids. Results and discussion Physical state at 20oC and 1013 hPa liquid Colour clear amber Odour other: faint ether like Substance type organic 4.2 Melting point/freezing point Melting point/freezing point.001 UUID IUC5-42e97e77-427a-4bba-b872-7d19c69b97b0 Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-06-13 17:47:35 EDT Remarks

Administrative Data Purpose flag key study ( ) robust study summary ( ) used for classification ( ) used for MSDS

Study result type read-across from supporting substance (structural analogue or surrogate) Reliablility 2 (reliable with restrictions) Rationale for reliability Melting point data come from DOT 3 and DOT 4 specifications for brake fluid. Substance is available commercially only as a component in brake fluids. Data source Reference Reference type company data Author Year Title Pennzoil brake fluid DOT 4 data sheet Bibliographic

source Available online at http://www. p ennzoil.com/documents/Super%20HD%20Dot%203and4%20Bra ke%20Fluid. p df Testing laboratory Report no.

Owner company Company study

no. Report date

Materials and methods GLP complianceno data Test materials Test material equivalent to submission substance identity

no Test material identity Identifier Common name

Identity Pennzoil brake fluid DOT 4 Details on test material Data are for DOT 3 or 4 specification automotive brake fluid, of which tetraethylene glycol ethyl ether is a component. Tetraethylene glycol ethyl ether is not available commercially as a neat material. Results and discussions Melting / freezing point Melt./Freez. p t. ca. -40 °C Atm. p ressure Decomposition no Decomp. temp. Sublimation no Subl. temp. Remarks 4.3 Boiling point Boiling point.001 UUID IUC5-aa6cfb2b-e461-4173-b317-45f19ce938cd Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-06-14 11:32:34 EDT Remarks

Administrative Data Purpose flag key study ( ) robust study summary ( ) used for classification ( ) used for MSDS Study result type no data

Reliablility 2 (reliable with restrictions) Rationale for reliability Data were obtained from brake fluid Manufacturer's technical data sheet. Tetraethylene glycol ethyl ether is available commercially only as a brake fluid component. Data source Reference

Reference type company data

Author Year

Title Pennzoil Technical Data Sheet for Pennzoil (trademark) Brake Fluid (Dot 4) Bibliograp Available online athic source http://www. p ennzoil.com.au/downloads/tds/Pennzoil

_ Brake

_ Fluid

_ Dot

_ 4. p df Testing laboratory Rep
ort

no. Owner company Company study no. Rep
ort date
Reference type company data Author Year Title Pennzoil product data sheet for Pennzoil brake fluid Bibliographic

source available online at http://www. p ennzoil.com/documents/Super%20HD%20Dot%203and4%20Bra ke%20Fluid. p df Testing laboratory Report no.

Owner company Company study

no. Report date

Materials and methods GLP compliance no data Test materials Test material equivalent to submission substance identity

no Test material identity Identifier Common name

Identity Pennzoil (trademark) Brake Fluid (DOT 4) Results and discussions Boiling point Boiling pt. >= 272 °C Atm. p ressure 1013 hPa Decomposition no Decomp. temp. Remarks Equilibrium Reflux Boiling Point 4.6 Vapour pressure Vapour pressure.001 UUID IUC5-6c922304-3983-471a-9134-5f423bc369a6 Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-06-13 17:52:42 EDT RemarksAdministrative Data Purpose flag key study ( ) robust study summary ( ) used for classification ( ) used for MSDS

Study result type no data

Reliablility 2 (reliable with restrictions)

Rationale for reliability Data are from brake fluid manufacturer's safety data sheet for DOT 3 and DOT 4 specification brake fluid. Tetraethylene glycol ethyl ether is one of the major components in automotive brake fluids. Therefore the data are reliable for commercial product, but the vapor pressure determination study is not available. Data source Reference Reference type company data

Author Year Title Shell Brake and Clutch Fluid DOT 4 Super Safety Data Sheet Bibliographic

source Available online at http://www.enerquip.com.au/brochures/shell /Shell%20PDFs/Brake%20&%20c lutch%20fluid%20Dot%204%20super. p df Testing laboratory Report no.

Owner company Company study no. Report date

Materials and methods Type of method other: method not known GLP compliance no data Test materials Test material equivalent to submission substance identity

no Test material identity Identifier Common name

Identity Shell Brake and Clutch Fluid DOT 4 Super Details on test material Mixture typically containing 30-50% triethyleneglycol monomethyl ether borate ester (CAS N o. 106008-94-0),3-30% triethylene glycol monobutyl ether borate ester, 20-30% triethylene glycol monomethyl ether (CAS No. 112-35-6), 2-10% triethylene glycol monobutyl ether (CAS N o. 143-22-6), 20-30% tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 2-10% tetraethylene glycol monobutyl ether (CAS No. 1559-34-8), and < 1% minor additives. Borate esters have the general molecular formula of B(OR)3, where R = glycol ether, e.g., -O(CH2CH2O)nCH3.or -O(CH2 CH2O)n CH2CH2CH2CH3. Results and discussions Vapour pressure <= 0.005 hPa at ca. 20 °C Remarks 4.7 Partition coefficient Partition coefficient.001 UUID IUC5-dc534c7d-a0a2-4f36-ae98-837be71ceea4 Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-06-13 16:18:02 EDT Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type estimated by calculation Study p eriod 20 09 Reliablility 2 (reliable with restrictions) Rationale for reliability Data were obtained using a recognized Computer model program

Data source Reference Reference type other: Computer model program output Author Year 2009 Title EPIWIN KOWWIN (v1.67) Bibliographic

source Testing laboratory Report no.

Owner company

Company study

no. Report date 2009-06-09

Materials and methods Partition coefficient type octanol-water Type of method other: Test materials Test material equivalent to submission substance identity
yes Test material identity Identifier CAS number Identity 5650-20-4Identifier EC number Identity 227-090-6

Identifier IUPAC name

Identity 3,6,9,12-tetraoxatetradecan-1-ol Details on methods Input to Kowwin model was CAS No. 005650-20-4. Results and discussions Partition coefficient Type Pow Partition coefficient ca. -1.24 Temp. p H 4.8 Water solubility Water solubility.001 UUID IUC5-8a849970-4f07-4aa4-96ad-65b4612fbe33 Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-06-13 17:56:13 EDT Remarks

Administrative Data Purpose flag key study ( ) robust study summary ( ) used for classification ( ) used for MSDS Study result type no data

Reliablility 2 (reliable with restrictions) Rationale for reliability Data were obtained from the brake fluid manufacturer's Safety Data Sheet. tetraethylene glycol ethyl ether is available commercially only as a component in automotive brake fluid. Data source Reference Reference type company data

Author Year Title Safety Data Sheet for Shell Brake and Clutch Fluid DOT 4 Super Bibliographic

source available online at http://www.enerquip.com.au/brochures/shell /Shell%20PDFs/Brake%20&%20cl utch%20fluid%20Dot%204%20super. p df Testing laboratory Report no.

Owner company Company Report datestudy no. Materials and methods GLP compliance no data Test materials Test material equivalent to submission substance identity

no Test material identity Identifier Common name Identity Shell Brake and Clutch Fluid DOT 4 Super Details on test material Mixture typically containing 30-50% triethyleneglycol monomethyl ether borate ester (CAS No. 106008-94-0),3-30% triethylene glycol monobutyl ether borate ester, 20-30% triethylene glycol monomethyl ether (CAS No. 112-35-6), 2-10% triethylene glycol monobutyl ether (CAS No. 143-22-6), 20-30% tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 2-10% tetraethylene glycol monobutyl ether (CAS No. 1559-34-8), and < 1% minor additives. Borate esters have the general molecular formula of B(OR)3, where R = glycol ether, e.g., -O(CH2 CH2O)nCH3.or -O(CH2 CH2O)n CH2CH2CH2CH3. Results and discussions Water solubility ca. 1000000 mg/L Temp. 20 °C
p H Remarks on results including tables and figures

Test material is miscible in water.
4.11 Flash point Flash point.001 UUID IUC5-23e5e813-1084-4c7e-b16d-2f1c01587ae0 Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-06-13 17:56:46 EDT Remarks

Administrative Data Purpose flag key study ( ) robust study summary ( ) used for classification ( ) used for MSDS

Study result type no data

Reliablility 2 (reliable with restrictions) Rationale for reliability Data were obtained from the safety data sheet of the brake fluid manufacturer. The study for flash point determination is not available. Tetraethylene glycol ethyl ether is available commercially only as a component in automotive brake fluide.Data source Reference Reference type company data

Author Year Title Safety Data Sheet for Shell Brake and Clutch Fluid DOT 4 Super Bibliographic

source available online at http://www.enerquip.com.au/brochures/shell /Shell%20PDFs/Brake%20&%20cl utch%20fluid%20Dot%204%20super. p df Testing laboratory Report no.

Owner company Company study no. Report date

Materials and methods GLP compliance no data Test materials Test material equivalent to submission substance identity

no Test material identity Identifier Common name Identity Shell Brake and Clutch Fluid DOT 4 Super Results and discussions Flash point ca. 155 °C
at 5 Environmental fate and pathways 5.1 Stability 5.1.1 Phototransformation in air Phototransformation in air.001 UUID IUC5-da1ebb09-9496-43fc-8ee0-511156436d13 Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-06-14 12:01:25 EDT Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type estimated by calculation Study p eriod 20 09 Reliablility 2 (reliable with restrictions)Rationale for reliability Data were estimated using a recognized computer program.

Data source Reference Reference type other: computer model program output Author Year Title EPIWIN AOP (v1.92) Bibliographic

source Testing laboratory Report no.

Owner company Company study

no. Report date 2009-06-08

Materials and methods Test materials Test material equivalent to submission substance identity
yes Test material identity Identifier CAS number Identity 5650-20-4

Identifier EC number

Identity 227-090-6

Identifier IUPAC name

Identity 3,6,9,12-tetraoxatetradecan-1-ol Study design Estimation method (if used) PHOTOCHEMICAL REACTION WITH OH RADICALS - Concentration of OH radicals: 1.5E6 OH/cm3 - Degradation rate constant 59.3889 E-12 cm3/molecule-sec: - Computer programme: EPIWIN AOP (v1.92) - 12-hour day - half-life: 0.180 day or 2.161 hours Light source sunlight 5.2 Biodegradation 5.2.1 Biodegradation in water: screening tests Biodegradation in water: screening tests Waggy TGME 1987.001 UUID IUC5-3a55abfe-7469-4ed6-ab01-8680f352f421 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-24 17:15:30 EDTRemarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1 9 8 7

Reliablility 2 (reliable with restrictions) Rationale for reliability Test material purity was not specified. N o data on GLP. Some deviations on test design. Otherwise a reliable study. Data source Reference Reference type study report

Author Waggy GT Year 1987 Title Glycol ethers: Summary of available ecological fate and effects data. Bibliographi

c source

Testing laboratory Report

no. File Number 35931 Owner company Union Carbide

Company study no. Report date 1987-11-19

Materials and methods Test type other: Test guideline

Qual ifier according to

Guid eline other guideline: A modified version of the biochemical oxygen demand (BOD) method p ublished in "Standard Methods for the Examination of Water and Wastewater", 16th edition, Am. Public Health Association, 1985 was used. Devi ation

s yes See test condition section for details.

GLP compliance no data Test materials Test material equivalent to submission substance identity

no Test material identityIdentifier Common name Identity triethylene glycol monomethyl ether

Identifier CAS number

Identity 112-35-6

Identifier EC number

Identity 203-962-1 Details on test material no data Study design Oxygen conditions aerobic Inoculum or test system activated sludge, domestic, non-adapted Duration of test (contact time) 20 d Parameter followed for biodegradation estimation O2 consumption Details on study design N onacclimated domestic sewage organisms were used as seed in the test. The test period was extended to 20 days. Reaeration (if needed) was accomplished by dividing the BOD bottle contents between 2BOD bottles, sealing, shaking twenty times, returning contents to the original BOD bottle, recording the oxygen level, resealing, and returning the BOD bottle to the incubator. A discussion of these modifications appears in Price et al., "Brine shrimp bioassay and seawater BOD of petrochemicals", J. Water Poll. Control Fed., Jan. 1974. Results and discussions Test performance The calculated theoretical oxygen demand was 1.75 mg/mg. After 5, 10 and 20 days of incubation, the percent biooxidation was 29, 33, and 71%. % Degradation of test substance %Degr. 71 St. dev. Parameter O2 consumption Sampling time 20 d Remarks BOD5 / COD results Overall remarks

Biological oxygen demand (BOD) of triethylene glycol monoethyl ether (TGEE, CAS No. 112-50-5) and triethylene glycol monobutyl ether (TGBE, CAS No. 143-22-6) were also tested in this study. The BOD of TGME was similar to that of TGEE, and greater than that of TGBE. The concentrations of test material and bacteria used in the test were not listed in the report.
Applicant's summary and conclusion Interpretation of results readily biodegradable5.3 Bioaccumulation 5.3.1 Bioaccumulation: aquatic / sediment Bioaccumulation: aquatic / sediment.001 UUID IUC5-049fe4d0-c961-479f-ab2c-2525c990cdab Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-06-13 17:28:25 EDT Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type estimated by calculation Study p eriod 20 09 Reliablility 2 (reliable with restrictions) Rationale for reliability Data were estimated using a recognized, approved model.

Data source Reference Reference type other: computer model program output Author Year 2009 Title EPIWIN BCFBAF Program (v3.00) Bibliographic

source Testing laboratory Report no.

Owner company Company study

no. Report date 2009-06-13

Materials and methods Test materials Test material equivalent to submission substance identity
yes Test material identity Identifier CAS number Identity 5650-20-4

Identifier EC number

Identity 227-090-6

Identifier IUPAC name

Identity 3,6,9,12-tetraoxatetradecan-1-ol Study design Water media typefreshwater Test conditions Details on estimation of bioconcentration BASIS INFORMATION - Measured/calculated logPow: -1.24

BASIS FOR CALCULATION OF BCF - Estimation software: EPIWIN BCFBAF (v3.00) - Result based on calculated log Pow of: -1.24 Results and discussions Bioaccumulation factor Conc. in environment / dose Type other: log BCF Value ca. 0.5 Basis Time of plateau Calculation basis Remarks 5.4 Transport and distribution 5.4.2 Henry's Law constant Henry's Law constant.001 UUID IUC5-f5985d27-dfd8-4bf6-922c-357e73c9d20d Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-06-13 16:20:51 EDT Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type estimated by calculation Study p eriod 20 09 Reliablility 2 (reliable with restrictions) Rationale for reliability Data were obtained using a recognized computer model program.

Data source Reference Reference type other: computer model program output Author Year 2009 Title EPIWIN HENRY (v3.20) Bibliographic

source Testing Report no.laboratory Owner company Company study

no. Report date 2009-06-08

Materials and methods Test materials Test material equivalent to submission substance identity
yes Test material identity Identifier CAS number Identity 5650-20-4

Identifier EC number Identity 227-090-6

Identifier IUPAC name Identity 3,6,9,12-tetraoxatetradecan-1-ol Details on methods CAS No. 5650-20-4 was the input to EPIWIN HENRY program Results and discussions Henry's Law constant H H ca. 0 atm m3/mol Temp. (°C) Atm. p ress. 5.4.3 Distribution modelling Distribution modelling.001 UUID IUC5-ec1f2658-f61a-4d0b-95fd-bbda6f6db3e3 Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-06-13 16:24:21 EDT Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type estimated by calculation Study p eriod 20 09 Reliablility 2 (reliable with restrictions) Rationale for reliability Data were obtained using a recognized, approved computer program.

Data source Reference Reference type other: computer model program output Author YearTitle EPIWIN Fugacity Level III model program Bibliographic

source Testing laboratory Report no.

Owner company

Company study

no. Report date 2009-06-08

Materials and methods Model Calculation according to Mackay, Level III Calculation programme EPIWIN Fugacity Level III model Release year 2009 Media air - biota - sediment(s) - soil - water Test materials Test material equivalent to submission substance identity
yes Test material identity Identifier CAS number Identity 5650-20-4

Identifier EC number Identity 227-090-6

Identifier IUPAC name Identity 3,6,9,12-tetraoxatetradecan-1-ol Test substance input data - Molar mass: 222.28 - Data temperature:25 deg C - Water solubility: 1,000,000 mg/L - Vapour pressure: 0.000881 mm Hg - log Pow: -1.24 - Melting point: - 40 deg C - Boiling point 270 deg C - Reaction half-life estimates for - Air: 4/322 hours - Water: 360 hours - Soil: 720 hours - Sediment:3240 hours Results and discussions Percent distribution in media Air (%) 0Water (%) 30.6 Soil (%) 69.4 Sediment (%) 0.07 6 Ecotoxicological Information 6.1 Aquatic toxicity 6.1.1 Short-term toxicity to fish Short-term toxicity to fish DOW MPEG.006 UUID IUC5-cf740418-a178-416a-b52c-8a6b72b1618d Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-25 13:16:56 EDT Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Reliablility 2 (reliable with restrictions) Rationale for reliability Original data from which MSDS was written were not available.

Data source Reference Reference type Author Year Title Bibliograp hic source Dow MSDS for CARBOWAX methoxypolyethylene glycol 350 (CAS No. 9004-74-4), N umbe r 870, Dated 7/5/2000. Testing laboratory Report

no. Owner company Dow Chemical Company

Company study no. N umbe r 870 Report date 2000-07- 05 Materials and methods Test guideline Qualifier Guideline other guideline: no data on guideline Deviations GLP complianceno data Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 9004-74-4

Identifier IUPAC name

Identity Carbowax MPEG-350 Details on test material Test material (CARBOWAX MPEG-350; CAS No. 9004-74-4) is a mixture of several methylated glycol ethers of differing molecular weight (ranging from diethylene glycol monomethyl ether (C2) to heptadecaethylene glycol monomethyl ether (C17)). The majority of the material is in the C5-C11 range (87.445%). It contains 4.347 % (by weight) tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 1.303% triethylene glycol monomethyl ether (CAS No. 112-35-6), 0.181% diethylene glycol monomethyl ether (CAS No. 111-77-3). Analytical monitoring no data Details on sampling no data Details on analytical methods no data Vehicle no data Details on test solutions no data Test organisms Test organisms (species) other: fathead minnow Details on test organisms no data Study design Test type no data Water media type no data Total exposure duration 96 h Remarks Post exposure observation period no data Test conditions Hardness no data Test temperature no datap H no data Dissolved oxygen no data Salinity no datano data N ominal and measured concentrations no data Details on test conditions no data Reference substance ( p ositive control) no data Results and discussions Effect concentrations Duration 96 h Endpoint LC50 Effect conc. > 10000 mg/L N ominal/Measured no data Conc. based on no data Basis for effect no data Remarks (e.g. 95% CL) 6.1.3 Short-term toxicity to aquatic invertebrates Short-term toxicity to aquatic invertebrates DOW MPEG 2000.002 UUID IUC5-b7684406-ad5e-4472-be22-7de5571acfbe Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-25 13:16:59 EDT Remarks

Administrative Data Purpose flag weight of evidence (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Reliablility 4 (not assignable) Rationale for reliability Study data were available only from a secondary source

Data source Reference Reference type company data

Author Year 2000 Title Dow MSDS for CARBOWAX methoxypolyethylene glycol 350 (CAS No. 9004-74-4),Bibliographic

source Testing laboratory Report

no. Owner company Dow Chemical Company

Company study no. N umbe r 870 Report date 2000-07-05

Materials and methods Principles of method if other than guideline N o data on guideline followed. Study probably conducted by typical method. GLP compliance no data Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 9004-74-4

Identifier Common name

Identity Carbowas MGEP-350 Details on test material Test material (CARBOWAX MPEG-350; CAS No. 9004-74-4) is a mixture of several methylated glycol ethers of differing molecular weight (ranging from diethylene glycol monomethyl ether (C2) to heptadecaethylene glycol monomethyl ether (C17)). The majority of the material is in the C5-C11 range (87.445%). It contains 4.347 % (by weight) tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 1.303% triethylene glycol monomethyl ether (CAS No. 112-35-6), 0.181% diethylene glycol monomethyl ether (CAS No. 111-77-3). Analytical monitoring no data Details on sampling no data Details on analytical methods no data Vehicle

no Details on test solutions no data Test organisms Test organisms (species) Daphnia magna Details on test organisms no data Study design Test typeno data Water media type no data Total exposure duration 48 h Remarks Post exposure observation period no data Test conditions Hardness no data Test temperature no data
p H no data Dissolved oxygen no data Salinity no data N ominal and measured concentrations no data Details on test conditions no data Reference substance ( p ositive control) no data Any other information on materials and methods incl. tables

no data

Results and discussions Effect concentrations Duration 48 h Endpoint LC50 Effect conc. > 10000 mg/L N ominal/Measured no data Conc. based on no data Basis for effect Remarks (e.g. 95% CL)

6.1.4 Long-term toxicity to aquatic invertebrates Long-term toxicity to aquatic invertebrates Waggy TGME 1987.001 UUID IUC5-e4adc107-2c59-4dbc-bda7-e2647dcc1310 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-24 17:15:30 EDTRemarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 87 Reliablility 2 (reliable with restrictions) Rationale for reliability well conducted study, but purity of test material was not given.

Data source Reference

Reference type study report

Author Waggy GT Year 1987 Title Glycol ethers: Summary of available ecological fate and effects data. Union Carbide File Number 35931, N ovembe r 19, 1987. Bibliogra p hic

source Testing laboratory Repor
t no. File N umbe r 35931 Owner company Union Carbide Corporation

Company study no. Repor t date 1987-11-19

Materials and methods Principles of method if other than guideline Test practices followed those recommended by EPA and ASTM GLP compliance no data Test materials Test material equivalent to submission substance identity

no Test material identity Identifier Common name Identity triethylene glycol monomethyl ether

Identifier CAS number Identity 112-35-6

Identifier EC number Identity 203-962-1 Details on test materialno data Analytical monitoring

no Details on sampling no data Details on analytical methods no data Vehicle

no Test organisms Test organisms (species) Daphnia magna Details on test organisms Daphnia magna stocks were originally obtained from the EPA laboratory at Duluth, MN. They were maintained at 20-22 degrees C in a series of 600 ml beakers filled with Kanawha River water obtained from the South Side Boat Ramp (Charleston, SC). Daphnia were fed three times a week with a laboratory - p repared food consisting of trout food, yeast and alfalfa powder. Daphnia used in the test were offspring of 20-50 gravid females isolated for 24 hours. Study design Test type static Water media type freshwater Limit test

no Total exposure duration 48 h Remarks Post exposure observation period N o. Test conditions Hardness Total hardness = 55 mg/l as CaCO3, 36 mg/l as CaCO3, 6.7, and 250 micromhos/cm (respectively). Test temperature Alkalinity was 36 mg/l as CaCO3
p H 6.7 Dissolved oxygen measured initially and at 48 hours. N ominal and measured concentrations A series of from 5-10 equidistant concentrations based on results of fish studies ( p lus control) were tested. Details on test conditions Tests were conducted in 250 ml beakers containing 100 ml of test solution (in Kanawha River water) and 5 Daphnia (less than 24 hours old). Tests were run in duplicate. Dissolved oxygenand pH were determined initially and at 48 hours for all test solutions. Mortalities were recorded at 24 and 48 hours. Any other information on materials and methods incl. tables
Water conductivity = 250 micromhos/cm.

Results and discussions Effect concentrations Duration 48 h Endpoint Effect conc. > 10 mg/L N ominal/Measured nominal Conc. based on test mat. Basis for effect mortality Remarks (e.g. 95% CL) Details on results The LC50 value was higher than the highest concentration used (10000 mg/l). Remarks on results including tables and figures
Toxicity of triethylene glycol monoethyl ether (TGEE, CAS No. 112-50-5) and of triethylene glycol monobutyl ether (TGBE, CAS No. 143-22-6) were also tested in this study. The LC50 values for TGEE and TGBE were >10000 and 2210 mg/l, respectively.
6.1.5 Toxicity to aquatic algae and cyanobacteria Toxicity to aquatic algae and cyanobacteria BASF TGME 1989.001 UUID IUC5-68513ab3-7121-4c6a-a2af-d2367f3ccaac Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-24 17:15:12 EDT Remarks

Administrative Data Purpose flag supporting study ( ) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1989

Reliablility 2 (reliable with restrictions) Rationale for reliability Original reference was not available. Information (including the reliability code) came from a previous IUCLID data set produced by the European Chemicals Bureau Data source Reference Reference type company dataAuthor Year 1989 Title Algentest for Methyltriglykol Bibliographic

source Testing laboratory Report no. 2/1017/88/t72

Owner company BASF AG Company study no. Report date 1990-03-09

Materials and methods Principles of method if other than guideline Typical acute aquatic toxicity procedure for algae. GLP compliance no data Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 112-35-6

Identifier EC number Identity 203-962-1

Identifier Common name

Identity Triethylene Glycol Methyl Ether Details on test material no data Analytical monitoring

no Details on analytical methods no data Vehicle no data Details on test solutions no data Test organisms Test organisms (species) Scenedesmus subspicatus (new name: Desmodesmus subspicatus) Details on test organisms no data Study design Test type no data Water media type no data Total exposure duration72 h Remarks Post exposure observation period no data Test conditions Hardness no data Test temperature no data
p H no data Dissolved oxygen no datano data N ominal and measured concentrations no data Details on test conditions no data Reference substance ( p ositive control) no data Results and discussions Effect concentrations Duration 72 h Endpoint EC20 Effect conc. > 500 mg/L N ominal/Measured no data Conc. based on no data Basis for effect biomass Remarks (e.g. 95% CL)

Duration 72 h Endpoint EC50 Effect conc. > 500 mg/L N ominal/Measured no data Conc. based on no data Basis for effect biomass Remarks (e.g. 95% CL)

Duration 72 h Endpoint EC90 Effect conc. > 500 mg/L N ominal/Measured no data Conc. based on no data Basis for effect biomass Remarks (e.g. 95% CL) 7 Toxicological information 7.1 Toxicokinetics, metabolism and distribution7.1.2 Dermal absorption Dermal absorption Ward and Scott TGME 1986.001 UUID IUC5-b63ce3c6-e7de-436e-be91-b6efaf9ae279 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-24 17:15:31 EDT Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 86 Reliablility 1 (reliable without restriction) Rationale for reliability Well conducted study with test material composition provided.

Data source Reference Reference type study report

Author Ward RJ, Scott RC Year 1986 Title Triethylene glycol ethers: Absorption through human epidermis in vitro. Bibliographic

source Testing laboratory Report

no. CTL/P/160 0 Owner company Imperial Chemical Industries

Company study no. Report date 1986-10-31

Materials and methods Type of method in vitro Principles of method if other than guideline standard in vitro skin absorption rate study. GLP compliance no data Test materials Radiolabelling no data Test material equivalent to submission substance identity

no Test material identityIdentifier Common name Identity triethylene glycol monomethyl ether

Identifier other: trade name

Identity POLYSOLV-TM

Identifier EC number Identity 203-962-1

Identifier CAS number Identity 112-35-6 Details on test material Purity of test material (POLYSOLV-TM, triethylene glycol monomethyl ether (TGME)) was 99.98%. Test animals Species human Strain no data Sex no data Administration / exposure Vehicle unchanged (no vehicle) Duration of exposure 12 hours Control animals

no Details on in vitro test system (if applicable) Human abdominal whole skin (2.54 cmE2) was mounted in a glass diffusion apparatus (at 30 +/- 1 degree C) and the diffusion of triethylene glycol monomethyl ether was monitored during a 12-hr period using gas chromatography (n = 6). The integrity of the epidermal membranes was first assessed by measuring permeability of membranes to tritiated water. Epidermal membranes displaying permeability constants greater than 1.5 x 10E-3 cm/hr were deemed to have been damaged during preparation and were rejected. Results and discussions Remarks on results including tables and figures

The mean steady rate of absorption for triethylene glycol monomethyl ether was 34.0 micrograms/cm2hr (SD +/- 7.73), which was close to 100-fold less than EGME. Test material caused a small change in permeability of the membrane (average damage ratio of 3.36).

Overall remarks, attachments Overall remarks

Absorption of ethylene glycol monomethyl ether (EGME), triethylene glycol monoethyl ether (TGEE), and triethylene glycol monobutyl ether (TGBE) also were tested in this study. The rate of absorption of EGME was 220 micrograms/cm2/hr. The rate of absorption of TGEE was 24.1 micrograms/cm2/hr andthe mean damage ratio was 1.37 (no increase in permeability). The rate of absorption of TGBE was 22.2 micrograms/cm2/hr and the mean damage ratio was 1.26 (no increase in permeability).
7.2 Acute Toxicity 7.2.1 Acute toxicity: oral Acute toxicity: oral Moreno Rat TGEE 1977 for Olin.001 UUID IUC5-d8f0fbad-d5cf-4f3b-a2f7-ef22460e45be Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-02-18 15:26:37 EST Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1977

Reliablility 2 (reliable with restrictions) Rationale for reliability Older study with somewhat limited detail, including purity not specified for test material. Otherwise well conducted standard test. Data source Reference Reference type study report Author Moreno OM. Year 1977 Title Report on oral LD50 in rats Bibliographic

source EPA/OTS File 0206799.

Testing laboratory MB Research Laboratories, Inc. Report no. MB 77-1818

Owner company Olin Corporation Company study no. Report date 1977-08-10

Materials and methods Test type standard acute method Limit test

no Principles of method if other than guideline N o guideline specified, but study was conducted according to typical standard procedure. GLP compliance no data Test materials Test material equivalent to submission substance identity

no Test material identityIdentifier CAS number Identity 112-50-5

Identifier EC number Identity 203-978-9

Identifier Common name

Identity triethylene glycol monoethyl ether Details on test material no data Test animals Species
rat Strain Wistar Sex male Details on test animals and environmental conditions Rats (200-300 g) were fasted for approximately 18 hours prior to test material administration. Administration / exposure Route of administration other: intubation Vehicle unchanged (no vehicle) Doses 5.0, 7.12, 10.14, and 14.43 g/kg N o. of animals per sex per dose 10 males per dose. Forty rats total. Control animals no data Details on study design Test material was given by intubation at 5.0, 7.12, 10.14, and 14.43 g/kg to groups of 10 animals. Food and water were freely available after treatment. Rats were observed for toxicity and death for 14 days. Statistics The LD50 value and 95% confidence limits were determined by the method of Horn (Biometrics 12:311, 1956). Results and discussions Effect levels Sex male Endpoint LD50 Effect level 8500 mg/kg bw 95% CL Remarks Mortality One rat given 7.12 g/kg died on day 10. N ine out of 10 rats given 10.14 g/kg died by day 3, andall rats given 14.43 g/kg died within 24 hours. Clinical signs Signs of toxicity were lethargy, ataxia, blood in the urogenital area and piloerection. Body weight no data Acute toxicity: oral Smyth Rat TGEE 1945.002 UUID IUC5-1a9bdaea-f483-4951-9e2d-a2439f223e0d Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-25 09:01:12 EDT Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1 9 4 5 Reliablility 2 (reliable with restrictions) Rationale for reliability Older study predating GLP and guidelines. Purity of TS not given. Otherwise, generally a reliable study. Data source Reference Reference type study report

Author Smyth HF, Jr. Year 1945 Title Special report on single dose and thirty-day dose toxicity of ethoxy triglycol. Bibliographi

c source

Testing laboratory Mellon Institute of Industrial Research, University of Pittsburgh Report

no. 8-63

Owner company Carbide and Carbon Chemicals Corporation

Company study no. Report date 1945-06-2 6

Reference type p ublication

Author Smyth HF and Carpenter CP. Year 1948 Title Further experience with the range-finding test in the industrial toxicology laboratory. Bibliographi J Ind Hyg 30:63-68.c source Testing laboratory Report

no. Owner company Company study no. Report date
Reference type p ublication Author Smyth HF, Carpenter CP, Weil CS. Year 1951 Title Range-finding toxicity data: List IV Bibliographic

source Arch Ind Hyg Occup Med 4:119-122.

Testing laboratory Report no.

Owner company

Company study

no. Report date

Materials and methods Test type standard acute method Limit test

no Principles of method if other than guideline Study predates guideline, but was conducted according to typical accepted procedure. GLP compliance

no Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 112-50-5

Identifier EC number Identity 203-978-9

Identifier Common name Identity triethylene glycol monoethyl ether Details on test material no data Test animals Species
rat Strain other: albinoSex male Details on test animals and environmental conditions Groups of 10 male rats (87-124 g). Forty animals total. Administration / exposure Route of administration oral: gavage Vehicle other: 1% Tergito Doses Dispersion in 1% Tergitol 7 at doses of 7.95, 8.9, 10.0, and 12.6 g/kg (1.4 to 3.0 ml of dispersion containing 0.5 g/ml). N o. of animals per sex per dose Groups of 10 male rats Control animals no data Details on study design Groups of 10 male rats (87-124 g) were given test material by gavage as a dispersion in 1% Tergitol 7 at doses of 7.95, 8.9, 10.0, and 12.6 g/kg (1.4 to 3.0 ml of dispersion containing 0.5 g/ml). Mortality was recorded over 14 days. Body weights were determined at study termination (for survivors). Statistics no data Results and discussions Effect levels Sex male Endpoint LD50 Effect level 10610 mg/kg bw 95% CL Remarks Mortality All rats given 7.95 g/kg lived to day 14. The incidence of mortality in the other groups was 1/10 for the 8.9 g/kg group, 6/10 for the 10.0 g/kg group, and 10.10 for the 12.6 g/kg group. All deaths occurred within 5 days. The LD50 value was calculated as 10.61 g/kg, with a range of 9.98 to 11.28 g/kg. Clinical signs no data Body weight All survivors gained weight. Gross pathology All survivors appeared normal histologically. Acute toxicity: oral Carpenter Rat TGME 1958.007 UUID IUC5-156d1b9a-884e-447c-a59e-3addc6ac070d Dossier UUID 0Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-24 17:15:13 EDT Remarks

Administrative Data Purpose flag supporting study ( ) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 58

Reliablility 2 (reliable with restrictions) Rationale for reliability Older preguideline and pre GLP study. Purity of test material was not noted.

Data source Reference Reference type study report Author Carpenter CP. Year 1958 Title Range finding tests on methoxytriglycol. Bibliographic

source Testing laboratory Mellon Institute of Industrial Research Report no. 21-44

Owner company

Company study

no. Report date 1958-06-12

Materials and methods Test type standard acute method Limit test

no Principles of method if other than guideline Standard acute oral toxicity study procedure. GLP compliance

no Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 112-35-6

Identifier EC number Identity 203-962-1Identifier Common name Identity triethylene glycol monomethyl ether Details on test material no data Test animals Species
rat Strain other: Carworth Farms- N elson Sex male Details on test animals and environmental conditions 5-6 weeks old, 90-120 g Administration / exposure Route of administration other: stomach intubation Vehicle unchanged (no vehicle) Details on oral exposure stomach intubation Doses 4, 8, or 16 ml/kg N o. of animals per sex per dose 5 males per dose Control animals no data Details on study design Male rats (5-6 weeks old, 90-120 g) were dosed with 4, 8, or 16 ml/kg test material by stomach intubation. Rats were observed for 14 days. Surviving rats were weighed on day 14. Autopsies were performed on those that died. Statistics The method of moving average was used to calculate the LD50 value. Results and discussions Effect levels Sex male Endpoint LD50 Effect level 11300 mg/kg bw 95% CL Remarks Mortality All rats dosed with 16 ml/kg died within 1 day. N one of the other animals died. Clinical signs no data Body weight All animals except 1 dosed with 4 ml/kg gained weight.Gross pathology Autopsies on rats that died revealed congested lungs, mottled livers and kidneys, GI tractirritation, and congested adrenals. Acute toxicity: oral MB Res rat TGME 1977 Olin Corp.001 UUID IUC5-c49e3814-a93f-403b-a2a9-4f769ed55c19 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-24 17:15:14 EDT Remarks

Administrative Data Purpose flag weight of evidence ( ) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 77

Reliablility 4 (not assignable) Rationale for reliability Too little detail in study to assign a reliability rating

Data source Reference Reference type study report

Author Year 1977 Title MB Research Laboratories, Inc. 1977. Unpublished report toOlin Corp. Bibliographic

source Testing laboratory MB Research Laboratories, Inc Report

no. Owner company Olin Corp.

Company study no. Report date Materials and methods Test type standard acute method Limit test

no Principles of method if other than guideline The LD50 and 95% confidence limits were calcuated by themethod of Litchfield and Wilcoxon (J Pharm Exp Ther 96:99,1949). GLP compliance no dataTest materials Test material equivalent to submission substance identity

no Test material identity Identifier Common name Identity Triethylene Glycol Methyl Ether

Identifier CAS number Identity 112-35-6

Identifier EC number Identity 203-962-1 Details on test material no data Test animals Species
rat Strain Wistar Sex no data Details on test animals and environmental conditions no data Administration / exposure Route of administration other: no data Vehicle no data Details on oral exposure no data Doses no data N o. of animals per sex per dose no data Control animals no data Details on study design no data Statistics no data Results and discussions Effect levels Sex no data Endpoint LD50 Effect level 12600 mg/kg bw 95% CLRemarks Mortality The LD50 ranged from 10.4 to 15.3 g/kg, and the average was 12.6 g/kg Acute toxicity: oral Gardner Rat Brake Fluid 1992.008 UUID IUC5-0ae2ba4e-0639-4e36-84cb-3d5bf224dfe4 Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-06-06 16:52:33 EDT Remarks

Administrative Data Purpose flag supporting study ( ) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1 9 9 2

Reliablility 2 (reliable with restrictions) Rationale for reliability Test substance composition was well characterized, and study followed GLP. Few study details provided however. Data source Reference Reference type study report

Author Gardner JR. Year 1992 Title Brake fluid DOT 4: Acute oral and dermal toxicity in rat, skin and eye irritancy in rabbit. Bibliograph ic source Testing laboratory Shell Research Limited, Sittingbourne Research Centre Report

no. Owner company Shell

Company study no. DocumentNumber SBGR.92.011 Report date 1992-06-3 0 Materials and methods Test type standard acute method Principles of method if other than guideline standard acute oral toxicity procedure. GLP compliance
yes Test materialsTest material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 106008-94-0

Identifier Common name Identity Brake fluid DOT 4 Details on test material Test material is a mixture containing 30-50% triethyleneglycol monomethyl ether borate ester (CAS No. 106008-94-0),3-30% triethylene glycol monobutyl ether borate ester, 20-30% triethylene glycol monomethyl ether (CAS No. 112-35-6), 2-10% triethylene glycol monobutyl ether (CAS No. 143-22-6), 20-30% tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 2-10% tetraethylene glycol monobutyl ether (CAS No. 1559-34-8), and < 1% minor additives Test animals Species
rat Strain Fischer 344 Sex male/female Details on test animals and environmental conditions no details Administration / exposure Route of administration oral: unspecified Vehicle unchanged (no vehicle) Details on oral exposure no data Doses 5000 mg/kg bw N o. of animals per sex per dose 10 Control animals

no Details on study design no data Statistics no data Results and discussions Effect levels Sex male/female Endpoint LD50 Effect level > 5000 mg/kg bw95% CL Remarks Acute toxicity: oral Reid Rat MPEG.003 UUID IUC5-67b8fbe2-1714-4726-8c41-af0a49a6e5da Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-25 13:17:00 EDT Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 88

Reliablility 1 (reliable without restriction) Rationale for reliability Well conducted, robust study following recognized procedure.

Data source Reference Reference type study report

Author Reid ME. Year 1988 Title Carbowax MPEG 350 N M W . Acute toxicity and primary irritancy studies. Bibliographi

c source

Testing laboratory Bushy Run Research Center Project Report 51-41 Report

no. Project Report 51-41 Owner company Union Carbide

Company study no. Report date 1988-05-23

Materials and methods Test type standard acute method Limit test

no Principles of method if other than guideline N o guideline mentioned. Study was conducted using typical standard protocol for acute oral
test. GLP compliance no data Test materialsTest material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 9004-74-4

Identifier Common name Identity CARBOWAX MPEG-350 Details on test material Test material (CARBOWAX MPEG-350; CAS No. 9004-74-4) is a mixture of several methylated glycol ethers of differing molecular weight (ranging from diethylene glycol monomethyl ether (C2) to heptadecaethylene glycol monomethyl ether (C17)). The majority of the material is in the C5-C11 range (87.445%). It contains 4.347 % (by weight) tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 1.303% triethylene glycol monomethyl ether (CAS No. 112-35-6), 0.181% diethylene glycol monomethyl ether (CAS No. 111-77-3). Test animals Species
rat Strain Sprague-Dawley Sex male/female Details on test animals and environmental conditions Rats were fasted overnight before dosing. Male and female rats weighed approximately 250 and 200 g at study initiation. Administration / exposure Route of administration other: stomach intubation Vehicle unchanged (no vehicle) Details on oral exposure Rats (5/sex/dose) received 8.0 or 16.0 ml/kg test material by stomach intubation. Two male rats were also dosed with 4.0 ml/kg. A total of 22 animals were used in the study. Doses 8.0 or 16.0 ml/kg N o. of animals per sex per dose 5/sex/dose Control animals no data Details on study design Rats (5/sex/dose) received 8.0 or 16.0 ml/kg test material by stomach intubation. Two male rats were also dosed with 4.0 ml/kg. Doses were varied by adjusting the volume of test material or its dilution. Rats were fasted overnight before dosing. Male and female rats weighed approximately 250 and 200 g at study initiation. Animals were weighed before dosing and at days 7 and 14 after dosing. At death or sacrifice, each animal was subjected to gross pathologic evaluation.Statistics no data Results and discussions Effect levels Sex male/female Endpoint LD50 Effect level > 16 mg/kg bw 95% CL Remarks Mortality N one of the animals treated with any dose of test material died. Clinical signs no data Body weight Animals were weighed before dosing and at days 7 and 14 after dosing. N one of the animals treated with any dose of test material died. Gross pathology At death or sacrifice, each animal was subjected to gross pathologic evaluation. Acute toxicity: oral Carpenter Rat MPEG 1947.004 UUID IUC5-f008b67b-4968-4421-9745-3ec11622bd61 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-25 13:17:01 EDT Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 47

Reliablility 2 (reliable with restrictions) Rationale for reliability Old study, conducted preguidelines and pre GLP

Data source Reference Reference type study report

Author Carpenter CP Year 1947 Title Range finding tests on methoxy polyethylene glycols of approximate molecular weights 350, 550 and 750. Bibliograp hic source Melon Institute of Industrial Research, University of Pittsburgh.Testing laboratory Report

no. Owner company Company study no. Report date 1947-05- 13 Materials and methods Test type standard acute method Limit test

no Principles of method if other than guideline Standard acute method conducted pre-guideline. GLP compliance

no Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 9004-74-4

Identifier Common name

Identity MPEG-350 Details on test material Methoxy polyethylene glycol of approximately 350 molecular weight. Test animals Species
rat Strain other: common albino Sex male Administration / exposure Route of administration other: stomach tube Vehicle unchanged (no vehicle) Details on oral exposure no details Doses 10 ml/kg and 50 ml/kg N o. of animals per sex per dose Six male animals per dose. Twelve animals were used in the study. Control animals no dataDetails on study design Groups of 6 rats (91-106 g) were dosed with 10 ml/kg (approximately 1 ml) or 50 ml/kg (approximately 4.7-5.3 ml) undiluted test material by stomach tube. Body weight gain and deaths were observed over a period of 14 days. Statistics no data Results and discussions Effect levels Sex male Endpoint LD50 Effect level 22 mL/kg bw 95% CL Remarks Method of estimation not given. Mortality All animals dosed with 50 ml/kg died within 1 day. N one of the rats dosed with 10 ml/kg died. The LD50 was estimated to be 22 ml/kg (method of extrapolation not given). Clinical signs no data Body weight Animals dosed with 10 ml/kg gained from 23 to 68 grams over 14 days. Gross pathology no data 7.2.2 Acute toxicity: inhalation Acute toxicity: inhalation Moreno Rat TGEE 1977 for Olin.001 UUID IUC5-ca8bbd02-91ef-4259-a6fa-90fe7d2f6461 Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-02-18 16:54:07 EST Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1 9 7 7 Reliablility 2 (reliable with restrictions) Rationale for reliability Older study, GLP or guideline not specified. TS purity not given. In general a good study run by typical procedure. Data source Reference Reference type study report Author Moreno OM. Year 1977Title Report on inhalation toxicity in rats Bibliographic

source EPA/OTS File 0206799.

Testing laboratory MB Research Laboratories, Inc. Report no. MB 77-1818

Owner company Olin Corporation

Company study

no. Report date 1977-08-01

Materials and methods Test type fixed concentration procedure GLP compliance no data Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 112-50-5

Identifier EC number Identity 203-978-9

Identifier Common name Identity triethylene glycol monoethyl ether Details on test material no data Test animals Species
rat Strain Wistar Sex no data Details on test animals and environmental conditions 200-250 g, sex not stated Administration / exposure Type of inhalation exposure no data Vehicle unchanged (no vehicle) Details on inhalation exposure
p robably whole body, since no statement to the contrary. Analytical verification of test atmosphere concentrations no data Duration of exposure1 h Remarks Concentrations A nominal concentration of 200 mg/liter N o. of animals per sex per dose 10 animals, one dose, sex not noted Control animals

no Details on study design Ten rats (200-250 g, sex not stated) were placed in a 50 liter chamber and exposed to a nominal concentration of 200 mg/liter of test material for one hour. The rats were observed daily over 14 days for signs of toxicity. Bodyweights were recorded prior to and 14 days after treatment. Statistics no data Results and discussions Effect levels Sex no data Endpoint LC0 Effect level > 200 mg/L air 95% CL Exp. duration Remarks Mortality All animals survived the exposure. Clinical signs There were no signs of toxicity. Body weight Rats gained weight over the 14 day period. Gross pathology no data Acute toxicity: inhalation Smyth TGME Rat 1962.002 UUID IUC5-4361a360-20fe-4360-a5c5-a2b0fdab8536 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-24 17:15:15 EDT Remarks

Administrative Data Purpose flag supporting study ( ) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 62

Reliablility 2 (reliable with restrictions)Rationale for reliability Purity of test material was not noted. Also older study predating guidelines or GLP. Data source Reference Reference type study report Author Year 1958 Title Range finding tests on methoxytriglycol. Bibliographic

source Testing laboratory Mellon Institute of Industrial Research Report no. 21-44

Owner company Company study

no. Report date 1958-06-12

Reference type p ublication Author Smyth HF, Carpenter CP, Weil CS, Pozzani U, Striegel JA Year 1962

Title Range-finding toxicity data: List VI Bibliographic

source Am Ind Hyg Assoc J 23:95-107.

Testing laboratory Report no.

Owner company Company study

no. Report date

Materials and methods Test type standard acute method Principles of method if other than guideline standard prodecure of the time for acute inhalation toxicology GLP compliance

no Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 112-35-6

Identifier EC number Identity 203-962-1

Identifier Common name Identity triethylene glycol monomethyl etherDetails on test material no data Test animals Species
rat Strain other: Carworth-Wistar Sex female Administration / exposure Route of administration inhalation: vapour Type of inhalation exposure no data Vehicle unchanged (no vehicle) Details on inhalation exposure Six female rats were exposed to a flowing stream of vapor-ladened air generated by passing 2.5 l/min of dried air at room temperature through a fritted disc immersed to a depth of at least once inch in approximately 50 ml of test material contained in a gas-washing bottle. Rats were exposed from time periods ranging from 15 minutes to 8 hours (until the inhalation period killing about one half of the rats within 14 days was defined). The result is the longest inhalation period which permitted all rats to survive the14-day observation period. Analytical verification of test atmosphere concentrations no data Duration of exposure 8 h Remarks Concentrations not measured but probably saturated N o. of animals per sex per dose six females Control animals no data Results and discussions Mortality All animals survived an 8-hr exposure period to concentrated vapor and had normal weight gains. Clinical signs no data Body weight All animals had normal weight gains. Gross pathology no data Other findings no data7.2.3 Acute toxicity: dermal Acute toxicity: dermal Smyth et al. Rabbit TGEE 1951.001 UUID IUC5-f45a9e98-de1a-42de-8738-bcbedf3d5db2 Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-02-18 16:37:17 EST Remarks

Administrative Data Purpose flag weight of evidence ( ) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 51

Reliablility 4 (not assignable) Rationale for reliability Details on how value was obtained were not given. N o data on test material p urity. Data source Reference Reference type p ublication Author Smyth HF, Carpenter CP, Weil CS. Year 1951 Title Range-finding toxicity data: List IV. Bibliographic

source Arch Ind Hyg Occup Med 4:119-122.

Testing laboratory Report no.

Owner company

Company study

no. Report date

Materials and methods Test type standard acute method Principles of method if other than guideline Predates guidelines or GLP. Standard acute method of the period GLP compliance

no Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 112-50-5

Identifier EC numberIdentity 203-978-9

Identifier Common name Identity triethylene glycol monoethyl ether Details on test material no data Test animals Species rabbit Strain no data Sex no data Administration / exposure Type of coverage no data Vehicle no data Details on dermal exposure no data Duration of exposure no data Doses no data N o. of animals per sex per dose no data Control animals no data Details on study design no data Statistics no data Results and discussions Effect levels Sex no data Endpoint LD50 Effect level 8200 mg/kg bw 95% CL Remarks Acute toxicity: dermal Moreno Rabbit TGEE 1976.002 UUID IUC5-faac3656-f262-409a-ae24-573babd140e9 Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-02-18 17:10:49 EST RemarksAdministrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 76

Reliablility 2 (reliable with restrictions) Rationale for reliability Test substance purity not given. Guideline or GLP not specified.

Data source Reference Reference type study report

Author Moreno OM. Year 1976 Title Report on acute dermal toxicity in rabbits. Bibliographic

source EPA/OTS Document File 0206799.

Testing laboratory MB Research Laboratories, Inc. Report no. Project Number MB 77-1818 Owner company Olin Corporation.

Company study no. Report date 1977-08-02

Materials and methods Test type standard acute method Limit test
yes Principles of method if other than guideline standard acute method, no guideline specified GLP compliance no data Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 112-50-5

Identifier EC number Identity 203-978-9

Identifier Common name Identity triethylene glycol monoethyl etherDetails on test material no data Test animals Species rabbit Strain N ew Zealand White Sex no data Details on test animals and environmental conditions 1.9 to 3.2 kg Administration / exposure Type of coverage occlusive Vehicle unchanged (no vehicle) Details on dermal exposure The rabbits were clipped free of abdominal hair. Epidermal abrasions were made longitudinally every 2 to 3 cm over the clipped area of 5 rabbits. The abrasions were deep enough to penetrate the stratum corneum, but not deep enough to produce bleeding. A single dose of 2.0 g/kg was applied to the exposed area. The area was covered with gauze and the trunk wrapped with impervious material for 24 hours. Duration of exposure 24 hours Doses 2.0 g/kg N o. of animals per sex per dose ten rabbits, sex not specified, one dose level. Epidermal abrasions were made longitudinally every 2 to 3 cm over the clipped area of 5 of the rabbits. Control animals

no Details on study design Ten rabbits (1.9 to 3.2 kg) were clipped free of abdominal hair. Epidermal abrasions were made longitudinally every 2 to 3 cm over the clipped area of 5 rabbits. The abrasions were deep enough to penetrate the stratum corneum, but not deep enough to produce bleeding. A single dose of 2.0 g/kg was applied to the exposed area. The area was covered with gauze and the trunk wrapped with impervious material for 24 hours. The dressing was removed, rabbits were cleaned, and animals were evaluated over 14 days. Statistics no data Results and discussions Effect levels Sex no data Endpoint LD0 Effect level 2000 mg/kg bw95% CL Remarks Mortality There were no deaths. Clinical signs N o signs of systemic toxicity. Body weight no data Gross pathology no data Acute toxicity: dermal Rabbit TGME Mellon 1958.001 UUID IUC5-4428421a-0f92-4dfe-8314-99c1aef4d436 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-24 17:15:32 EDT Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1 9 5 8 Reliablility 2 (reliable with restrictions) Rationale for reliability Adequate older study, but guideine and GLP not specified and test material p urity not specified. Data source Reference Reference type study report Author Year 1958 Title Range finding tests on methoxytriglycol Bibliographic

source Testing laboratory Mellon Institute of Industrial Research. Report no. 21-44,

Owner company Company study

no. Report date 1958-06-12

Materials and methods Test type standard acute method Principles of method if other than guidelinestandard acute method GLP compliance no data Test materials Test material equivalent to submission substance identity

no Test material identity Identifier Common name Identity Triethylene Glycol Methyl Ether

Identifier CAS number Identity 112-35-6

Identifier EC number Identity 203-962-1 Test animals Species rabbit Strain N ew Zealand White Sex male Details on test animals and environmental conditions Male rabbits (3-5 months old, avg. weight 2.5 kg). Eight animals total. Administration / exposure Type of coverage occlusive Vehicle unchanged (no vehicle) Details on dermal exposure Male rabbits (3-5 months old, avg. weight 2.5 kg) weretreated dermally on clipped trunk skin with 2.5 ml/kg ( N =2),5 ml/kg ( N =4), or 10 ml/kg ( N =2) test material. VINYLITE sheeting used to keep the material in contact with the skin. Rabbits were immobilized for 24 hours. After 24 hours, the sheeting was removed. The rabbits were observed for a totalof 14 days. The moving average method was used to calculatethe LD50 value. Duration of exposure 24 hours Doses 2.5 ml/kg ( N =2),5 ml/kg ( N =4), or 10 ml/kg ( N =2), where N=number of animals per dose. N o. of animals per sex per dose See "doses" above for information. Control animals no data Details on study design no further details Results and discussionsEffect levels Sex male Endpoint LD50 Effect level 7.13 mL/kg bw 95% CL Remarks Mortality The two rabbits treated with 10 ml/kg died within 4 days. Clinical signs Marked erythema of skin was noted after removal of thedressing (doses and number affected not noted). One of the rabbits reated with 10 ml/kg had internal hemorrhage asevidence by bloody exudate in the peritoneal cavity atautopsy. All other rabbits survived and appeared normal. Body weight no data Gross pathology no data Acute toxicity: dermal Gardner BF DOT 4 1992.004 UUID IUC5-e2d25c04-5a3a-4961-aea4-136f0b27eca6 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-24 17:24:52 EDT Remarks

Administrative Data Purpose flag supporting study ( ) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 92

Reliablility 2 (reliable with restrictions) Rationale for reliability few study details given

Data source Reference Reference type study report

Author Gardner JR. Year 1992 Title Brake fluid DOT 4: Acute oral and dermal toxicity in rat, skin and eye irritancy in rabbit Bibliographi

c source Testing Shell Research Limited, Sittingbourne Research Centre Reportlaboratory no. Owner company Shell

Company study no. DocumentNumber SBGR.92.011 Report date 1992-06-3 0 Materials and methods GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 106008-94-0

Identifier Common name Identity Brake fluid DOT 4 Details on test material Test material is a mixture containing 30-50% triethylene glycol monomethyl ether borate ester (CAS No. 106008-94-0), 3-30% triethylene glycol monobutyl ether borate ester, 20-30% triethylene glycol monomethyl ether (CAS No. 112-35-6), 2-10% triethylene glycol monobutyl ether (CAS No. 143-22-6), 20-30% tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 2-10% tetraethylene glycol monobutyl ether (CAS No. 1559-34-8), and < 1% minor additives Test animals Species
rat Strain Fischer 344 Sex male/female Administration / exposure Type of coverage no data Vehicle unchanged (no vehicle) Details on dermal exposure no data Duration of exposure no data Doses 2000 mg/kg bw N o. of animals per sex per dose 5 p er sex per dose Control animals no dataDetails on study design no data Statistics no data Results and discussions Effect levels Sex male/female Endpoint LD50 Effect level > 2000 mg/kg bw 95% CL Remarks Acute toxicity: dermal Reid MPEG Rabbit 1988.003 UUID IUC5-babe08a6-9fc1-478e-8fb1-fa7c0b961d11 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-25 13:17:02 EDT Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1 9 8 8 Reliablility 1 (reliable without restriction) Rationale for reliability well conducted study with good documentation. Test material is well characterized as to composition. Data source Reference Reference type study report

Author Reid ME. Year 1988 Title Carbowax MPEG 350 N M W . Acute toxicity and primary irritancy studies. Bibliographi

c source Testing laboratory Bushy Run Research Center Report

no. Project Report 51-41 Owner company Company study no. Union Carbide Report date 1988-05-23

Materials and methodsTest type standard acute method Principles of method if other than guideline standard acute inhalation test method GLP compliance no data Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 9004-74-4

Identifier Common name Identity CARBOWAX MPEG-350 Details on test material Test material (CARBOWAX MPEG-350)(CAS No. 9004-74-4) is a mixture of several methylated glycol ethers of differing molecular weight (ranging from diethylene glycol monomethyl ether (C2) to heptadecaethylene glycol monomethyl ether (C17)). The majority of the material is in the C5-C11 range (87.445%). It contains 4.347 % (by weight) tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 1.303% triethylene glycol monomethyl ether (CAS No. 112-35-6), 0.181% diethylene glycol monomethyl ether (CAS No. 111-77-3). Test animals Species rabbit Strain N ew Zealand White Sex male/female Details on test animals and environmental conditions Ten animals total were used in the study. Five rabbits of each sex (weighing between 2 and 3 kg). Administration / exposure Type of coverage occlusive Vehicle unchanged (no vehicle) Details on dermal exposure Five rabbits of each sex (weighing between 2 and 3 kg) were subjected to 24 hours of contact with the test material (16 ml/kg) , which was retained under impervious sheeting on the clipped, intact skin of the trunk. If necessary, gauze was wrapped around the trunk over the sample to p revent leakage. Bandaging tape was wrapped over the impervious sheeting. Excess fluid was removed after the contact period to diminish ingestion. Duration of exposure 24 hours of skin contact. Doses16 ml/kg, single dose level N o. of animals per sex per dose five per sex per dose Control animals

no Details on study design Body weights were determined before and 7 and 14 days following test material application. Deaths were monitored for 14 days. Statistics no data Results and discussions Preliminary study (if fixed dose study) no preliminary study Effect levels Sex male/female Endpoint LDLo Effect level > 16 mL/kg bw 95% CL Remarks Mortality N o animals died during the course of the study. Clinical signs N o signs of systemic toxicity or irritation were noted. Body weight no data Gross pathology no data 7.2.4 Acute toxicity: other routes Acute toxicity: other routes NAMSA MPEG 1997.001 UUID IUC5-2a6353e6-f244-4575-9bf5-d18c1cb8d2c7 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-25 13:17:11 EDT Remarks

Administrative Data Purpose flag supporting study ( ) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 97

Reliablility 1 (reliable without restriction) Rationale for well conducted, thorough study following GLP. Test substance was wellreliability defined. Data source Reference Reference type study report

Author Pohl DR, et al Year 1997 Title Acute systemic toxicity screen in the rat. Carbowax Sentry MPEG 350, N F grade Bibliograph ic source Testing laboratory Report

no. N AMSA Study N umbe r 97U1635 Owner company Company study no. Report date 1997-08-20

Materials and methods GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity CAS No. 9004-74-4

Identifier Common name

Identity CARBOWAX Sentry MPEG 350 Details on test material Test material was CARBOWAX Sentry MPEG 350 (CAS No. 9004-74-4), N F grade. This a mixture of several methylated glycol ethers of differing molecular weight (ranging from diethylene glycol monomethyl ether (C2) to heptadecaethylene glycol monomethyl ether (C17)). The majority of the material is in the C5-C11 range (87.445%). It contains 4.347 % (by weight) tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 1.303%triethylene glycol monomethyl ether (CAS No. 112-35-6), and 0.181% diethylene glycol monomethyl ether (CAS No. 111-77-3). Test animals Species
rat Strain Sprague-Dawley Sex male Details on test animals and environmental conditions no data Administration / exposure Route of administrationother: i.v. Vehicle unchanged (no vehicle) Details on exposure Two rats/group were injected daily with 0.5, 1.1 and 2.2 g/kg/day for 5 days. Doses 0.5, 1.1 and 2.2 g/kg/day for five days N o. of animals per sex per dose Two male rats/group Control animals no data Details on study design N ecropsies were performed on Day 6. Results and discussions Effect levels Sex no data Endpoint other: toxic dose Effect level > 1100

—<= 2200 mg/kg bw 95% CL Remarks Mortality There were no overt signs of toxicity (either clinical or gross upon necropsy) in rats (191 to 222 g) injected with 0.5g/kg/day or 1.1 g/kg/day for 5 days. Both animals injected with 2.2 g/kg/day for 5 days had labored breathing, ataxia and hypoactivity following each daily dose. N o animals died. Clinical signs There were no overt signs of toxicity (either clinical or gross upon necropsy) Body weight no data Gross pathology N o signs of toxicity upon necropsy. Other findings Both animals injected with 2.2 g/kg/day for 5 days had labored breathing, ataxia and hypoactivity following each daily dose. 7.3 Irritation / corrosion 7.3.1 Skin irritation / corrosion Skin irritation / corrosion Moreno Rabbit TGEE 1977.001 UUID IUC5-5b6e3058-fa4a-4977-b835-f80d3b45df4d Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-02-18 17:09:17 EST Remarks

Administrative DataPurpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 77

Reliablility 2 (reliable with restrictions) Rationale for reliability Purity of TS not provided.

Data source Reference Reference type Author Moreno OM. Year 1977 Title Report on primary dermal irritation in rabbits. Bibliographic

source EPA/OTS File 0206799.

Testing laboratory MB Research Laboratories, Inc. Report no. Project number MB 77-1818 Owner company Olin Corporation

Company study no. Report date 1977-08-08

Materials and methods Type of method in vivo Principles of method if other than guideline N o guideline specified, but test was carried out per typical recgonized procedure. GLP compliance no data Test material equivalent to submission substance identity

no Test materials Test material identity Identifier CAS number Identity 112-50-5

Identifier EC number Identity 203-978-9

Identifier Common name Identity triethylene glycol monoethyl ether Details on test material no data Test animals Species rabbitStrain no data Test system Type of coverage occlusive Preparation of test site abraded Vehicle unchanged (no vehicle) Amount/concentration applied 0.5 ml Duration of treatment / exposure 24 hours Observation period 24 and 72 hours in accordance with the Consumer Product Safety Act, Title 16 CFR 1500.41. N umber of animals Six rabbits Control animals

no Details on study design Six rabbits were clipped over the back and sides with an electric clipper. A site to the left of the spinal column was abraded. Abrasions were minor incisions through the stratum corneum that did not disturb the derma or produce bleeding. Test material (0.5 ml) was applied to a surgical gauze (1" square, 2 layers thick). The patches were placed on test sites and secured with adhesive tape. The trunk was wrapped with impervious material. Patches were removed after 24 hours. Dermal reactions were evaluated at 24 and 72 hours in accordance with the Consumer Product Safety Act, Title 16 CFR 1500.41. Results and discussions Irritation / corrosion results Irritation parameter p rimary dermal irritation index (PDII) Basis mean Time point 24 and 72 hours Score 0.17 Max. score 1 Reversibility Remarks Irritant/corrosive response data An erythema score of 1 (barely perceptible) was observed in 2 rabbits at 24 hours (intact and abraded skin). All others received erythema scores of 0. The mean erythema score was 0.33. N o edema was observed at 24 or 72 hours. The mean primary irritation score was 0.17. Applicant's summary and conclusion Interpretation of results not irritating Skin irritation / corrosion Smyth TGME 1962.007 UUID IUC5-c4be5879-bee8-41ba-ab31-eaaf8f96b405Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-24 17:15:15 EDT Remarks

Administrative Data Purpose flag supporting study ( ) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1 9 6 2

Reliablility 2 (reliable with restrictions) Rationale for reliability Some study details of test method animals and TS purity are lacking, but otherwise the study was well conducted. Data source Reference

Reference type p ublication

Author Smyth HF, Carpenter CP, Weil CS, Pozzani U, Striegel JA. Year 1962

Title . Range-finding toxicity data: List VI. Bibliographic

source Am Ind Hyg Assoc J 23:95-107.

Testing laboratory Report no.

Owner company Company study no. Report date

Reference type study report Author Carpenter CP Year 1958 Title Range finding tests on methoxytriglycol. Bibliographic

source Testing laboratory Mellon Institute of Industrial Research Report no. 21-44

Owner company Company study

no. Report date 1958-06-12

Materials and methodsType of method in vivo Principles of method if other than guideline N o test guideline specified, but study was conducted according to procedure commonly used. GLP compliance no data Test material equivalent to submission substance identity

no Test materials Test material identity Identifier CAS number Identity 112-35-6

Identifier EC number Identity 203-962-1

Identifier Common name Identity triethylene glycol monomethyl ether Details on test material no data Test animals Species rabbit Strain no data Details on test animals and environmental conditions no data Test system Type of coverage
open Preparation of test site shaved Vehicle unchanged (no vehicle) Amount/concentration applied undiluted substance Duration of treatment / exposure 24 hours Observation period 24 hours N umber of animals 5 rabbits Control animals no data Details on study design Undiluted test solution (0.01 ml) was applied to the clipped belly skin of 5 rabbits. Irritation thatoccurred within 24 hours was scored in a graded fashion (from 1 to 10), with Grade 1 = no irritation, Grade 2 = the least visible capillary injection, Grade 6 = necrosis when undiluted. Results and discussions Irritation / corrosion results Irritation parameter overall irritation score Basis Time point 24 hours Score 2 Max. score Reversibility Remarks Applicant's summary and conclusion Interpretation of results slightly irritating Conclusions An irritation Grade of 2 was obtained with undiluted test material, indicating minimal irritation. Skin irritation / corrosion Palazzolo TGME 1969.001 UUID IUC5-336e80e1-75f9-4814-8e1a-a96cc7302b09 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-24 17:15:16 EDT Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 69

Reliablility 2 (reliable with restrictions) Rationale for reliability Good study but predating current guidelines and GLP and not providing test substance purity. Data source Reference Reference type study report

Author Palazzolo RJ. Year 1969 Title Comparative human skin irritation study on five test materials. Industrial Bibliographi

c source

Testing laboratory Bio-Test Laboratories Report

no. IBT F7445

Owner Olin Research Centercompany Company study no. Report date 1969-06-25

Materials and methods Type of method in vivo Test material equivalent to submission substance identity

no Test materials Test material identity Identifier Common name Identity triethylene glycol monomethyl ether

Identifier CAS number Identity 112-35-6

Identifier EC number Identity 203-962-1 Details on test material no data Test animals Species other: human volunteers Strain other: Caucasian Details on test animals and environmental conditions 10/sex, 20-56 years old, 90% Caucasian Test system Type of coverage semiocclusive Preparation of test site other: no special preparation Vehicle unchanged (no vehicle) Amount/concentration applied 0.03 ml Duration of treatment / exposure 3 days Observation period daily one hour after exposure N umber of animals 10 p er sex Control animals

no Details on study design Twenty human subjects (10/sex, 20-56 years old, 90% Caucasian) were employed in the study.Band-aids (3/8 " x 1-1/2 ") with gauze centers were coated with 0.03 ml of test material just p rior to application. Patches were placed on skin for 24 hours, and then removed. The skin site was examined approximately 1 hour after patch removal. After grading, a second patch was applied to the same site. The procedure was repeated for 3 consecutive days. Erythema and Eschar formation were scored on a basis of 0-4, with 1= barely perceptible erythema, 2= well-defined erythema. 3 = moderate to severe erythema, and 4 = severe erythema to slight eschar formation. Edema was scored on a basis of 0-4, with 1= barely perceptible, 2 = slight(definite raising), 3 = moderate (area raised 1 mm), 4 = severe (raised more than 1 mm and extends beyond area of exposure). The total possible primary irritation score is the sum of the highest erythema and edema scores (8). Results and discussions Irritation / corrosion results Irritation parameter overall irritation score Basis mean Time point 72 hours Score 1.65 Max. score Reversibility Remarks Irritant/corrosive response data By 24 hours, erythema scores of 1 or 2 were present in 10/20, and 3/20 subjects, respectively. At 48 hours, erythema scores of 1 or 2 were present in 11/20 and 9/20 subjects, respectively. At 72 hours, more subjects had scores of 2 (13/20), than 1 (7/20). Edema scores were 0 throughout the test. The average total irritation score by 72 hours was 1.65. Applicant's summary and conclusion Interpretation of results slightly irritating Skin irritation / corrosion MB Res TGME 1977.002 UUID IUC5-bd4beac8-a6ab-4e13-8798-ec437b656154 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-24 17:15:17 EDT Remarks

Administrative Data Purpose flag supporting study ( ) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1977

Reliablility 2 (reliable with restrictions) Rationale for reliability Adequate study, but no guideline or GLP specified, test substance purity not noted, rabbit strain not noted. Irration scores not given. Data sourceReference Reference type study report Author Year 1977 Title MB Research Laboratories, Inc. 1977. Bibliographic

source Testing laboratory MB Research Laboratories, Inc. Report no.

Owner company Company study

no. Olin Corp. Report date

Materials and methods Type of method in vivo Principles of method if other than guideline Standard type of dermal absorption study in vivo GLP compliance no data Test material equivalent to submission substance identity

no Test materials Test material identity Identifier Common name Identity Triethylene Glycol Methyl Ether

Identifier CAS number Identity 112-35-6

Identifier EC number Identity 203-962-1 Test animals Species rabbit Strain no data Test system Type of coverage occlusive Preparation of test site abraded Vehicle unchanged (no vehicle) Amount/concentration applied Test material (2.0 g/kg) was applied to intact and abraded skin and covered for 24 hours. Duration of treatment / exposure 24 hoursObservation period not stated N umber of animals five Control animals

no Details on study design Dermal reactions were evaluated by the Draize technique Results and discussions Irritant/corrosive response data Erythema was obsered in 4/5 rabbits with intact skin and 1/5 rabbits with abraded skin. Edema was observed in 1/5 rabbits with abraded skin and none of the rabbits with intact skin. Skin irritation / corrosion UC MSDS TGME 2000.003 UUID IUC5-097dc352-b1a6-44e9-a2f9-918661d0a948 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-24 17:15:18 EDT Remarks

Administrative Data Purpose flag weight of evidence ( ) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod not p rovid ed Reliablility 4 (not assignable) Rationale for reliability Secondary source (company MSDS)

Data source Reference

Reference type company data Author Year 2000 Title Material Safety Data Sheet for Methoxytriglycol Bibliographic

source Testing laboratory Report no. MSDS #1286.

Owner company Union Carbide Corporation

Company study

no. Report date

Materials and methods Type of methodin vivo GLP compliance no data Test material equivalent to submission substance identity

no Test materials Test material identity Identifier EC number Identity 203-962-1

Identifier CAS number Identity 112-35-6

Identifier Common name

Identity Triethylene Glycol Methyl Ether (TGME) Details on test material no data Test animals Species rabbit Strain no data Details on test animals and environmental conditions no data Test system Type of coverage
open Preparation of test site no data Vehicle unchanged (no vehicle) Amount/concentration applied no data Duration of treatment / exposure 24 hours Observation period no data N umber of animals five Control animals

no Results and discussions Irritant/corrosive response data Minimal erythema in 2/5 rabbits and no irritation in 3/5. Skin irritation / corrosion Gardner BF DOT 4 1992.006 UUID IUC5-b12ca6b1-af6a-4130-94fe-44178f4aecddDossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-24 17:24:52 EDT Remarks

Administrative Data Purpose flag supporting study ( ) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1992

Reliablility 2 (reliable with restrictions) Rationale for reliability Study well conducted following GLP and providing good data on test material p urity. Details provided in the study were somewhat limited as to methodology. Data source Reference Reference type study report

Author Gardner JR. Year 1992 Title Brake fluid DOT 4: Acute oral and dermal toxicity in rat, skin and eye irritancy in rabbit. Bibliograph ic source Testing laboratory Shell Research Limited, Sittingbourne Research Centre Report

no. SBGR.92. 011 Owner company Shell

Company study no. Report date 1992-06-3 0 Materials and methods Principles of method if other than guideline N o guideline specified, but study was conducted according to normally followed procedures for this type of study. GLP compliance
yes Test material equivalent to submission substance identity

no Test materials Test material identity Identifier CAS number Identity 106008-94-0

Identifier Common name Identity Brake fluid DOT 4Details on test material Test material is a mixture containing 30-50% triethylene glycol monomethyl ether borate ester (CAS No. 106008-94-0), 3-30% triethylene glycol monobutyl ether borate ester, 20-30% triethylene glycol monomethyl ether (CAS No. 112-35-6), 2-10% triethylene glycol monobutyl ether (CASNo. 143-22-6), 20-30% tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 2-10% tetraethylene glycol monobutyl ether (CAS No. 1559-34-8), and < 1% minor additives. Test animals Species rabbit Strain no data Details on test animals and environmental conditions no data Test system Type of coverage semiocclusive Preparation of test site no data Vehicle unchanged (no vehicle) Amount/concentration applied applied undiluted Duration of treatment / exposure 4 hours Observation period no data N umber of animals six Control animals no data Details on study design no data Applicant's summary and conclusion Interpretation of results not irritating Conclusions not irritating Skin irritation / corrosion Reid MPEG 1988.004 UUID IUC5-f34f885b-8184-4d8d-996a-e22151307e57 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-25 13:17:03 EDTRemarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 88 Reliablility 1 (reliable without restriction) Rationale for reliability Well conducted study with strong detail documentation

Data source Reference Reference type study report

Author Reid ME. Year 1988 Title Carbowax MPEG 350 N M W . Acute toxicity and primary irritancy studies. Bibliographi

c source Testing laboratory Bushy Run Research Center Report

no. Project Report 51-41 Owner company Union Carbide

Company study no. Report date 1988-05-23

Materials and methods Type of method in vivo Principles of method if other than guideline Standard Draize procedure. GLP compliance no data Test material equivalent to submission substance identity

no Test materials Test material identity Identifier CAS number Identity 9004-74-4

Identifier Common name Identity CARBOWAX MPEG-350 Details on test material Test material (CARBOWAX MPEG-350, CAS No. 9004-74-4) is a mixture of several methylated glycol ethers of differing molecular weight (ranging from diethylene glycol monomethyl ether (C2) to heptadecaethylene glycol monomethyl ether (C17)). The majority of the material is in the C5-C11 range (87.445%). It contains 4.347 % (by weight) tetraethyleneglycol monomethyl ether (CAS No. 23783-42-8), 1.303% triethylene glycol monomethyl ether (CAS No. 112-35-6), 0.181% diethylene glycol monomethyl ether (CAS No. 111-77-3). Test animals Species rabbit Strain no data Details on test animals and environmental conditions no data Test system Type of coverage occlusive Preparation of test site shaved Vehicle unchanged (no vehicle) Amount/concentration applied Test material (0.5 ml) was applied to the clipped, intact skin of six rabbits (3 of each sex). The material was loosely covered with a gauze patch an impervious sheeting. Rabbits were restrained for a 4-hour contact period. Excess material was removed after contact. Duration of treatment / exposure 4-hour contact period N umber of animals three of each sex Control animals

no Details on study design The skin reaction was scored by the method of Draize at one hour, and 1, 2, 3, and 7 days following dosing. Results and discussions Irritation / corrosion results Irritation parameter overall irritation score Basis mean Time point 1 hr, and 1, 2, 3 and 7 days Score ca. 0 Max. score 0 Reversibility Remarks Irritant/corrosive response data Scores of 0 were obtained for both erythema (and eschar formation) and edema. The material was therefore non-irritating. Applicant's summary and conclusion Interpretation of results not irritating 7.3.2 Eye irritationEye irritation Moreno Rabbit TGEE 1976.001 UUID IUC5-9cc80ff2-db99-4739-9719-88de07d19db4 Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-02-18 23:57:05 EST Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 76

Reliablility 2 (reliable with restrictions) Rationale for reliability Well conducted older study. GLP and guideline not specified. TS purity not specified. Data source Reference

Reference type study report Author Moreno OM. Year 1976 Title Report on rabbit eye irritation. Bibliographic

source EPA/OTS File 0206799.

Testing laboratory MB Research Laboratories, Inc. Report no. Project number MB 77-1818

Owner company Olin Corporation

Company study

no. Report date 1977-08-12

Materials and methods Type of method in vivo Principles of method if other than guideline Standard eye irritation study. GLP compliance no data Test material equivalent to submission substance identity

no Test materials Test material identity Identifier CAS number Identity 112-50-5

Identifier EC numberIdentity 203-978-9

Identifier Common name Identity triethylene glycol monoethyl ether Details on test material no data Test animals Species rabbit Strain N ew Zealand White Test system Vehicle unchanged (no vehicle) Amount/concentration applied Test material (0.1 ml) in neat form Duration of treatment / exposure 72 hours after instillation of test material Observation period 1, 2, and 3 days after instillation of the test material N umber of animals Six Control animals other: The contralateral (untreated) eye of each animal served as a control. Details on study design Six New Zealand white rabbits were used in the study. Test material (0.1 ml) was instilled into the conjunctival sac of one eye of each rabbit on Day 0. The contralateral eye served as a control. Ocular reactions were graded in accordance with the Consumer Product Safety Act, Title 16 CFR 1500.42 at 1, 2, and 3 days after instillation of the test material. Results and discussions Overall irritation / corrosion results Irritation parameter cornea score Basis other: all animals Time point all time points 0

—8 Max. score 110 Reversibility not fully reversible within: 72 hours Remarks Irritant/corrosive response data Conjunctival redness, chemosis and/or discharge scores of 1 or 2 were noted at 24 hours in all rabbits. These findings completely resolved in 2 rabbits by 72 hours. Slight redness and discharge was observed in 4 and 2 rats (respectively) at 72 hours. Iris and corneal opacity scores of 0 were observed in all animals at each time point. The total conjunctival score [(redness + chemosis + discharge) x 2] at 24 hours ranged from 2-8 out of a possible 20. The highest overall score was 8 out of a possible 110. Applicant's summary and conclusionInterpretation of results irritating Eye irritation Smyth TGME 1962.006 UUID IUC5-9da90c34-0bb6-42d6-8a27-8fc06b81df81 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-24 17:15:18 EDT Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1958

Reliablility 2 (reliable with restrictions) Rationale for reliability Rabbit strain not given. Details of number of animals exposed to each dose not given. GLP not specified. Purity of test substance not noted. Otherwise thie was a credible study. Data source Reference Reference type p ublication Author Smyth HF, Carpenter CP, Weil CS, Pozzani U, Striegel JA. Year 1962

Title Range-finding toxicity data: List VI. Bibliographic

source Am Ind Hyg Assoc J 23:95-107

Testing laboratory Report no.

Owner company Company study

no. Report date

Reference type study report Author Carpenter CP. Year 1958 Title Range finding tests on methoxytriglycol. Bibliographic

source Testing laboratory Mellon Institute of Industrial Research Report no. 21-44

Owner company Company study

no. Report date 1958-06-12Materials and methods Type of method in vivo Principles of method if other than guideline N o guideline specified, but study was conducted according to typical procedure for eye irritation. GLP compliance no data Test material equivalent to submission substance identity

no Test materials Test material identity Identifier CAS number Identity 112-35-6

Identifier EC number Identity 203-962-1

Identifier Common name Identity triethylene glycol monomethyl ether Details on test material no details. Test animals Species rabbit Strain no data Details on test animals and environmental conditions no data Test system Vehicle unchanged (no vehicle) Amount/concentration applied .5 ml Duration of treatment / exposure no data Observation period no data N umber of animals not specified Control animals no data Details on study design Various volumes and concentrations of test material were applied to rabbit eyes (number of rabbits and time of exposure was not indicated). Eye injury was scored on a 10 p oint scale according to the degree of corneal necrosis that resulted from instillation of the variousconcentrations. Grade 1 = very small area of necrosis from 0.5 ml undiluted material, Grade 5 = severe burn from 0.005 ml undiluted material, Grade 10 = severe burn from 0.5 ml of a 1% solution in water or propylene glycol. Results and discussions Overall irritation / corrosion results Irritation parameter overall irritation score Basis Time point

Max. score 1 Reversibility Remarks Irritant/corrosive response data Five rabbit eyes were not injured by 0.5 ml undiluted test material (grade 1). Applicant's summary and conclusion Interpretation of results slightly irritating Eye irritation Gardner BF DOT 1992.005 UUID IUC5-04899188-a49c-496e-b723-da44c6bc006f Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-24 17:24:53 EDT Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1 9 9 2 Reliablility 1 (reliable without restriction) Rationale for reliability Well conducted study following GLP, with the composition of the test material well characterized. Data source Reference Reference type study report

Author Gardner JR. Year 1992 Title Brake fluid DOT 4: Acute oral and dermal toxicity in rat, skin and eye irritancy in rabbit Bibliograph ic sourceTesting laboratory Shell Research Limited, Sittingbourne Research Centre Report

no. SBGR.92. 011 Owner company Company study no. Report date 1992-06-3 0 Materials and methods Type of method in vivo Principles of method if other than guideline N o guideline specified, but study was conducted according to standard procedure for eye irritation. GLP compliance
yes Test material equivalent to submission substance identity

no Test materials Test material identity Identifier CAS number Identity 106008-94-0

Identifier Common name Identity Brake fluid DOT 4 Details on test material Test material is a mixture containing 30-50% triethylene glycol monomethyl ether borate ester (CAS No. 106008-94-0), 3-30% triethylene glycol monobutyl ether borate ester, (20-30% triethylene glycol monomethyl ether (CAS No. 112-35-6), 2-10% triethylene glycol monobutyl ether (CASNo. 143-22-6), 20-30% tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 2-10% tetraethylene glycol monobutyl ether (CAS No. 1559-34-8), and < 1% minor additives Test animals Species rabbit Strain no data Details on test animals and environmental conditions no data Test system Vehicle unchanged (no vehicle) Amount/concentration applied .1 ml Duration of treatment / exposure 72 hours Observation period 72 hoursN umber of animals six Control animals no data Details on study design no data Results and discussions Irritant/corrosive response data sllightly irritating Applicant's summary and conclusion Interpretation of results slightly irritating Eye irritation Reid MPEG 1988.003 UUID IUC5-35d9d086-c13f-4db2-af80-6a9c2dad0f6a Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-25 13:17:04 EDT Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1 9 8 8

Reliablility 1 (reliable without restriction) Rationale for reliability Study was well conducted with detailed information. Test material was well characterized with regard to composition. Data source Reference Reference type Author Reid ME. 1988 Year 1988 Title MPEG 350 N M W . Acute toxicity and primary irritancy studies. Bibliographic

source Testing laboratory Bushy Run Research Center Report no. 51-41

Owner company Union Carbide

Company Report 1988-05-23study no

. date Materials and methods Principles of method if other than guideline N o guideline specified. GLP compliance no data Test material equivalent to submission substance identity

no Test materials Test material identity Identifier CAS number Identity 9004-74-4

Identifier Common name Identity CARBOWAX MPEG-350 Details on test material Test material (CARBOWAX MPEG-350, CAS No. 9004-74-4) is a mixture of several methylated glycol ethers of differing molecular weight (ranging from diethylene glycol monomethyl ether (C2) to heptadecaethylene glycol monomethyl ether (C17)). The majority of the material is in the C5-C11 range (87.445%). It contains 4.347 % (by weight) tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 1.303% triethylene glycol monomethyl ether (CAS No. 112-35-6), 0.181% diethylene glycol monomethyl ether (CAS No. 111-77-3). Test animals Species rabbit Strain N ew Zealand White Details on test animals and environmental conditions no data Test system Vehicle unchanged (no vehicle) Amount/concentration applied 0.1 ml Duration of treatment / exposure N ot specified whether eye was rinsed at some point after instillation of test material. Observation period 1 and 4 hours, and 1, 2, 3, and 7 days after dosing N umber of animals Six Control animals yes, concurrent no treatment Details on study design Six male New Zealand white rabbits were dosed with 0.1 ml of test material. The test material was instilled into the lower conjunctival sac or placed directly on one eye per animal. The other eye served as a control. The eyes were scored at 1 and 4 hours, and 1, 2, 3, and 7 days afterdosing. Florescein (2%) was added to the eyes before dosing and after 1 day of exposure to assess corneal injury. Results and discussions Irritant/corrosive response data Instillation of test material resulted in no corneal injury or iritis. Minor conjunctival irritation developed in all 6 rabbits. Moderate discharge was seen in several of the eyes. These effects resolved by 24 hours. Applicant's summary and conclusion Interpretation of results slightly irritating 7.5 Repeated dose toxicity 7.5.1 Repeated dose toxicity: oral Repeated dose toxicity Smyth Rat TGEE 1945: oral.001 UUID IUC5-98f184d2-309e-48e5-870a-f882f46018dd Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-25 09:14:27 EDT Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1945

Reliablility 2 (reliable with restrictions) Rationale for reliability Study predates guidelines or GLP. Purity of test substance not given. Otherwise, a very well-conducted study for the time period. Data source Reference Reference type study report

Author Smyth HF, Jr. Year 1945 Title Special report on single dose and thirty-day dose toxicity of ethoxy triglycol. Bibliographi

c source Testing laboratory Mellon Institute of Industrial Research, University of Pittsburgh Report

no. 8-63

Owner company Carbide and Carbon Chemicals Corporation

Company study no. Report date 1945-06-26

Materials and methods Test typesubacute Limit test

no Principles of method if other than guideline Study predates guidelines, but procedure was typical for oral subacute studies using drinking
water GLP compliance

no Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 112-50-5

Identifier EC number Identity 203-978-9

Identifier Common name Identity triethylene glycol monoethyl ether Details on test material no data Test animals Species
rat Strain no data Sex male Details on test animals and environmental conditions no data Administration / exposure Route of administration oral: drinking water Vehicle
water Details on oral exposure Groups of 10 rats (90-120 g) were given doses of test material in the drinking water at concentrations of 0 (control), 0.12, 0.5, 2 and 8% for 30 days. The actual doses received were 0, 180, 750, 3300 and 13290 mg/kg/d. Analytical verification of doses or concentrations no data Details on analytical verification of doses or concentrations no data Duration of treatment / exposure 30 daysFrequency of treatment daily Doses/concentrations 0, 180, 750, 3300 and 13290 mg/kg/d Basis nominal in water N o. of animals per sex per dose 10 male rats per dose Control animals yes, concurrent vehicle Examinations Observations and examinations performed and frequency Water consumption and deaths were monitored daily. Sacrifice and pathology no data Other examinations no data Statistics no data Results and discussions Effect levels

Endpoin
t N OEL

Effect level 750 mg/kg bw/day (nominal)

Sex male Basis for effect level / Remarks Rats exposed to 3300 mg/kg/d exhibited decreased weight gain, high blood urea concentrations (4/10), kidney damage (1/10), liver abnormalities (6/10). Animals exposed to 750 or 180 mg/kg/day appeared normal.

Observations Clinical signs and mortality
yes Body weight and weight gain no data Food consumption and compound intake (if feeding study) no data Food efficiency no data Water consumption and compound intake (if drinking water study)
yes Ophthalmoscopic examination no data Urinalysisno data N eurobehaviour no data Organ weights no data Gross pathology
yes Histopathology: non-neoplastic
yes Histopathology: neoplastic no data Details on results Rats receiving the highest dose consumed only 25% of the amount of water as controls. All of them died within 6 to 24 days of exposure (average 13). N ecropsy of these animals revealed congestion and cloudy swelling of the liver and cloudy swelling and degeneration of epithelium of the convoluted tubules of the kidneys. N one of the other rats died. Rats exposed to 3300 mg/kg/d exhibited decreased weight gain, high blood urea concentrations (4/10), kidney damage (1/10), liver abnormalities (6/10). Animals exposed to 750 or 180 mg/kg/day appeared normal. Repeated dose toxicity: oral Gill and Negley TGME 1990.001 UUID IUC5-8f04c5e5-4cf0-46e4-9582-8ffb211e8bbc Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-24 17:15:20 EDT Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 90 Reliablility 1 (reliable without restriction) Rationale for reliability Guideline study performed following GLP

Data source Reference

Reference type study report

Author Gill MW and Negley JE. Year 1990 Title Triethylene glycol monomethyl ether. N inety day subchronic drinking water inclusion neurotoxicity study in rats. Bibliogra p hic

sourceTesting laboratory Bushy Run Research Center Repor
t no. Project Report 52-607,

Owner company Union Carbide

Company study no. Repor t date 1990-09-21

Reference type p ublication

Author Gill MW, Fowler EH, Gingell R, Lomax LG, Corely RA. Year 1998 Title Subchronic dermal toxicity and oral neurotoxicity of triethylene glycol monomethyl ether in CD rats. Bibliograph ic source Int J Toxicol 17:1-22.

Testing laboratory Report

no. Owner company Company study no. Report date Cross-reference to same study This study is also summarized as a fertility study in Toxicity to reproduction.003 Materials and methods Test type subchronic Limit test

no Test guideline Qualifier equivalent or similar to Guideline EPA OPPTS 870.3100 (90-Day Oral Toxicity in Rodents) Deviations Principles of method if other than guideline EPA. 1989. 40 CFR 799, Fed Reg 54:13470-13477 GLP compliance
yes Test materials Test material equivalent to submission substance identity
yes Test material identity Identifier CAS number Identity 112-35-6

Identifier EC number Identity 203-962-1Identifier Common name Identity triethylene glycol monomethyl ether Details on test material The purity of the material was at least 98.7%. Test animals Species
rat Strain Sprague-Dawley Sex male/female Details on test animals and environmental conditions 8 weeks old Administration / exposure Route of administration oral: drinking water Vehicle unchanged (no vehicle) Details on oral exposure Male and female rats (8 weeks old, 15/sex/group) were treated with triethylene glycol monomethyl ether (TGME) for 91 days via drinking water at target doses of 0, 400, 1200 and 4000 mg/kg/day. Analytical verification of doses or concentrations no data Details on analytical verification of doses or concentrations It is assumed that test material of 98.7% p urity was diluted into the drinking water, such that the animals drinking an historically expected amount of water daily would ingest the target dose. Duration of treatment / exposure 91 days Frequency of treatment daily Doses/concentrations 0, 400, 1200 and 4000 mg/kg/day. Basis nominal in water N o. of animals per sex per dose 15/sex/group Control animals yes, concurrent no treatment Positive control no data Examinations Observations and examinations performed and frequency Rats were observed daily for clinical signs and weekly for body weight and water and food consumption. Ten rats/sex/group were observed periodically for behavior (functional observational battery) and motor activity.Sacrifice and pathology After 91 days of treatment, tissues of 10 animals/sex/group were fixed in situ, and brains were removed. These animals received complete necropsies, and tissues from 6 animals/sex/group were processed for evaluation of the nervous system by light microscopy. The 5 animals/sex/group not sacrificed and perfused in situ were killed by severing the brachial vessels to permitexsanguination. These animals received complete necropsies, and the liver, kidneys, brain, lungs, adrenals, and testes (males) were weighed. Liver and testes were examined by light microscopy. Statistics Data for continuous variables were analyzed with Levene's test for homogeneity of variance, analysis of variance (ANOVA), and by pooled variance t-tests. If Levene's test indicated heterogeneous variances, groups were analyzed with an ANOVA for unequal variances, followed by separate variance t-tests. Fisher's exact 2 x 2 groups comparisonswere used to analyze functional observational battery data. Motor activity counts were log transformed prior to analysis. Motor activity dose-effects, dose-sex interactions, and time-dose interactions were determined using repeated measures ANOVAs with dose and sex as grouping factors and time as a within-subject factor. Comparisons between treated and control groups were made for total test session activity (the sum of the counts across the 90-min test session) using ANOVA. To reduce the increased false positives associated with repeated significance testing, the correction p rocedure described by Mantel (Biometrics 36:381-399, 1980) was used when testing for overall significance. The frequency data for anatomic pathology were analyzed as described by Sokal and Rohlf (Biometry, WHFreeman, 1981). Any other information on materials and methods incl. tables

No post obs. period was conducted.

Results and discussions Effect levels Endpoint N OAEL Effect level 400 mg/kg bw/day (nominal) Sex male Basis for effect level / Remarks Liver weight effects.
Endpoint LOAEL Effect level 1200 mg/kg bw/day (nominal) Sex male Basis for effect level / Remarks Liver weight effects.
Endpoint N OAEL Effect level 1200 mg/kg bw/day (nominal) Sex male Basis for effect level / Remarks Testicular effects.
Endpoint LOAEL Effect level 4000 mg/kg bw/day (nominal) Sex maleBasis for effect level / Remarks Testicular effects. Observations Clinical signs and mortality
yes Body weight and weight gain
yes Food consumption and compound intake (if feeding study)
yes Food efficiency no data Water consumption and compound intake (if drinking water study)
yes Ophthalmoscopic examination no data Haematology no data Clinical chemistry no data Urinalysis no data N eurobehaviour
yes Organ weights
yes Gross pathology
yes Histopathology: non-neoplastic
yes Histopathology: neoplastic no data Details on results The actual doses attained in the study (time weighted average) were 0, 420, 1240 and 4300 mg/kg/day for males and 0, 420, 1290 and 4100 mg/kg/day for females.
One female in the high dose treatment group (approximately 4000 mg/kg/day) died on Day 37. Males and females treated with the highest dose consumed less food and had lower body weights and body weight gains than control animals. Water consumption decreased in high-dose females (by an average of 17%).
Treatment with triethylene glycol monomethyl ether did not result in any clinical signs of toxicity, alterations in the functional observational battery, or gross microscopic lesions in the nervous system. Significant, small decreases in total test session motor activity were observed in the high-dose treatment group at the Day 60 (males only) and Day 90 (females) evaluation p eriods. Study personnel stated that “the decreases in motor activity were not considered to be neurotoxicologically significant based on the small magnitude of the changes, the parallel changes in body weights at the evaluation periods, and the lack of corroborative behavioraleffects from the functional observational battery evaluations or histological changes in central or peripheral nervous system tissues.”
Increased relative liver weight was observed in males treated with 4000 mg/kg/day (5.229 ± 0.3984) and 1200 mg/kg/day (3.951 ± 0.4191) versus control (3.214 ± 0.1519). Absolute liver weights of males treated with 4000 mg/kg/day were significantly greater than controls (25.926 ± 3.1591 versus 18.978 ± 1.4925). Microscopic changes (hepatocellular cytoplasmic vacuolization and/or hypertrophy) were noted in livers of high-dose males (14/15). The severity of these liver lesions was minimal or mild (with the exception of moderate or marked vacuolization for 4 high dose males). Mild cholangiofibrosis was observed around a small number of bile ducts in high-dose males (7/15). This was not considered by study personnel to be physiologically significant due to the limited number of bile ducts affected and the mild nature of the effect (Gill et al., Int J Toxicol. 17:1-22, 1998). Minimal or mild hepatocellular hypertrophy was seen in 10/15 high dose females. Three males treated with 400 mg/kg/day and 4 treated with 1200 mg/kg/day also exhibited minimal-mild hepatocellular cytoplasmic vacuolization and/or cellular hypertrophy (not statistically different from the controls). One control male had mild hepatocellular cytoplasmic vacuolization. N one of the females treated with 400 or 1200 mg/kg/day exhibited these changes. Hepatocellular hypertrophy was considered by study personnel to be a possible adaptive change to accommodate increased demand to metabolize the test substance.
The testes of males in the high dose group exhibited degeneration (12/15) and/or atrophy (5/5) of the seminiferous tubules (spermatocytes or developing spermatids). These effects were concluded to be related to treatment. The severity of the lesions was primarily mild to moderate for degeneration (11/12) and minimal to moderate for atrophy (5/5), indicating that not all tubules were affected and that a limited number of cells was affected within the affected tubules. One male treated with 1200 mg/kg had severe seminiferous tubule atrophy, a complete loss of cell types in the tubules (except for Sertoli cells) and moderate Leydig cell hypertrophy (not significant from control). This was not considered to be related to treatment because of the lack of a plausible explanation for the unusual dose-response relationship (the effect at this dose was more severe than that of a higher dose) and the low incidence of animals affected at this dose level (Gill et al., Int J Toxicol 17:1-22, 1998). N o testicular changes were noted in males treated with 400 mg/kg/day TGME. Remarks on results including tables and figures

Overall remarks, attachments Overall remarks

The route of administration and maximum dose level was specified in a testing consent order (EPA. 1989. 40 CFR 799, Fed Reg 54:13470-13477). The highest dose level was initially set at 5000 mg/kg/day, but was decreased to 4000 mg/kg/day based on results of a 14-day dose range-finding drinking water study that demonstrated signs of debilitationat levels greater than 4000 mg/kg/day (Gill and Hurley, 1990).The authors state that a possible contributing factor in the development of testicular lesions at the high dose was low-level contamination of the test substance with the known testicular toxicant 2-methoxyethanol (EGME). EGME was present in the test substance at a concentration of 0.02  0.04 %, resulting in a EGME dose up to 1.7 mg/kg/day for animals in the high dose group. Given the length of the study, it is possible that EGME contributed to the testicular lesions. A comparison between the doses of EGME and TGME required to produce testicular toxicity indicated that TGME is 350 times less potent than EGME in producing testicular lesions in the rat. The dose of TGME that caused testicular toxicity (4200 mg/kg/day) is 4 times greater than the 1000 mg/kg/day limit dose generally recommended for subchronic studies.

Based on the results of the study, the summary preparer assigned a NOAEL for effects on the liver of 400 mg/kg/day, and a LOAEL of 1200 mg/kg/day (based on increased relative liver weight of males at this dose). The summary preparer-assigned NOAEL and LOAEL for testicular effects are 1200 and 4000 mg/kg/day, respectively. The EPA has determined the NOAEL for testicular effects is between 400 and 1200 mg/kg/day (Anderson, L. Triethylene glycol monomethyl, monoethyl and monobutyl ethers RM1 screening document (draft), Feb. 24, 1995).
Repeated dose toxicity: oral Rat TGME DW Gill and Hurley 14 day 1990.001 UUID IUC5-8d0a00b9-e400-4e19-a21a-aba4486f3a7b Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-24 17:15:20 EDT Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1990

Reliablility 1 (reliable without restriction) Rationale for reliability Well conducted guideline study following GLP and providing test substance p urity. However, since only a 2 week study, it cannot be a key study. Data source Reference

Reference type study report

Author Gill MW, Hurley JM Year 1990 Title Triethylene glycol monomethylether: Fourteen-day drinking water inclusion dose rangefinding study in rats Bibliograp hic source Testing laboratory Bushy Run Research Center Report

no. Project Report 52-606 Ownercompany Company study no. Report date 1990-03-06

Materials and methods Test guideline Qualifier according to Guideline other guideline: OECD Guideline 401 Deviations GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 112-35-6

Identifier Common name Identity Triethylene Glycol Methyl Ether (TGME)

Identifier EC number Identity 203-962-1 Details on test material Purity of test material was 99.23%. Test animals Species
rat Strain Sprague-Dawley Sex male Details on test animals and environmental conditions 8 weeks old Administration / exposure Route of administration oral: drinking water Vehicle unchanged (no vehicle) Details on oral exposure Groups of 10 male rats (8 weeks old) were treated with testmaterial in drinking water for 14 days. Target doses were0, 0.5, 1.0, 2.5 and 5.0 g/kg/day; actual doses were 0,0.75, 1.6, 3.9 and 8.0 g/kg/day. Analytical verification of doses or concentrations no data Details on analytical verification of doses or concentrations no detailsDuration of treatment / exposure 14 days Frequency of treatment daily Doses/concentrations 750, 1600, 3900, 8000 mg/kg/day Basis nominal in water N o. of animals per sex per dose 10 male rats per dose Control animals yes, concurrent no treatment Details on study design

Positive control

none Examinations Observations and examinations performed and frequency Evaluations of toxicity included daily clinical signs, p eriodic water consumption (approximately every two to three days), weekly food consumption and body weights and a functional observational battery and necropsy at study termination. Statistics Homogeneous data were analyzed using Levene's test, analysis of variance, and pooled variance t-tests. If Levene's test indicated heterogeneous variances, groups were compared by anaysis of variance for unequal variance, follwed (if necessary) by separate variance t-tests. Intergroup comparisons for functional observational battery frequency data were performed using Fisher's exact probability testand linear trends across dose levels were evaluated with achi-square test. The fiducial limit of 0.05 was used as the critical level of significance for all tests. Results and discussions Effect levels Endpoint N OAEL Effect level 1600 mg/kg bw/day (nominal) Sex Basis for effect level / Remarks Observations Clinical signs and mortality
yes Body weight and weight gain
yes Food consumption and compound intake (if feeding study)
yes Food efficiency no data Water consumption and compound intake (if drinking water study)
yes Ophthalmoscopic examinationno data Haematology not examined Urinalysis not examined N eurobehaviour
yes Organ weights no data Gross pathology
yes Histopathology: non-neoplastic not examined Histopathology: neoplastic not examined Details on results All animals survived treatment. Treatment with 8 g/kg/dayresulted in decreases in mean water consumption, decreases in food consumption (56 to 64% lower than control), and decreased body weight. Clinical signs and functiona lobservational battery findings in animals treated with 8g/kg/day included cachexia, p iloerection, gait alterations, decreases in mean hind-limb grip strength and mean rearing events (vertical acitivty) compared to controls. There was also a tendency for labored or slow respiration and/or decreased mean rectal temperature. Seven out of 10 rats treated with the high dose had focal and multifocal discoloration in the lungs (compared to 1 or 2 animals inthe other groups). Mean food consumption and body weightgain were also decreased for the 3.9 g/kg/day group. The No effect level was 1.6 g/kg/day. Repeated dose toxicity: oral Cosse and Atkin (DOW) TGME Rat 2-Week 1989.002 UUID IUC5-08a3f55d-a5d4-417c-9d34-d72e0a81206c Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-24 17:15:21 EDT Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1 9 8 9

Reliablility 2 (reliable with restrictions) Rationale for reliability Two week study with guideine not specified. Test material purity not provided. Otherwise good study following GLP.Data source Reference

Reference type study report

Author Cosse PF, Atkin L. Year 1989 Title Triethylene glycol monomethylether: Two-week dietary and drinking water p alatabilitystudy in Sprague-Dawley rats. Bibliograp hic source Testing laboratory Report

no. Owner company Dow Chemical Company

Company study no. Laboratory Project Study ID K-005610-003. Report date Materials and methods Test type subacute Principles of method if other than guideline typical two week drinking water study procedure. Palatability study GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier EC number Identity 203-962-1

Identifier CAS number Identity 112-35-6

Identifier Common name Identity Triethylene Glycol Methyl Ether Details on test material no data Test animals Species
rat Strain Sprague-Dawley Sex male/female Details on test animals and environmental conditions no data Administration / exposureRoute of administration oral: drinking water Vehicle unchanged (no vehicle) Details on oral exposure no data Analytical verification of doses or concentrations no data Duration of treatment / exposure Two weeks Frequency of treatment daily Doses/concentrations 5000 mg/kg bw/day Basis other: nominal in drinking water and diet N o. of animals per sex per dose no data Control animals
yes Details on study design Male and remale rats were fed diets or drinking water formulated to provide 0 (control) or 5000 mg test material/kg/day for two weeks. Paramters measured included in-life clinical observations, body weight, and feed and/or water consumption. Positive control

none Examinations Observations and examinations performed and frequency Paramters measured included in-life clinical observations, body weight, and feed and/or water consumption. Sacrifice and pathology no data Other examinations no data Statistics no data Results and discussions Observations Clinical signs and mortality
yes Body weight and weight gain
yes Food consumption and compound intake (if feeding study)
yes Food efficiency no dataWater consumption and compound intake (if drinking water study)
yes Ophthalmoscopic examination no data Haematology not examined Clinical chemistry not examined Urinalysis not examined N eurobehaviour not examined Organ weights not examined Gross pathology not examined Histopathology: non-neoplastic not examined Histopathology: neoplastic not examined Details on results N o effects were noted in the dietary palatability study. Inthe drinking water study, decreased body weights in males(17.2% versus control) decreased food consumption in males (up to 34.2% versus control) and females (up to 20.8% versus control) and increased water consumption (up to 48.0% versus control) were noted in treated animals versus controls. Repeated dose toxicity: oral Taupin BF DOT 1993.002 UUID IUC5-781f189d-6f30-4e92-8b0d-36f76336bc68 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-24 17:24:57 EDT Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1993

Reliablility 2 (reliable with restrictions) Rationale for reliability Well conducted study run according to GLP and with good characterization of test material composition. N umber of animals per dose not completely specified. Data source ReferenceReference type study report

Author Taupin PJY Year 1993 Title Brake fluid DOT 4: A 28 day oral (gavage) toxicity study in the rat. Bibliographic

source Testing laboratory Shell Research Limited, Sittingbourne Research Centre Report

no. Owner company Shell

Company study no. SBGR.92.180 Report date 1993-10-07

Materials and methods Test type subacute Limit test

no Principles of method if other than guideline Guideline was not specified, but study was conducted according to typical procedures for 28 day oral repeated dose testing. GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 106008-94-0

Identifier Common name Identity Brake fluid DOT 4 Details on test material Test material is a mixture containing 30-50% triethylene glycol monomethyl ether borate ester (CAS No. 106008-94-0), 3-30% triethylene glycol monobutyl ether borate ester, 20-30% triethylene glycol monomethyl ether (CAS No. 112-35-6), 2-10% triethylene glycol monobutyl ether (CAS No. 143-22-6), 20-30% tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 2-10% tetraethylene glycol monobutyl ether (CAS No. 1559-34-8), and < 1% minor additives. Test animals Species
rat Strain Sprague-Dawley Sex male/female Details on test animals and environmental conditionsno data Administration / exposure Route of administration oral: gavage Vehicle unchanged (no vehicle) Details on oral exposure no data Analytical verification of doses or concentrations no data Details on analytical verification of doses or concentrations no data Duration of treatment / exposure 28 days Frequency of treatment daily Doses/concentrations 25, 150, 1000 mg/kg/day Basis N o. of animals per sex per dose not detailed Control animals
yes Details on study design no data Positive control no data Examinations Sacrifice and pathology Gross pathology examinations were performed Statistics no data Results and discussions Effect levels Endpoint N OEL Effect level 150 mg/kg bw/day (nominal) Sex male/female Basis for effect level / Remarks N o treatment related effects seen at 150 mg/kg bw per day. Effects were seen at the next higher dose

Observations Clinical signs and mortality
yes Body weight and weight gain
yesFood consumption and compound intake (if feeding study)
yes Food efficiency no data Water consumption and compound intake (if drinking water study) no data Ophthalmoscopic examination no data Haematology no data Clinical chemistry
yes Urinalysis no data N eurobehaviour no data Organ weights
yes Gross pathology
yes Histopathology: non-neoplastic no data Histopathology: neoplastic not examined Details on results Food intake of males dosed with 1000 mg/kg/day was slightly reduced for first 2 weeks of treatment. Livers of all 5 males and some females dosed with 1000 mg/kg/day showed slight centrilobular hypertrophy (which was considered by the investigators to be adaptive). N one o f the controls exhibited this effect. There was no significant effect of treatment on liver weight. N o effects on other organs (including ovaries and testes) were noted. A NOEL of 150 mg/kg/day was assigned by the investigator. 7.5.2 Repeated dose toxicity: dermal Repeated dose toxicity: dermal Corley TGME 1990.001 UUID IUC5-b027845b-b085-4e1c-adee-4a5b7d285d64 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-24 17:15:22 EDT Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study 19p eriod 90 Reliablility 1 (reliable without restriction) Rationale for reliability Well conducted guideline study per GLP, with purity of test substance p rovided. Data source Reference

Reference type Author Corley RA, Ciesslak, Breslin WJ, Lomax LG. 13-Week dermal toxicity study in Sprague-Dawley rats Year 1990

Title 13-Week dermal toxicity study in Sprague-Dawley rats Bibliograp hic source Testing laboratory Report

no. Study ID K-005610-004 Owner company Dow Chemical Company

Company study no. Report date 1990-09-26

Reference type p ublication

Author Gill MW, Fowler EH, Gingell R, Lomax LG, Corely RA. Year Title Subchronic dermal toxicity and oral neurotoxicity of triethylene glycol monomethyl ether in CD rats. Bibliograph ic source Int J Toxicol 17:1-22.

Testing laboratory Report

no. Owner company Company study no. Report date Cross-reference to same study The same study is summarized as a fertility study in Sprague-Dawley rats. Materials and methods Test type subchronic Limit test

no Test guideline Qualifier according to Guideline other guideline: as specified in a testing consent order (EPA. 1989. 40 CFR 799, Fed Reg 54:13470-13477). DeviationsGLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 112-35-6

Identifier EC number Identity 203-962-1

Identifier Common name Identity triethylene glycol monomethyl ether Details on test material The test substance was triethylene glycol monomethyl ether (CAS 112-35-6). Purity (as determined by gas chromatography) was 99.23 % at the onset of the study and 99.24% at completion of the in-life phase. Test animals Species
rat Strain Sprague-Dawley Sex male/female Details on test animals and environmental conditions 8 week-old rats Administration / exposure Type of coverage semiocclusive Vehicle unchanged (no vehicle) Details on exposure Triethylene glycol monomethyl ether (TGME) was administered dermally to 8 week-old rats (10/sex/dose level) at 0 (sham control), 400, 1200 or 4000 mg/kg/day for 13 weeks. Test material was applied to shaved areas of skin on the back and sides of each rat (12 cm2 in area), uniformly spread, and covered with a semiocclusive dressing for 6 hours. After removal of the dressing, the application site was wiped with a dampened towel. Material was applied in this manner daily, 5 days/week for 13 weeks. Analytical verification of doses or concentrations
yes Details on analytical verification of doses or concentrations Purity (as determined by gas chromatography) was 99.23 % at the onset of the study and 99.24% at completion of the in-life phase. Duration of treatment / exposure Six hours daily, 5 days/week for 13 weeks, 91 days. There was no post exposure observationp eriod. Frequency of treatment 5 days/week for 13 weeks Doses/concentrations 0 (sham control), 400, 1200 or 4000 mg/kg/day Basis analytical per unit body weight N o. of animals per sex per dose 10/sex/dose level Control animals yes, sham-exposed Details on study design Triethylene glycol monomethyl ether (TGME) was administered dermally to 8 week-old rats (10/sex/dose level) at 0 (sham control), 400, 1200 or 4000 mg/kg/day for 13 weeks. Test material was applied to shaved areas of skin on the back and sides of each rat (12 cm2 in area), uniformly spread, and covered with a semiocclusive dressing for 6 hours. After removal of the dressing, the application site was wiped with a dampened towel. Material was applied in this manner daily, 5 days/week for 13 weeks. Parameters evaluated throughout the study included clinical and ophthalmic observations, dermal irritation, body weight, food consumption, clinical p athology, estrous cyclicity (daily vaginal smears during study weeks 12 and 13), hematology ( j ust prior to sacrifice), clinical chemistry ( j ust prior to sacrifice), and urinalysis ( j ust prior to dosing and during final week of dosing). Organ weight (standard set), gross pathology and histopathology (control and high dose group) were evaluated upon necropsy. The oocytes, corpora lutea, and follicles from each ovary were evaluated with regard to their normal development. Bone marrow smears were prepared from each animal from the shaft of the femur.The testes and epididymes also were examined microscopically for males in the intermediateand low-dose groups. Examinations Observations and examinations performed and frequency Parameters evaluated throughout the study included clinical and ophthalmic observations, dermal irritation, body weight, food consumption, clinical pathology, estrous cyclicity (daily vaginal smears during study weeks 12 and 13), hematology ( j ust prior to sacrifice), clinical chemistry ( j ust prior to sacrifice), and urinalysis ( j ust prior to dosing and during final week of dosing). Sacrifice and pathology Organ weight (standard set), gross pathology and histopathology (control and high dose group) were evaluated upon necropsy. The oocytes, corpora lutea, and follicles from each ovary were evaluated with regard to their normal development. Bone marrow smears were prepared from each animal from the shaft of the femur. The testes and epididymes also were examined microscopically for males in the intermediate- and low-dose groups. Other examinations Additional satellite groups of 5 rats/sex/dose level were administered TGME for 30 days for interim hematological (48 hr and 30 days), clinical chemistry (48 hr and 30 days), body weight determinations, clinical observations, and dermal irritation. Statistics For the main study group, the data for continuous variables were evaluated by Bartlett's test for equality of variances. Depending on the outcome of the test, data were analyzed using ap arametric or nonparametric analysis of variance (ANOVA), followed by a Dunnett's test ( p arametric data) or Wilcoxon rank-sum test (nonparametric data) with a Bonferroni correction for multiple comparisons when appropriate. Statistical outliers were identified by a sequential test, but were not excluded from analyses.
For the satellite group, all data (except those for differential leukocyte count and red blood cell p arameters) were first tested for equality of variance using Bartlett’s test. Hematologic and clinical chemistry parameters were evaluated during a two-way analysis of variance with the factors of sex and dose. Examinations were first made for a significant sex-dose interaction. If this existed, a one-way ANOVA was preformed separately for each sex. If no sex-dose interaction was identified and a dose effect was identified, or if in the subsequent ANOVA separated by sex a dose-effect was identified, then separate ANOVAs were used for each treatment group with the control. A Bonferroni correction was used to control for multiple comparisons. Any other information on materials and methods incl. tables

The route of administration and maximum dose level was specified in a testing consent order (EPA. 1989. 40 CFR 799, Fed Reg 54:13470-13477). The highest dose level (4000 mg/kg/day) represented the maximum amount of test substance that could be retained on the back and sides of the rat as determined in a preliminary 2-week study (Yano et al. 1987. Dow Chemical Company Study ID: K-005610-001, Dated Nov. 25, 1987). The EPA has determined that based on severe testicular toxicity in 1/10 rats given 4000 mg/kg/day and minimal decreases in developing germ cells (1-5% of seminiferous tubules affected) in 1/10 rats given 1,200 mg/kg/day, the NOAEL for systemic toxicity is between 400 and 1200 mg/kg/day (Anderson, L. Triethylene glycol monomethyl, monoethyl and monobutyl ethers RM1 screening document (draft), Feb. 24, 1995). This value was reached even though it was recognized that the testicular changes in the 1,200 mg/kg/day rat were within historical control limits for Sprague-Dawley rats (0-17%).

Results and discussions Effect levels

Endpoin
t N OAEL

Effect level 4000 mg/kg bw/day (actual dose received)

Sex male/female Basis for effect level / Remarks N OAEL = 4000 mg/kg bw (summary preparer); > 400 and < 1200 mg/kg bw (EPA). A significant decrease (15%) in platelet counts was noted in females dosed with 4000 mg/kg for 13 weeks when compared to control.

Observations Clinical signs and mortality
yes Dermal irritation
yes Body weight and weight gain
yes Food consumptionyes Food efficiency no data Water consumption no data Ophthalmoscopic examination
yes Haematology
yes Clinical chemistry
yes Urinalysis
yes N eurobehaviour no data Organ weights
yes Gross pathology
yes Histopathology: non-neoplastic
yes Histopathology: neoplastic no data Details on results Mean body weight and food consumption were comparable to controls throughout the study. There were no treatment-related hematological changes in the interim groups or in males administered test material for 13 weeks. A significant decrease (15%) in platelet counts was noted in females dosed with 4000 mg/kg for 13 weeks when compared to control (1217 +/- 280 x 103/cu mm); however, the value (1034 +/- 92 x 103/cu mm) was only slightly below the historical control range (1050 to 1262 +/- 93 to 294 x 103/cu m) Therefore, it was not considered to be toxicologically significant (Gill et al., Int J Toxicol 17:1-22, 1998). There were no other changes in any hematological parameters (hematocrit, hemoglobin, erythrocyte count, total leukocyte count, and red blood cell indices). There were no changes in clinical chemistries, urinalyses, organ weights, or estrous cyclicity measurements.
Bilaterally decreased spermatogenesis in seminiferous tubules and decreased spermatozoa in the epididymes (both were graded as severe) were noted in the testes of one high dose male rat. This animal had a complete lack of mature spermatids in greater than 41% of tubules in each testicle, few spermatids beyond stage 12 of development in the seminiferous epithelium, and decreased spermatic elements in the head and tail of greater than 41% of the tubules and ducts in the epididymides. The testes of one male treated with 1200 mg/kg exhibited different testicular changes [bilateral multifocal degeneration of spermatocytes and spermatids from germinal epithelium (graded as very slight), and multinucleated spermatids]. In this rat, all stages of the cycle of the seminiferous epithelium were observed in morphologically normal tubules. The epididymides of this rat had decreased spermatic elements in the head and tail of 1-5% of ducts. Some of the ducts also contained immature spermatids.Remarks on results including tables and figures

Study personnel concluded that the bilateral microscopic testicular changes observed in one high-dose and one mid-dose male rat were unrelated to treatment. Reasons given were that the dissimilarity of the lesions for the two animals suggested that they occurred spontaneously, and the incidence of animals with lesions (1/10 in each group) was well within that of historical controls (0-17%). Study personnel also stated that the degenerative changes in the testes of one mid-dose and one high-dose rat were not consistent with the types of lesions that have been attributed to 2-methoxyethanol (2-ME). The cell types that are most vulnerable to 2-ME are the pachytene spermatocytes and round spermatids (Chapin et al., Fund Appl. Toxicol 5:182-189, 1985). As the dose of 2-ME is increased, the number and types of cells affected increase up to the point that the germinal epithelium is significantly degenerated and all stages of spermatogenesis are affected (Chapin et al., Fund Appl. Toxicol 5:182-189, 1985; Miller et al., Fund Appl Toxicol 3:49-54, 1983.). In contrast, the testicular effects seen with the high dose animal treated with TGME consisted of a virtually complete lack of mature spermatids beyond stage 12. All other stages, including spermatogonia and spermatocytes, were present and appeared morphologically normal. In the mid-dose rat, the only effects noted consisted of very slight degeneration of spermatocytes and spermatids similar to those seen in historical control animals.

Study personnel also stated that the lymphoid tissues and hematologic parameters, which have been reported to be affected at doses of 2-methoxyethanol that have been associated with testicular changes (Miller et al., Fund. Appl. Toxicol. 3:49-54, 1983) were unattected in this TGME study. Taking all factors into considereation, the testicular lesions observed in this dermal study could not be directly attributed to TGME exposure.
Repeated dose toxicity: dermal Yano TGME 1987.006 UUID IUC5-c813ffe0-38cc-4fc7-a413-59a7bced453d Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-24 17:15:22 EDT Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 87

Reliablility 2 (reliable with restrictions) Rationale for reliability Well conducted study, but of only 2 week duration. Purity of test substance not stated. Data source Reference

Reference type study report

Author Yano BL, Phillips JE, Battjes JE. Year 1987Title Triethylene glycol monomethyl ether: 2-week dermal toxicity study in male and female Sprague-Dawley rats. Bibliograp hic source Testing laboratory Report

no. Owner company Dow Chemical Company

Company study no. Study ID:K-005610-001, Report date 1987-11- 25 Materials and methods Test type subacute Limit test

no Principles of method if other than guideline Standard procedure used at the time for a two week repeat dose dermal study. GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 112-35-6).

Identifier EC number Identity 203-962-1

Identifier Common name Identity triethylene glycol monomethyl ether Details on test material Purity is unknown. Test animals Species
rat Strain Sprague-Dawley Sex male/female Details on test animals and environmental conditions 200 to 350 g weight Administration / exposure Type of coverage semiocclusive Vehicleunchanged (no vehicle) Details on exposure Groups of five rats/sex (200 to 350 g)were dosed with 0, 1000, 2500, or 4000 mg/kg/day of test material on clipped back skin, 6 hours/day for a total of 9 applications during a 12 day period. Test material was held in place with a gauze patch and elastic bandage. Analytical verification of doses or concentrations no data Details on analytical verification of doses or concentrations no data Duration of treatment / exposure two weeks, 9 dose applications Frequency of treatment daily Doses/concentrations 0, 1000, 2500, 4000 mg/kg/day Basis nominal per unit body weight N o. of animals per sex per dose five rats/sex Control animals yes, concurrent no treatment Examinations Observations and examinations performed and frequency Parameters evaluated included clinical observations (including skin evaluations), body weight, feed consumption, clinical chemistry, hematology, urinalysis, and fasted body weights. Sacrifice and pathology Organ weight measurement, gross pathology, and histopathology were conducted. Other examinations no data Statistics no data Results and discussions Effect levels Endpoint N OAEL Effect level 4000 mg/kg bw/day (nominal) Sex male/female Basis for effect level / Remarks N o significant obverse effects were observed at this or lower doses that were considered treatment related.

Observations Clinical signs and mortality
yes Body weight and weight gain
yes Food consumption
yesFood efficiency no data Water consumption no data Ophthalmoscopic examination no data Haematology
yes Clinical chemistry
yes Urinalysis
yes N eurobehaviour no data Organ weights
yes Gross pathology
yes Histopathology: non-neoplastic
yes Histopathology: neoplastic not examined Details on results There were no treatment-related adverse systemic effects. A few males and females treated with either 1000 or 2500 mg/kg/day had a few small scabs or crusts at the test site. These alterations were slight in degree and did not adversely affect the rats.
A number of clinical chemistry, hematological and urinalysis variables were significantly different from control. The lower albumin concentration in females from the 1000 mg/kg/day group and higher urea nitrogen concentration in males from the 2500 mg/kg/day group were not considered by study personnel to be related to treatment because the effects were not noted at higher concentrations. The lower albumin concentration in males treated with 4000 mg/kg/day also was not attributed to treatment by study personnel because the value was within the range of individual animal values in the control group. A slightly higher alanine aminotransferase activity was also statistically identified in rats from the 4000 mg/kg/day group. As the value was only marginally different from control and was not associated with any histologic changes in the liver, study personnel did not consider this to be related to treatment. A slightly higher red blood cell count and hemoglobin concentration was observed in rats given 4000 mg/kg/day. Since these were only slightly higher than control values, study personnel did not consider them to be related to treatment. A few of therats given 2500 or 4000 mg/kg/day had watery cecal contents and/or hemolyzed blood in the stomach. These gross pathologic observations were not associated with any histologic abnormalities in these tissues or alterations in hematologic and clinical chemistry parameters. Therefore, they were not attributed by study personnel to be related to treatment. Repeated dose toxicity: dermal IRDC Rabbit 21-Day TGME 1986.002 UUID IUC5-5ce59765-2907-4266-a845-3f34f42bb820Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-24 17:15:23 EDT Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 86

Reliablility 2 (reliable with restrictions) Rationale for reliability 3 week study per GLP, but no guideline specified and test material purity not p rovided Data source Reference Referenc e type study report

Author Year 1986

Title 21-Day dermal toxicity study in rabbits-limit test on triethylene glycol monobutyl ether, triethylene glycolmonoethyl ether and triethylene glycol monomethyl ether. Bibliogr aphic

source Testing laborator
y International Research and Development Corportation (IRDC). Rep
ort

no. Owner company
Compan

y study

no. Rep
ort date 1986-0 7-22

Referenc e type p ublication

Author Leber AP, Scott RC, Hodge MCE, Johnson D, Krasavage WJ. Year 1990

Title Triethylene gylcol ethers. Evaluation of in vitroabsorption through human epidermis, 21-day dermal toxicityin rabbits and a developmental toxicity screen in rats Bibliogra p hic J AmColl Toxicol 9:507-515source Testing laborator
y Repo
rt no.

Owner company
Compan

y study

no. Repo
rt date Materials and methods Test type subacute GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier Common name Identity triethylene glycol monomethyl ether

Identifier CAS number Identity 112-35-6

Identifier EC number Identity 203-962-1 Details on test material no data Test animals Species rabbit Strain N ew Zealand White Sex male/female Details on test animals and environmental conditions Rabbits were observed over a 51-52 day pretest period for clinical abnormalities. Prior to randomization, rabbits were fasted (19-23 hours), and blood samples were taken from the central ear artery for control hematological and biochemical evaluations. Healthy rabbits (4- 4.5 months of age) were randomly divided into groups of 5 p er sex. Administration / exposure Type of coverage occlusive Vehicle unchanged (no vehicle)Details on exposure Prior to study initiation, hair was removed from the back of each rabbit with an electric clipper. Rabbits were shaved as necessary during the course of the study to prevent the test material from becoming matted in the hair and to facilitate accurate observations. One group of rabbits was left untreated and the other was treated with 1000 mg/kg test material, five days per week for 3 weeks. Dose volumes were calculated based on the specific gravity of test material (as determined at the study site) and the body weight of animals (determinedweekly). Test material was placed on the back using a 5 cc plastic syringe. A glass rod was used to evenly distribute the dose over the test site. Following dosing, test sites (of all animals, including controls) were wrapped with gauze bandaging and Dermiform tape and plastic restraint collars were attached to the rabbits. Collars were removed after 6hours, and test sites (of all animals, including controls) were washed with tepid tap water and dried with paper towels. All animals were fasted for 19-23 hours before study termination. Analytical verification of doses or concentrations no data Duration of treatment / exposure 3 weeks Frequency of treatment 6 hr/day, 5 days/week Doses/concentrations 1000 mg/kg test material Basis nominal per unit body weight N o. of animals per sex per dose 5 p er sex Control animals yes, concurrent no treatment Examinations Observations and examinations performed and frequency Animals were observed once daily for clinical signs and twice daily for mortality. Food consumption was estimated daily based on a visual assessment of remaining food. Body weights were recorded weekly. Rabbits were scored immediately prior to each dosing for dermal irritation in accordance with the Draize method. Sacrifice and pathology Blood samples taken fromthe central ear artery of animals at study termination were analyzed for standard hematological (total and differential leukocyte count, erythrocyte count, hemoglobin, hematocrit, p latelet count, reticulocyte count, mean corpuscular volume, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration) and biochemical (sodium, p otassium, chloride, calcium, p hosphorus, total bilirubin, gamma glutamyltranspeptidase, aspartate aminotransferase, alanine aminotransferase, ornithine carbamoyltransferase, urea nitrogen, creatinine, total protein, albumin, globulin, cholesterol and glucose) p arameters. All animals were examined grossly upon study termination. Weights of adrenals, brain, kidneys, liver, ovaries and testes were taken. A full complement of tissueswas examined microscopically. Statistics Body weights (weeks 1, 2, 3, and 4), clinical pathology parameters and organ weights (absolute and relative) were analyzed using Bartlett’s test for homogeneity of variance and analysis ofvariance (one-way). The treatment groups were compared to the controls using the appropriate t-statistic (for equal or unequal variance). Dunnett’s multiple comparison tables were used to j udge the significance of the differences. Total bilirubin data was transformed to ranks and analyzed using a non- p arametric test. All tests were two-tailed, with p < 0.05 and p < 0.01 as levels of significance. Results and discussions Effect levels Endpoint N OAEL Effect level 1000 mg/kg bw/day (nominal) Sex male/female Basis for effect level / Remarks N o adverse effects observed at only dose level tested.

Observations Clinical signs and mortality
yes Dermal irritation
yes Body weight and weight gain
yes Food consumption
yes Food efficiency no data Water consumption no data Ophthalmoscopic examination no data Haematology
yes Clinical chemistry
yes Urinalysis no data N eurobehaviour no data Organ weights
yes Gross pathology
yes Histopathology: non-neoplastic
yes Histopathology: neoplastic not examined Details on results Some hematological and biochemical values from treated animals were different from controlsat termination. However, since the same changes were noted in blood samples taken from the animals prior to treatment, they were not considered by the investigators to be related to
treatment. N o macroscopic skin lesions were observed in treated animals. There were no organ weight variations that could be related to test material administration. Microscopic changes (trace acanthosis and trace to moderate dermatitis) were observed in skin of treated animals. Testicular degeneration (trace in severity) occurred in one rabbit. This lesion was characterized by the presence of spermatid giant cells, focal tubular hypospermatogenesis or cytoplasmic vacuolization. This was not considered to be related to test material by the study investigators since there is a high spontaneous incidence of similar changes in normal New Zealand White rabbits. Based on the results, the investigators concluded that in this study, there was no systemic toxicity induced by treatment with 1000 mg/kg/day test material. Repeated dose toxicity: dermal UC MPEG 1985.002 UUID IUC5-fcd8f596-8f6c-4657-a83b-7944a9d0b03b Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-25 13:17:05 EDT Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS

Study result type experimental result Study p eriod 198 5 Reliablility 1 (reliable without restriction) Data source Reference Reference type study report

Author Year 1985 Title N ine-day and ninety-day dermal toxicity studies of CARBOWAX MPEG-350 in rabbits Bibliographi

c source

Testing laboratory Bushy Run Research Center Report

no. Owner company Union Carbide

Company study no. Report date 1985-05-3 0

Reference type Author Hermansky SJ, Leung HW. Year 1997Title Cutaneous toxicity studies with methoxy polyethylene glycol-350 (MPEG-350) in rats and rabbits. Bibliograph ic source Testing laboratory Report

no. Owner company Company study no. Report date Cross-reference to same study The same study is summarized as a fertility study. This is toxicity to reproduction.002 Materials and methods GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 9004-74-4

Identifier Common name Identity CARBOWAX MPEG 350 Details on test material The test material (CARBOWAX MPEG 350, CAS No. 9004-74-4) was reported to be chemically inert (stable for > 6 months at room temperature) and 99.8% p ure. This material is a mixture of several methylated glycol ethers of differing molecular weight (ranging from diethylene glycol monomethyl ether (C2) to heptadecaethylene glycol monomethyl ether (C17)). The majority of the material is in the C5-C11 range (87.445%). It contains 4.347 % (by weight) tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 1.303% triethylene glycol monomethyl ether (CAS No. 112-35-6), 0.181% diethylene glycol monomethyl ether (CAS No. 111-77-3). Test animals Species rabbit Strain N ew Zealand White Sex male/female Details on test animals and environmental conditions Body weights of males and females ranged from 2.5 to 3.2 kg and 2.5 to 3.1 kg at study initiation Administration / exposure Type of coverage
openVehicle other: methyl cellulose in distilled water Details on exposure Dosing: N ew Zealand white rabbits (10/sex/dose) were treated dermally on clipped dorsal skin with 1.0 ml of vehicle (0.1% (w/v) methyl cellulose in distilled water), 50% CARBOWAX MPEG-350 (w/v dilution in 0.1% methyl cellulose in water) or 100% CARBOWAX MPEG-350, for six hours/day, five days per week for 90 days. Body weights of males and females ranged from 2.5 to 3.2 kg and 2.5 to 3.1 kg at study initiation. Rabbits were fitted with Elizabethan collars after dosing to prevent ingestion of test material. After each 6-hour exposure the application site was wiped with a paper towel dampened with water and then dried using a towel. Rabbitswere then uncollared until the next treatment. Analytical verification of doses or concentrations
yes Details on analytical verification of doses or concentrations The test material (CARBOWAX MPEG 350, CAS No. 9004-74-4) was reported to be chemically inert (stable for > 6 months at room temperature) and 99.8% p ure. Duration of treatment / exposure six hours/day, five days per week for 90 days. Frequency of treatment five days per week Doses/concentrations 1 ml of 50% and 100% material (approximately 169 and 338 mg/kg/day) Basis analytical per unit body weight N o. of animals per sex per dose 10/sex/dose Control animals yes, concurrent vehicle Examinations Observations and examinations performed and frequency Observations: All rabbits were observed daily (weekdays) for death, clinical signs and dermal irritation. Any irritation was scored immediately prior to dosing using the Draize system. Body weights were recorded on the morning of the first day of dosing, weekly thereafter and prior tosacrifice. Food consumption was measured weekly. Urine was collected from 5 animals/sex/group during the last two weeks of dosing and subjected to standard analyses. Standard hematology and clinical chemistry parameters were evaluated for all animals just prior to sacrifice. Sacrifice and pathology N ecropsy: All animals were sacrificed and necropsied after 13 weeks of treatment. Weights were recorded for liver, kidneys, brain and adrenals of all animals and testes of males. Histopathologic examinations were performed on tissues from high-dose and control animals. Statistics Statistical Analyses: Body weight, food consumption, organ weight and clinical pathology data from the three groups were compared using Levene's test for homogeneity of variance. An analysis of variance was performed on the groups when data were homogeneous. If significantdifferences were found, group differences were delineated by grouped variance Student t-tests. When data were heterogeneous, Welch and Brown-Forsyth analyses werep erformed and significant differences among groups were determined using separate variance Student t-tests. Draize skin irritation scores were analyzed using the Kruskal-Wallis test, and significant differences in groups were determined using the Wilcoxon rank sum test (as modified by Mann-Whitney). Frequency data (i.e. histological) were compared using Fisher's exact tests. The p value of 0.05 (two-tailed) was used as the critical level of significance for all analyses. Any other information on materials and methods incl. tables

A preliminary range-finding study in 15 rabbits dosed 6 hr /day for 9 days (Carpenter, Range finding tests on methoxy polyethylene glycols of approximate molecular weights 350, 550 and 750. Melon Institute of Industrial Research, University of Pittsburgh. Report dated 5-13-47.1947) showed that daily administration of 1 ml of 50% or 100% test material only caused mild skin irritation. Therefore, these doses were chosen for the 90-day study.

Results and discussions Effect levels Endpoint N OAEL Effect level 338 mg/kg bw/day (actual dose received) Sex female Basis for effect level / Remarks Mild acanthosis (epidermal thickening)

Observations Clinical signs and mortality
yes Dermal irritation
yes Body weight and weight gain
yes Food consumption
yes Food efficiency no data Water consumption no data Ophthalmoscopic examination no data Haematology
yes Clinical chemistry
yes Urinalysis
yes N eurobehaviour no data Organ weights
yes Gross pathologyyes Histopathology: non-neoplastic
yes Histopathology: neoplastic not examined Details on results Mild acanthosis (epidermal thickening) was found in 3 females dosed with 100% material. Transient, dose-related erythema (Grade 1) and desquamation of skin occurred. N o systemic effects were observed in rabbits treated with either 50% or 100% test material. Remarks on results including tables and figures

The NOAELs for local or systemic effects were not listed by the investigators. Based on the data, these values are 50% and 100%, respectively. Based on weights of animals determined at weekly intervals and the reported density of test material (1.09 g/ml) doses can be calculated on average mg/kg/day basis. These doses are 169 mg/kg/day (for 50 %) and 338 mg/kg/day (for 100%).
Repeated dose toxicity: dermal Gray MPEG 1987.003 UUID IUC5-a152eeff-b2c3-44ce-b497-3da04a5800af Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-25 13:17:06 EDT Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1987

Reliablility 1 (reliable without restriction) Rationale for reliability Robust study following GLP with test substance well characterized as to composition. N o guideline specified but study was conducted according to standard procedures. Data source Reference Reference type study report

Author Gray TM. Year 1987 Title A 28-day dermal toxicity study in rats on PEG-methyl ether (Medical Group N umbe r #85-166). Bibliograp hic source Testing laboratory Report

no. Document N umbe r 4257, Owner Armour-Dial, Inc.company Company study no. Report date 1987-05-15

Reference type study report

Author Hermansky SJ, Leung HW. Year 1997 Title Cutaneous toxicity studies with methoxy polyethylene glycol-350 (MPEG-350) in rats and rabbits. Bibliograph ic source Testing laboratory Report

no. Owner company Company study no. Report date Materials and methods Test type subacute Limit test

no Principles of method if other than guideline N o guideline specified but study was conducted according to standard procedures. GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 9004-74-4

Identifier Common name

Identity Carbowax MPEG-350 ( Details on test material Test material was Carbowax MPEG-350 (CAS No. 9004-74-4) from Union Carbide. This material is a mixture of several methylated glycol ethers of differing molecular weight (ranging from diethylene glycol monomethyl ether (C2) to heptadecaethylene glycol monomethyl ether (C17)). The majority of the material is in the C5-C11 range (87.445%). It contains 4.347 % (by weight) tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 1.303% triethylene glycol monomethyl ether (CAS No. 112-35-6), 0.181% diethylene glycol monomethyl ether (CAS No. 111-77-3).

Test material also contained 1 p pm o f 2-methoxyethanol. Test animalsSpecies
rat Strain Sprague-Dawley Sex male Details on test animals and environmental conditions The animals were 52 days old. Administration / exposure Type of coverage
open Vehicle unchanged (no vehicle) Details on exposure Male rats (52 days old) were divided into 4 groups of 15 animals (control, low-, mid-, and high-dose groups and were acclimated to Elizabethan collars for 7 days before treatment. One mid-dose and 3 high-dose animals were dropped before treatment because they appeared dehydrated. Each group was treated with 0 (sham control), 1.25, 2.5 or 5 g/kg/day test material on shaved backs. Analytical verification of doses or concentrations no data Duration of treatment / exposure four weeks Frequency of treatment five days per week Doses/concentrations 0 (sham control), 1.25, 2.5 or 5 g/kg/day Basis no data N o. of animals per sex per dose 15 male animals per dose Control animals yes, sham-exposed Details on study design Rats were sacrificed 3 days after the last treatment. Positive control no data Examinations Observations and examinations performed and frequency Signs of irritation, body weights of animals Sacrifice and pathology Organ weights, gross pathology Statistics no data Results and discussions Effect levelsEndpoint N OAEL Effect level 1250 mg/kg bw/day Sex male Basis for effect level / Remarks This value is based on significant effects on body weight or weight gain at higher doses. Observations Clinical signs and mortality
yes Dermal irritation
yes Body weight and weight gain
yes Food consumption no effects Food efficiency no data Water consumption no data Ophthalmoscopic examination no data Haematology no data Clinical chemistry no data Urinalysis no data N eurobehaviour no data Organ weights
yes Gross pathology
yes Histopathology: non-neoplastic no data Histopathology: neoplastic not examined Details on results Minor, transient irritation was noted at the application site of all treated animals. Body weights of animals given 5.0 g/kg/day and body weight gains of animals given 2.5 g/kg/day were depressed. Absolute weights of the thymus and testes of rats treated with 1.25 g/kg/day were 83% and 93%, respectively of control weights (significantly different). Relative weights of these organs were not significantly different from control. There were no pathological abnormalities in either of these organs. Remarks on results including tables and figures

One, 3, and 2 animals in the low-, mid- and high-dose groups slipped their collars and therefore mayhave ingested the material during grooming. Results in these animals were not significantly different from those animals that did not slip their collars. Therefore, possible ingestion of material in these animals did not appear to affect the results of the study.

The investigators did not identify a NOAEL for the study. However, they stated that there were no indications of systemic toxicity secondary to repeated cutaneous exposure to MPEG-350 in this study. Based on the information given, the summary preparer assigned a NOAEL of 1250 mg/kg/day. This value is based on significant effects on body weight or weight gain at higher doses (although the authors stated that these effects may have been due to use of Elizabethan collars). Although the absolute weights of the thymus and testes of rats treated with 1.25 g/kg/day were significantly less than control, relative weights of these organs were not different from control, there were no histological changes in these organs, and these effects were not noted at higher doses. Therefore, they were considered by the summary preparer to be unrelated to treatment.
7.5.4 Repeated dose toxicity: other routes Repeated dose toxicity: other routes NAMSA MPEG 1997.001 UUID IUC5-cdd9494a-be57-4406-a8ac-8dcbb9f859b0 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-25 13:17:07 EDT Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 97

Reliablility 1 (reliable without restriction) Rationale for reliability well conducted, thorough study following GLP. Test substance was well defined. Data source Reference

Reference type study report

Author Year 1997 Title Subchronic intravenous toxicity study in the rat. Carbowax Sentry M-PEG 350- N F and Carbowax Sentry PEG 400 N F and FCC. Bibliogra p hic

source Testing laboratory N orth American Science Associates, Inc ( N AMSA). Repor
t no. Report TS064-900/S. Owner company Company study no. Repor t date Materials and methods Test type subchronic Limit test

no Principles of method if other than guideline One i.v. dose plus concurrent control. Typical battery of observations for a two week study. GLP compliance

no Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 9004-74-4

Identifier Common name Identity CARBOWAX Sentry MPEG-350 Details on test material Test material was CARBOWAX Sentry MPEG-350 (CAS No. 9004-74-4), N F grade. This material is a mixture of several methylated glycol ethers of differing molecular weight (ranging from diethylene glycol monomethyl ether (C2) to heptadecaethylene glycol monomethyl ether (C17)). The majority of the material is in the C5-C11 range (87.445%). It contains 4.347 % (by weight) tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 1.303% triethylene glycol monomethyl ether (CAS No. 112-35-6), 0.181% diethylene glycol monomethyl ether (CAS No. 111-77-3). Test animals Species
rat Strain Sprague-Dawley Sex male/female Details on test animals and environmental conditions Groups of six rats/sex (6-8 weeks of age, 114 g to 189 g Administration / exposure Route of administration intraveneous Vehicle other: Details on exposureGroups of six rats/sex (6-8 weeks of age, 114 g to 189 g) were dosed intravenously for 14 consecutive days with either vehicle (0.9% sodium chloride, USP), or 1 g/kg/day test material. Analytical verification of doses or concentrations
yes Duration of treatment / exposure fourteen days Frequency of treatment daily for fourteen consecutive days Doses / concentrations either vehicle (0.9% sodium chloride, USP), or 1 g/kg/day test material. N o. of animals per sex per dose six rats/sex Control animals yes, concurrent vehicle Examinations Observations and examinations performed and frequency Animals were observed daily for general health. Body weights were recorded on days 1, 8 and 15 of treatment. Sacrifice and pathology All animals were euthanized on day 15. Blood was collected from the posterior vena cava and standard hematological and clinical chemistries were performed. The heart, liver, spleen, kidneys, adrenal glands and gonads were weighed, fixed, and processed for microscopic evaluation. The data were analyzed using a standard BMDP Statistical Software Package. Statistics The data were analyzed using a standard BMDP Statistical Software Package. Results and discussions Effect levels Endpoint N OAEL Effect level 1000 mg/kg bw/day (actual dose received) Sex male/female Basis for effect level / Remarks N o adverse effects were observed at the single dose tested.

Observations Clinical signs and mortality
yes Body weight and weight gain
yes Food consumption no data Food efficiency no data Water consumption no data Ophthalmoscopic examination no dataHaematology
yes Clinical chemistry
yes Urinalysis no data N eurobehaviour no data Organ weights
yes Gross pathology
yes Histopathology: non-neoplastic
yes Histopathology: neoplastic not examined Details on results There was no effect of treatment on body or organ weights or hematological values. Tissues (including testes) from treated animals were histologically similar to those of controls. There was a significant difference in aspartate aminotransferase activity in control (95 +/- 13 IU/L) and treated males (81 +/- 6 IU/L) that was not considered by the investigators to be related to treatment since the values for both groups were within the normal expected range. An increase in aspartate aminotransferase activity, rather than a decrease would be indicative of liver toxicity. 7.6 Genetic toxicity 7.6.1 Genetic toxicity in vitro Genetic toxicity in vitro Samson & Gallapudi TGME Ames 1990.002 UUID IUC5-cd79d78d-780a-4457-a831-6f03cd84dcad Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-24 17:15:24 EDT Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 90

Reliablility 2 (reliable with restrictions) Rationale for reliability Only four strains of bacteria were used in the test.

Data sourceReference Referenc e type study report

Author Samson YE and Gollapudi BB. Yea

r 1990

Title Evaluation of triethylene glycol monomethyl ether (TGME) in the Ames Salmonella/mammalian-microsome bacterial mutagenicity assay. Bibliogr aphic

source Testing laborator
y Rep
ort

no. Study ID TXT:K-00561 0-005, Owner compan y Dow Chemical Company

Compan

y study

no. Rep
ort date 1990-03-07

Materials and methods Type of genotoxicity gene mutation Type of study bacterial reverse mutation assay (e.g. Ames test) Test guideline Qualifier equivalent or similar to Guideline other guideline: Test Standard 40 CFR 798.5265 Deviations GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 112-35-6

Identifier EC number Identity 203-962-1

Identifier Common name Identity triethylene glycol monomethyl ether Details on test material Purity was 99.23%. MethodSpecies/strain Species/strain S. typhimurium TA 1535, TA 1537, TA 98 and TA 100 Details on mammalian cell lines (if applicable) Additional strain

characteristics Metabolic activation with and without Metabolic activation system not stated Test concentrations up to 5000 micrograms/ p late Vehicle DMSO and water Controls N egative controls yes

Solvent / vehicle controls True negative controls Positive controls yes

Positive control substance other: 2-nitrofluorene, ICR-191, 2-anthramine and sodium azide

Remarks Details on test system and conditions Test Concentrations: The test material was dissolved in distilled water at stock concentrations of 50, 16.67, 5, 1.667, and 0.5 mg/ml. Concentrations were verified by HPLC to be: 51.4, 18.3, 4.91, 1.75 and 0.523 mg/ml. All positive control solutions (1 mg/ml 2-nitrofluorene, 100 micrograms/ml ICR-191, 30 micrograms/ml 2-anthramine) were prepared in DMSO (with the exception of 250 micrograms/ml sodium azide dissolved in water).
Test: Bacteria (0.1 ml of 10E8 or 10E9 S. typhimurium TA 98, TA100, TA1535, or TA1537), test chemical (0.1 ml of test solution, p ositive control, or solvent) and either buffer or S-9 mix (0.5 ml) were pre-incubated in sterile 12 x 75 mm tightly-capped culture tubes in a gyratory incubator (300rpm) at 30 degrees C for 30 minutes. Supplemented top agar (2 ml) was then added, the overlay was poured onto plates, and plates were incubated at 37 degrees C for 2 days. All dose levels (including positive and negative controls) were assayed in triplicate.
Revertant colonies were counted manually or with an automatic colony counter. The counter was calibrated periodically. A correction factor was used to compensate for the area not scanned by the counter (i.e. dish edge) and overlapping colonies. Evaluation criteria Evaluation Criteria: The test material was considered a mutagen if both the mean number of revertant colonies was at least 3 times higher than the mean of the negative (solvent) control and it induced a reproducible dose-response relationship over several concentrations. If the dose-response was not definitive, it was considered to be a presumptive mutagen. If the reversion rates were between 2 and 3 times that of negative controls, the results were considered equivocal or inconclusive.Statistics no data Results and discussions Test results Species/strain S. typhimurium TA 1535, TA 1537, TA 98 and TA 100 Metabolic activation with and without Test system all strains/cell types tested Genotoxicity negative Cytotoxicity yes Vehicle controls valid yes N egative controls valid

Positive controls valid yes Additional information on results Concentrations up to 5000 micrograms/ p late did not cause toxicity or cause an increase in mutagenicity above that of negative controls.
The study was valid, as the positive controls induced at least 3 times the number of revertants as the negative controls in each tested strain. Remarks on results including tables and figures

Cytotoxic concentration = > 5000 micrograms/plate
Genetic toxicity in vitro Liscombe & Gollapudi TGME 1990.004 UUID IUC5-84ed9121-fd34-4892-8608-896d6e34aa66 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-24 17:15:25 EDT Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 90

Reliablility 1 (reliable without restriction) Rationale for reliability Guideline study following GLP. Purity of test substance stated.

Data source Reference Reference type study report

Author Liscombe VA, Gollapudi BB. Year 1990Title Evaluation of triethylene glycol monomethyl ether in the Chinese hamster ovary cell/hypoxanthine-guanine- p hosphoribosyl-transferase(CHO/HGPRT) forward mutation assay Bibliographi

c source

Testing laboratory Report

no. Owner company Dow Chemical Company

Company study no. ID TXT:K-005610-006 Report date 1990-03-0 7 Materials and methods Type of genotoxicity gene mutation Type of study mammalian cell gene mutation assay Test guideline Qualifier according to Guideline other guideline: Test Standard 40 CFR 798.5300 Deviations Principles of method if other than guideline HGPRT Assay using Chinese hamster ovary cell GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 112-35-6

Identifier EC number Identity 203-962-1

Identifier Common name Identity triethylene glycol monomethyl ether Details on test material Purity was 99.23%. Method Target gene the gene locus for the enzyme (hypoxanthine-guanine phosphoribosyl transferase) Species/strain Species/strain Chinese hamster Ovary (CHO) Details on mammalian cell lines (if applicable) Additional strain characteristicsMetabolic activation with and without Metabolic activation system S-9 Test concentrations 2000 to 5000 micrograms/ p late Vehicle water and DMSO Controls N egative controls yes Solvent / vehicle controls yes True negative controls no data Positive controls yes Positive control substance other: EMS or 20-MC Remarks Details on test system and conditions Indicator cells: The CHO-K1-BH4 cell line was used in the study. Periodic examinations revealed no mycoplasma contamination. Cells were grown as a monolayer in Ham's F-12 nutrient mix supplemented with 5% heat-inactivated, dialyzed fetal bovine serum, 25 mM HEPES, 0.25 micrograms/ml Fungizone, 100 units/ml penicillin G and 0.1 mg/ml streptomycin sulfate. The selection medium used for the detection of mutants was Ham's F-12 nutrient mix without hypoxanthine, and supplemented with 10 micromolar 6-thioguanine, 5% serum, 25 mM HEPES, 2 mM L-glutamine and the antibiotics mentioned above.

Test materials: Test material was dissolved in water and further diluted (1:100) in culture medium. The concentrations of test material in stock solutions (200, 300, 400, 500 mg/ml)were verified by analytical methods.20-methylchlolanthrene (20-MC) was initially dissolved in DMSO, and further diluted in culture medium. Ethyl methanesulfonate (EMS) was dissolved in culture medium.
Preliminary test : The cytotoxicity of the test material was assessed by determining the ability of the treated cells to form colonies. The cultures (3 p er dose level) were treated with test material in the absence or presence of S-9, incubated for up to 7 days, fixed with methanol and stained with crystal violet. The number of colonies/dish was counted and the mean colonies/dish/treatment were expressed relative to the negative control value. The test material was not cytotoxic at up to 5000 micrograms/ml. Based on this result, this was the highest concentration used for the genemutation assay.
Mutation test: Cells in logarithmic growth phase were trypsinized and plated in medium containing 5% serum at a standard density (200 cells/100 mm dish for toxicity assay and 1 x 10E6 cells/100 mm dish for gene mutation assay) p rior to treatment. Approximately 24 hours after plating,the medium was replaced with Ham's medium without serum, S-9 mix prepared from liver homogenate of Aroclor-1254 treated (500 mg/kg) male, Sprague Dawley rats (when applicable) and test material (2000 to 5000 micrograms/ml), p ositive control (either 621 micrograms/ml EMS or 4 micrograms/ml 20-MC) or water. The total volume of the treatment medium was 10 ml/100 mm dish. The number of dishes treated at each dose level was based on the expected degree of toxicity that would yield at least 1 x 10E6 surviving cells. Cells were treated for 4 hours at 37 degrees C. Exposure was terminated by washing the cells withp hosphate-buffered saline. Cells were trypsinized 18-24 hours after termination of the treatment and replated at a density of 1 x 10E6 cells/100 mm dish. This step was repeated on the third and sixth days following treatment. On Day 8, cultures were trypsinized and plated at a density of 2 x 10E5 cells/100 mm dish (5 dishes per treatment) in selection medium for the determination of HGPRT-mutants and 200 cells/60 mm dish (5 dishes/treatment) in Ham's medium without hypoxanthine for determination of cloning efficiency. Dishes were incubated for 7-9 days, fixed with methanol and stained with crystal violet. The mutation frequency per 10E6 clonable cells was calculated as the total number of mutant colonies/cloning efficiency(number of colonies per number of cells plated). Evaluation criteria The assay was considered valid, if the positive control chemicals induced significant increased in mutation frequencies in assays with and without S-9 (EMS: 142.0-153.6; 20-MCA: 64.7-86.3). Statistics Statistical analysis: The frequencies of mutants per 10E6 clonable cells were statistically evaluated by pairwise tests (treatment vs. negative control) and by linear and quadratic trend analysis over the dose range. Results and discussions Test results Species/strain Chinese hamster Ovary (CHO) Metabolic activation with and without Test system all strains/cell types tested Genotoxicity negative Cytotoxicity yes Vehicle controls valid yes N egative controls valid yes

Positive controls valid yes Additional information on results The mutation frequencies observed in cultures treated with the test chemical in the absence (1.4 to 7.1) and presence of S-9 (0 to 7.1) were not significantly different from the concurrent negative control values (1.4 to 9.6) and were within the laboratory historical negative control range.
Cytotoxic concentration: > 5000 micrograms
The assay was valid, since the positive control chemicals induced significant increased in mutation frequencies in assays with and without S-9 (EMS: 142.0-153.6; 20-MCA: 64.7-86.3). Applicant's summary and conclusion Interpretation of results negative Genetic toxicity in vitro Brooks & Wiggins AMES BF DOT 1992.005 UUID IUC5-bca2ad09-6b79-4a3d-9a5b-04be1e640b35 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of AmericaDate 2009-03-24 17:24:58 EDT Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1 9 9 2 Reliablility 1 (reliable without restriction) Rationale for reliability well conducted study run according to glp, with good characterization of test material composition. Data source Reference Reference type study report Author Brooks TM, Wiggins DE. Year 1992 Title Brake fluid Dot 4: Bacterial mutagenicity studies Bibliographic

source Testing laboratory Shell Research Limited, Sittingbourne Research Centre Report no. SBGR.92.022

Owner company Shell

Company study

no. Report date 1992-04-09

Materials and methods Type of genotoxicity gene mutation Type of study bacterial reverse mutation assay (e.g. Ames test) Principles of method if other than guideline Guideline not specified, but study was run according to standard Ames study procedure GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 106008-94-0

Identifier Common name Identity Brake fluid Dot 4 Details on test materialTest material is a mixture containing 30-50% triethylene glycol monomethyl ether borate ester (CAS No. 106008-94-0), 3-30% triethylene glycol monobutyl ether borate ester, 20-30% triethylene glycol monomethyl ether (CAS No. 112-35-6), 2-10% triethylene glycol monobutyl ether (CAS No. 143-22-6), 20-30% tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 2-10% tetraethylene glycol monobutyl ether (CAS No. 1559-34-8), and < 1% minor additives. Method Species/strain Species/strain other: TA98, TA100, TA1535, TA1537, TA1538 and E. coli WP2uvrA pKM101 Details on mammalian cell lines (if applicable) Additional strain

characteristics Metabolic activation with and without Metabolic activation system Test concentrations up to 5000 micrograms per plate Vehicle no vehicle Controls N egative controls no data Solvent / vehicle controls no data True negative controls no data Positive controls no data Positive control substance no data Remarks Details on test system and conditions no data Evaluation criteria no data Statistics no data Any other information on materials and methods incl. tables

Results and discussions Test results Species/strain other: TA98, TA100, TA1535, TA1537, TA1538 Metabolic activation with and without Test system Genotoxicity negative Cytotoxicity no, but tested up to limit concentrations Vehicle controls valid no dataN egative controls valid no data Positive controls valid no data Remarks on results including tables and figures
Cytotoxic concentration = > 5000 micrograms per plate
Genetic toxicity in vitro Brooks & Wiggins BF DOT CHO 1992.006 UUID IUC5-b78d5368-f874-4f09-9c1d-e5e5dd901d8d Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-24 17:24:59 EDT Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1 9 9 2 Reliablility 1 (reliable without restriction) Rationale for reliability Robust well conducted study following GLP, with good characterization of the test substance composition. Data source Reference Reference type study report

Author Brooks TM, Wiggins DE Year 1992 Title Brake fluid Dot 4: In vitro chromosome studies using cultured Chinese hamster ovary cells. Bibliograph ic source Testing laboratory Shell Research Limited, Sittingbourne Research Centre Report

no. SBGR.92. 090 Owner company Shell

Company study no. Report date 1992-07-2 3 Materials and methods Type of genotoxicity chromosome aberration Type of study in vitro mammalian chromosome aberration testPrinciples of method if other than guideline Guideline was not specified, but study was carried out following standard procedures for this type of study. GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 106008-94-0

Identifier Common name Identity Brake fluid Dot 4 Details on test material Test material is a mixture containing 30-50% triethylene glycol monomethyl ether borate ester (CAS No. 106008-94-0), 3-30% triethylene glycol monobutyl ether borate ester, 20-30% triethylene glycol monomethyl ether (CAS No. 112-35-6), 2-10% triethylene glycol monobutyl ether (CAS No. 143-22-6), 20-30% tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 2-10% tetraethylene glycol monobutyl ether (CAS No. 1559-34-8), and < 1% minor additives. Method Species/strain Species/strain Chinese hamster Ovary (CHO) Details on mammalian cell lines (if applicable) no details

Additional strain characteristics Metabolic activation with and without Metabolic activation system S-9 Test concentrations The concentrations of test material used (from 10 to 5000 micrograms/ml without S-9 and 100 to 5000 micrograms/ml with S-9). Vehicle no vehicle Controls N egative controls yes Solvent / vehicle controls yes

True negative controls Positive controls yes

Positive control substance other: methyl methanesulphonate and benzo(a) p yrene

Remarks Details on test system and conditions Cells (2 x 10E5) were incubated with medium containing the test compound or relevant controls [untreated control, solvent control and positive controls methyl methanesulphonate (20micrograms/ml without S-9) and benzo(a) p yrene (25 micrograms/ml with S-9)] for either 3 hours in the presence of S9 mix (from Aroclor 1254-induced rat liver) or 24 hours in the absence of S9 mix. The concentrations of test material used (from 10 to 5000 micrograms/ml without S-9 and 100 to 5000 micrograms/ml with S-9) were chosen based on the results of p reliminary miscibility and mitotic index studies. Duplicate cultures were prepared for each test condition. Two separate experiments were conducted using different concentrations. Metaphase cells were prepared on glass microscope slides for the analysis of chromosome aberrations 24 hours following exposure for the cultures with or without S9 mix. All slides were coded. Where p ossible, 200 metaphases were scored for each dose group. Only those cells showing the modal chromosome number (20) +/- 2 were analyzed for chromosome damage. Chromosome aberrations were classified according to the scheme described by Savage (J Med Genetics 12:103-122, 1976). Evaluation criteria N ot specified. Statistics The mitotic index of each group was assessed by counting the number of metaphases in a total of 1000 cells. Data were assessed for heterogeneity using the Fisher’s exact test. The number of aberrations excluding gaps, aberrations including gaps, isogaps and/or chromatid gaps and p olyploidy and/or endoreduplication of treated cells was compared to controls using the Fisher’s exact test. A Cochran-Armitage trend test was carried out on the dose/response. The test was p erformed twice, once excluding control data and the other including the solvent control. Results and discussions Test results Species/strain Chinese hamster Ovary (CHO) Metabolic activation with and without Test system all strains/cell types tested Genotoxicity negative Cytotoxicity no, but tested up to limit concentrations Vehicle controls valid N egative controls valid

Positive controls valid Additional information on results Cells exposed to test material at concentrations up to 5000 micrograms/ml showed no increase in chromosome damage or no linear trend compared to negative controls in either experiment. The positive control induced significantly more cells with aberrations compared to the negative controls (for untreated control and for solvent control). In the first experiment with S-9 (up to 1875 micrograms/ml test material), there was no effect of treatment on the incidence of type of aberration observed. However, there was a significant difference in the number of cells with chromatid gaps and/or isogaps between the untreated control (7/200) and solvent control cultures (1/200). In the second experiment with S-9 (cells were treated with 1500, 3000 or 5000 micrograms/ml test material), there was a significant difference in the number of cells with aberrations including gaps (11/200) and cells with chromatid gaps and/or isogaps (8/200) at the 1500 micrograms/ml compared to the solvent control (2/199 and 0/199, respectively). There also was a significant increase in the number of cells with chromatid gaps and/or isogaps at the high concentration (5/200) compared to control, and between both controls (untreated control had 7/200). N o linear trend was observed either by including or excluding the solvent controlfrom the analysis. The positive control caused increases in aberrations with and without gaps compared to the solvent control in both studies.
The cytotoxic concentration was > 5000 micrograms/ml. Remarks on results including tables and figures
The small random increases in the number of chromatid gaps and/or isogaps in one experiment with S-9, which were not dose-dependent and not different from the untreated controls were not considered to be compound-related effects by study personnel.

Overall remarks, attachments Overall remarks

Applicant's summary and conclusion Interpretation of results negative Conclusions Study personnel concluded that under the test conditions, the test material did not induce chromosomal aberrations either in the presence or absence of S9 mix. Genetic toxicity in vitro UC MPEG 1984.003 UUID IUC5-69753a40-2c9e-4e54-8a36-02ad24a8bc1e Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-25 13:17:08 EDT Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 84

Reliablility 1 (reliable without restriction) Rationale for reliability Well conducted study per GLP and with test substance well characterized as to composition. Data source Reference Reference type study report

Author Year 1984 Title Carbowax methoxy polyethylene glycol 350 Salmonella/microsome (Ames) bacterial mutagenicity assay.Bibliograph ic source Testing laboratory Bushy Run Research Center. Report

no. Owner company Union Carbide

Company study no. Report date 1984-10-2 3 Materials and methods Type of genotoxicity gene mutation Type of study bacterial reverse mutation assay (e.g. Ames test) Principles of method if other than guideline N o guideline was referenced in the study, but the study method followed conventional p rocedure for Ames studies. GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 9004-74-4

Identifier Common name Identity Carbowax MPEG-350 Details on test material The test material (CARBOWAX MPEG-350; CAS No. 9004-74-4) is a mixture of several methylated glycol ethers of differing molecular weight (ranging from diethylene glycol monomethyl ether (C2) to heptadecaethylene glycol monomethyl ether (C17)). The majority of the material is in the C5-C11 range (87.445%). It contains 4.347 % (by weight) tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 1.303% triethylene glycol monomethyl ether (CAS No. 112-35-6), 0.181% diethylene glycol monomethyl ether (CAS No. 111-77-3).Purity of test material was 99.8%. Impurities included 0.1% water, 0.05% ethylene glycol, 0.05% diethylene glycol, and 50-150 p pm BHT. Method Species/strain Species/strain other: S. typhimurium TA98, TA100, TA1535, TA1537, TA1538 Details on mammalian cell lines (if applicable) Additional strain

characteristics Metabolic activation with and withoutMetabolic activation system 0.5 ml of S9 mix containing 50 microliters of S9 liver homogenate from Aroclor 1254-induced, Sprague-Dawley male rats Test concentrations 1, 3, 10, 30 and 110 mg/ p late Vehicle
water Controls N egative controls yes

Solvent / vehicle controls yes
True negative controls no
Positive controls yes

Positive control substance other: 4-nitro-o- p henylenediamine, sodium azide, 9-aminoacridine and 2-aminoanthracene Remarks Details on test system and conditions Test material was dissolved in water to a concentration of 300 mg/ml for doses of 30 mg/ p late and below. All subsequent dilutions were made in the same solvent. Dilutions of test substance were made fresh each day and were gravimetrically analyzed. The volume of test material used in each test was 100 microliters. If necessary, p hosphate buffered saline was added to adjust the volume.
A preliminary toxicity test was performed in strain TA100 to determine concentrations to use on other strains (TA98, TA1535, TA1537, TA1538). N one of the doses used (up to 100 mg/ p late) were toxic. Test material was tested in the Ames assay in triplicate at five doses (1, 3, 10, 30 and 110 mg/ p late). Testing was performed with and without metabolic activation (0.5 ml of S9 mix containing 50 microliters of S9 liver homogenate from Aroclor 1254-induced, Sprague-Dawley male rats). Concurrent water and positive controls (4-nitro-o- p henylenediamine for TA98 and TA 1538, sodium azide for TA100 and TA1535 and 9-aminoacridine for TA1537 in the absence of S9 and 2-aminoanthracene for all stains in the p resence of S9) were run with each test. Evaluation criteria The test was considered valid, if positive controls caused mutagenicity and negative controls exhibited spontaneous reversion rates that were within historical range. Statistics no data Results and discussions Test results Species/strain other: S. typhimurium TA98, TA100, TA1535, TA1537, TA1538 Metabolic activation with and without Test system all strains/cell types tested Genotoxicity negative Cytotoxicity yes Vehicle controls valid yes N egative controls validPositive controls valid yes Additional information on results The test was valid, as positive controls caused mutagenicity and negative controls exhibited spontaneous reversion rates that were within historical range.
Cycotoxic concentration: > 110 mg/ p late Applicant's summary and conclusion Interpretation of results negative Conclusions Mutagenic activity was not observed with any concentration in any of the strains (with or without bacterial activation). 7.6.2 Genetic toxicity in vivo Genetic toxicity in vivo McClintock & Gallapudi Mouse MN TGME 1990.001 UUID IUC5-0fa2b92b-8f46-46bd-b785-b62cbe5a929b Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-24 17:15:25 EDT Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 90 Reliablility 1 (reliable without restriction) Rationale for reliability Guideline study following GLP with test substance purity noted.

Data source Reference Reference type study report

Author McClintock ML and Gollapudi B. Year 1990 Title Evaluation of triethylene glycol monomethyl ether in the mouse bone marrow micronucleus test. Bibliograph ic source Testing laboratory Report

no. Owner company Dow Chemical Company

Company Study ID TXT:K-005610-007 Report 1990-03-0study no. date 7 Materials and methods Type of study micronucleus assay Test guideline Qualifier according to Guideline EPA OPPTS 870.5200 (Mouse Visible Specific Locus Test) Deviations Principles of method if other than guideline Study reference for protocol used is: Test Standard 40 CFR 798.5395 GLP compliance
yes Test materials Test material equivalent to submission substance identity
yes Test material identity Identifier CAS number Identity 112-35-6

Identifier EC number Identity 203-962-1

Identifier Common name Identity triethylene glycol monomethyl ether Details on test material Purity was 99.23%. Test animals Species

mouse Strain CD-1 Sex male/female Details on test animals and environmental conditions Strain specifically denoted to be CD-1 (ICR)BR. The animals were approximately 8 weeks old. Administration / exposure Route of administration oral: gavage Vehicle(s)
water Details on exposure Test material was dissolved in water and administered to mice (approximately 8 weeks old) by single oral gavage at dose levels of 0 (water), 500, 1667 and 5000 mg/kg body weight (10 ml/kg). A previous study revealed that 5000 mg/kg did not affect survival. Concentrations of test material in dosing solutions were verified by HPLC. Groups of animals(5/sex/dose/sacrifice time) were sacrificed by cervical dislocation 24, 48 and 72 hours after treatment. Mice (5/sex)treated with 120 mg/kg cyclophosphamide and sacrificed after 24 hours of treatment served as p ositive controls. Duration of treatment / exposure Single dose Frequency of treatment Single dose Post exposure period up to 72 hours Doses / concentrations 500, 1667, 5000 mg/kg bw Basis nominal in water N o. of animals per sex per dose 5 animals per sex per dose Control animals yes, concurrent vehicle Positive control(s) Mice (5/sex) treated with 120 mg/kg cyclophosphamide and sacrificed after 24 hours of treatment served as positive controls. Examinations Tissues and cell types examined Bone marrow samples were obtained from both femurs at sacrifice. Cell smears were prepared from cell suspensions. Details of tissue and slide preparation The slides were air dried, fixed in methanol and stained in 5% Giemsa. Slides were coded and scored blindly. One thousand polychromatic erythrocytes (PCE) were evaluated from each surviving animal and the frequencies of micronucleated polychromatic erythrocytes (MN-PCE) were recorded. Micronuclei were identified as darkly stained bodies with sharp contours and varying shapes such as round, almond, or ring. The ratio of PCE- N CE (normochromatic erythrocytes) in the bone marrow was determined by examining 100 erythrocytes. Evaluation criteria The test was valid if positive controls had significantly more MN-PCE than controls (62.2 in males and 34.6 in females). Statistics Statistical Analysis: The raw data on the counts of MN-PCE for each animal were transformed by adding 1 to each count and then taking the natural log of the adjusted number. The transformed MN-PCE data and the data on percent PCE were analyzed by a three-way analysis of variance looking only at main effects. Pairwise comparisons between treated vs. negative controls were done (if necessary) by a t-test usingBonferroni correction for multiple comparisons. Results and discussions Test results Sex male/female Genotoxicity negative Toxicity Vehicle controls valid yesN egative controls valid Positive controls valid yes Additional information on results One female dose with 1667 mg/kg test material died prior to scheduled sacrifice. The cause of death was not determined. There were no significant increases in the frequencies of micronucleated polychromatic erythrocytes (MN-PCE) in groups treated with test material (range from 0.2 to 1.6) versus negative controls (range 0.4 to 1.2). The ratios of polychromatic erythrocytes (PCE) to normochromatic erythrocytes ( N CE) (% PCE) in test animals (67.3 to 82.0) also were similar to those of negative controls (70.6 to 78.7).
The test was valid as positive controls had significantly more MN-PCE than controls (62.2 in males and 34.6 in females). Applicant's summary and conclusion Interpretation of results negative 7.8 Toxicity to reproduction 7.8.1 Toxicity to reproduction Toxicity to reproduction Corley 13-Week TGME 1990.001 UUID IUC5-bc1d6241-8df0-4e2d-a692-b5539b165837 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-24 17:15:26 EDT Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1 9 9 0 Reliablility 2 (reliable with restrictions) Rationale for reliability Effect on mating was not characterized. Otherwise study was robust per current protocol following GLP. Data source Reference

Reference type study report Author Corley RA, Ciesslak, Breslin WJ, Lomax LG. Year 1990 Title 13-Week dermal toxicity study in Sprague-Dawley rats. Bibliographic

source Testing laboratory Report no.Owner
company Dow Chemical Company

Company study

no. Study ID K-005610-004 Report date 1990-09-26

Reference type p ublication

Author Gill MW, Fowler EH, Gingell R, Lomax LG, Corely RA. Year 1998 Title Subchronic dermal toxicity and oral neurotoxicity of triethylene glycol monomethyl ether in CD rats Bibliograph ic source Int J Toxicol 17:1-22.

Testing laboratory Report

no. Owner company Company study no. Report date Cross-reference to same study The same study is summarized as a 91 day dermal repeat dose study in Sprague-Dawley rats. This is repeated dose toxicity dermal.001 Materials and methods Test type fertility Limit test

no Test guideline Qualifier according to Guideline other guideline: EPA. 1989. 40 CFR 799, Fed Reg 54:13470-13477). Deviations GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 112-35-6

Identifier EC number Identity 203-962-1

Identifier Common name Identity triethylene glycol monomethyl ether Details on test material Purity (as determined by gas chromatography) was 99.23 % at the onset of the study and99.24% at completion of the in-life phase. Test animals Species
rat Strain Sprague-Dawley Sex male/female Details on test animals and environmental conditions 8 week-old rats Administration / exposure Route of administration dermal Vehicle unchanged (no vehicle) Details on exposure Triethylene glycol monomethyl ether (TGME) was administered dermally to 8 week-old rats (10/sex/dose level) at 0 (sham control), 400, 1200 or 400 mg/kg/day for 13 weeks. Test material was applied to shaved areas of skin on the back and sides of each rat (12 cm2 in area), uniformly spread, and covered with a semiocclusive dressing for 6 hours. After removal of the dressing, the application site was wiped with a dampened towel. Material was applied in this manner daily, 5 days/week for 13 weeks. Details on mating procedure N o mating Analytical verification of doses or concentrations
yes Details on analytical verification of doses or concentrations Purity of test substance as administered (as determined by gas chromatography) was 99.23 % at the onset of the study and 99.24% at completion of the in-life phase. Duration of treatment / exposure 91 days Frequency of treatment daily, 6 hr/day, 5 days/week Doses / concentrations 0 (sham control), 400, 1200 or 400 mg/kg/day Basis analytical conc. N o. of animals per sex per dose 10/sex/dose level Control animals yes, sham-exposed Examinations Parental animals: Observations and examinations Upon necropsy the test animals were examined. The oocytes, corpora lutea, and follicles from each ovary were evaluated with regard to their normal development. The testes and epididymes also were examined microscopically for males in the intermediate- and low-dose groups.Postmortem examinations (Parental animals) See Repeated dose dermal study.001 for details Results and discussions Effect levels Endpoint N OAEL Generation P Sex male/female Effect level 4000 mg/kg bw/day (actual dose received) Basis for effect level / Remarks N OAEL for systemic effects on test animals. Conclusion of summary preparer; no adverse systemic effects seen at highest dose.

Endpoint N OAEL

Generati

on P

Sex male/female Effect level >= 400

—< 1200 mg/kg bw/day (actual dose received)

Basis for effect level / Remarks Interpretation of EPA, based on bilaterally decreased spermatogenesis observed in one male treated with the highest dose (4000 mg/kg bw) and testicular changes observed in one male treated with 1200 mg/kg.

Observations: p arental animals Clinical signs ( p arental animals)
yes Body weight and food consumption ( p arental animals)
yes Reproductive function: estrous cycle ( p arental animals)
yes Reproductive function: sperm measures ( p arental animals)
yes Reproductive performance ( p arental animals) not examined Organ weights ( p arental animals)
yes Gross pathology ( p arental animals)
yes Histopathology ( p arental animals)
yes Details on results ( p arental animals) There were no indications of systemic toxicity at any dose. Mean body weight and food consumption were comparable to controls throughout the study. Bilaterally decreased spermatogenesis in seminiferous tubules and decreased spermatozoa in the epididymes (both were graded as severe) were noted in the testes of one high dose male rat. This animal had a complete lack of mature spermatids in greater than 41% of tubules in each testicle, few spermatids beyond stage 12 of development in the seminiferous epithelium, and decreasedspermatic elements in the head and tail of greater than 41% of the tubules and ducts in the epididymides. The testes of one male treated with 1200 mg/kg exhibited different testicular changes [bilateral multifocal degeneration of spermatocytes and spermatids from germinal epithelium (graded as very slight), and multinucleated spermatids]. In this rat, all stages of the cycle of the seminiferous epithelium were observed in morphologically normal tubules. The epididymides of this rat had decreased spermatic elements in the head and tail of 1-5% of ducts. Some of the ducts also contained immature spermatids. There were no effects on estrous cyclicity or ovaries of females. Observations: offspring Remarks on results including tables and figures

Study personnel concluded that the bilateral microscopic testicular changes observed in one high-dose and one mid-dose male rat were unrelated to treatment. Reasons given were that the dissimilarity of the lesions for the two animals suggested that they occurred spontaneously, and the incidence of animals with lesions (1/10 in each group) was well within that of historical controls (0-17%). Study personnel also stated that the degenerative changes in the testes of one mid-dose and one high-dose rat were not consistent with the types of lesions that have been attributed to 2-methoxyethanol (2-ME). The cell types that are most vulnerable to 2-ME are the pachytene spermatocytes and round spermatids (Chapin et al., Fund Appl. Toxicol 5:182-189, 1985). As the dose of 2-ME is increased, the number and types of cells affected increase up to the point that the germinal epithelium is significantly degenerated and all stages of spermatogenesis are affected (Chapin et al., Fund Appl. Toxicol 5:182-189, 1985; Miller et al., Fund Appl Toxicol 3:49-54, 1983.). In contrast, the testicular effects seen with the high dose animal treated with TGME consisted of a virtually complete lack of mature spermatids beyond stage 12. All other stages, including spermatogonia and spermatocytes, were present and appeared morphologically normal. In the mid-dose rat, the only effects noted consisted of very slight degeneration of spermatocytes and spermatids similar to those seen in historical control animals.

Study personnel also stated that the lymphoid tissues and hematologic parameters, which have been reported to be affected at doses of 2-methoxyethanol that have been associated with testicular changes (Miller et al., Fund. Appl. Toxicol. 3:49-54, 1983) were unaffected in this TGME study. Taking all factors into consideration, the testicular lesions observed in this dermal study could not be directly attributed to TGME exposure.

Overall remarks, attachments Overall remarks

Additional details for this study can be found in the Repeated dose dermal study.001 summary.

The EPA has determined that based on severe testicular toxicity in 1/10 rats given 4000 mg/kg/day and minimal decreases in developing germ cells (1-5% of semiferous tubules affected) in 1/10 rats given 1,200 mg/kg/day, the NOAEL for testicular toxicity is between 400 and 1200 mg/kg/day (Anderson, L. Triethylene glycol monomethyl, monoethyl and monobutyl ethers RM1 screening document (draft), Feb. 24, 1995). This value was reached even though it was recognized that the testicular changes in the 1,200 mg/kg/day rat were within historical control limits for Sprague-Dawley rats (0 1 7 %).
Toxicity to reproduction Gill & N egley TGME 1990.003 UUID IUC5-65051ae6-6747-493c-8e40-94db9826a616 Dossier UUID 0Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-24 17:15:26 EDT Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 90

Reliablility 2 (reliable with restrictions) Rationale for reliability Well conducted, robust study, following GLP, but the effect on mating was not characterized. Data source Reference

Reference type Author Gill MW and Negley JE. Year 1990 Title Triethylene glycol monomethyl ether. N inety day subchronic drinking water inclusion neurotoxicity study in rats. Bibliograp hic source Testing laboratory Bushy Run Research Center Report

no. Owner company Union Carbide

Company study no. Project Report 52-607, Report date 1990-09- 21 Cross-reference to same study This study is also summarized as a repeated dose study in Repeated dose study oral.001 Materials and methods Test type fertility Limit test

no Principles of method if other than guideline The route of administration and maximum dose level was specified in a testing consent order (EPA. 1989. 40 CFR 799, Fed Reg 54:13470-13477). GLP compliance
yes Test materials Test material equivalent to submission substance identity

noTest material identity Identifier CAS number Identity 112-35-6

Identifier EC number Identity 203-962-1

Identifier Common name Identity triethylene glycol monomethyl ether Details on test material The purity was at least 98.7%. Test animals Species
rat Strain Sprague-Dawley Sex male/female Details on test animals and environmental conditions no data Administration / exposure Route of administration oral: drinking water Vehicle unchanged (no vehicle) Details on exposure Rats were treated with triethylene glycol monomethyl ether (TGME) for 91 days via drinking water at target doses of 0, 400, 1200 and 4000 mg/kg/day. Details on mating procedure Study did not include mating. Study examined male reproductive organs. Analytical verification of doses or concentrations no data Duration of treatment / exposure 91 days Frequency of treatment daily Doses / concentrations 0, 400, 1200 and 4000 mg/kg/day. Basis nominal in water N o. of animals per sex per dose 15/sex/group Control animals other: concurrent water Positive control no data ExaminationsParental animals: Observations and examinations Rats were observed daily for clinical signs and weekly for body weight and water and food consumption. Rats were also observed periodically for behavior (functional observational battery) and motor activity. Estrous cyclicity (Parental animals) no data Sperm parameters (Parental animals) Yes, see results section. Litter observations

no Postmortem examinations (Parental animals) Gross lesions and organ weights were recorded at necropsy. Microscopic analyses of liver, testes and the nervous system also were performed. Postmortem examinations (Offspring)

no Statistics no data Reproductive indices no data Offspring viability indices no data Any other information on materials and methods incl. tables

The authors state that a possible contributing factor in the development of testicular lesions at the high dose was low-level contamination of the test substance with the known testicular toxicant 2-methoxyethanol (EGME). EGME was present in the test substance at a concentration of 0.02  0.04 %, resulting in a EGME dose up to 1.7 mg/kg/day for animals in the high dose group. Given the length of the study, it is possible that EGME contributed to the testicular lesions. A comparison between the doses of EGME and TGME required to produce testicular toxicity indicated that TGME is 350 times less potent than EGME in producing testicular lesions in the rat. The dose of TGME that caused testicular toxicity (4000 mg/kg/day) is 4 times greater than the 1000 mg/kg/day limit dose generally recommended for subchronic studies.

Results and discussions Effect levels Endpoint N OAEL Generation P Sex male/female Effect level 1200 mg/kg bw/day (nominal) Basis for effect level / Remarks Interpretation by summary preparer for reproduction organ toxicity.

Endpoint N OAEL Generation P Sex male/female Effect level > 400

—< 1200 mg/kg bw/day (nominal) Basis for effect Interpretation by the Environmental Protection Agency for testicularlevel / Remarks effects. Observations: p arental animals Clinical signs ( p arental animals)
yes Body weight and food consumption ( p arental animals)
yes Test substance intake ( p arental animals)
yes Reproductive function: estrous cycle ( p arental animals) no data Reproductive function: sperm measures ( p arental animals)
yes Reproductive performance ( p arental animals) no data Organ weights ( p arental animals)
yes Gross pathology ( p arental animals)
yes Histopathology ( p arental animals)
yes Details on results ( p arental animals) The testes of males in the high dose group exhibited degeneration (12/15) and/or atrophy (5/5) of the seminiferous tubules (spermatocytes or developing spermatids). The authors concluded that these effects were related to treatment. The severity of the lesions was primarily mild to moderate for degeneration (11/12) and minimal to moderate for atrophy (5/5), indicating that not all tubules were affected and that a limited number of cells was affected within the affected tubules. One male treated with 1200 mg/kg had severe seminiferous tubule atrophy, a complete loss of cell types in the tubules (except for Sertoli cells) and moderate Leydig cell hypertrophy (not significant from control). This was not considered to be related to treatment because of the lack of a plausible explanation for the unusual dose-response relationship (the effect at this dose was more severe than that of a higher dose) and the low incidence of animals affected at this dose level (Gill et al., Int J Toxicol 17:1-22, 1998) One male treated with 1200 mg/kg had severe seminiferous tubule atrophy and moderate Leydig cell hypertrophy (not significant from control). N o testicular changes were noted in males treated with 400 mg/kg/day TGME. Observations: offspring Viability (offspring) not examined Clinical signs (offspring) not examined Body weight (offspring) not examined Sexual maturation (offspring) not examined Organ weights (offspring) not examinedGross pathology (offspring) not examined Histopathology (offspring) not examined Details on results (offspring) 91 Day repeated dose study did not include mating, but examined male testes. Remarks on results including tables and figures

The NOAEL listed is for reproductive organ toxicity. Other results are shown in section 5.4. The summary preparer-assigned NOAEL and LOAEL for testicular effects is 1200 and 4000 mg/kg/day, respectively. By contrast, the EPA has determined that the NOAEL for testicular effects is between 400 and 1200 mg/kg/day (Anderson, L. Triethylene glycol monomethyl, monoethyl and monobutyl ethers RM1 screening document (draft), Feb. 24, 1995).
Toxicity to reproduction UC MPEG 1985.002 UUID IUC5-5d2c5dc1-58d6-41e5-9873-37382b3a4d95 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-25 13:17:09 EDT Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1985

Reliablility 2 (reliable with restrictions) Rationale for reliability Well conducted, robust study with test substance well characterized as to composition. Study conducted following GLP. N o guideline specified Data source Reference Reference type study report

Author Year 1985 Title N ine-day and ninety-day dermal toxicity studies of CARBOWAX MPEG-350 in rabbits. Bibliographi

c source

Testing laboratory Bushy Run Research Center Report

no. Owner company Union Carbide

Company study no. Report date 1985-05-3 0Reference type Author Hermansky SJ, Leung HW. Year 1997 Title Cutaneous toxicity studies with methoxy polyethylene glycol-350 (MPEG-350) in rats and rabbits. Bibliograph ic source Testing laboratory Report

no. Owner company Company study no. Report date Cross-reference to same study This study is also summarized as a 90 day repeated dose dermal study. See repeated dose toxicity dermal.002 for further details. Materials and methods Test type fertility Limit test

no Principles of method if other than guideline N o guideline specified, but study was conducted following standard procedures and principles. GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 9004-74-4

Identifier Common name Identity CARBOWAX MPEG 350 Details on test material The test material (CARBOWAX MPEG 350, CAS No. 9004-74-4) wasreported to be chemically inert (stable for > 6 months at room temperature) and 99.8% p ure. This material is a mixture of several methylated glycol ethers of differing molecular weight (ranging from diethylene glycol monomethyl ether (C2) to heptadecaethylene glycol monomethyl ether (C17)). The majority of the material is in the C5-C11 range (87.445%). It contains 4.347 % (by weight) tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 1.303% triethylene glycol monomethyl ether (CAS No. 112-35-6), 0.181% diethylene glycol monomethyl ether (CAS No. 111-77-3). Test animals Speciesrabbit Strain N ew Zealand White Sex male/female Details on test animals and environmental conditions Body weights of males and females ranged from 2.5 to 3.2 kg and 2.5 to 3.1 kg at study initiation. Administration / exposure Route of administration dermal Vehicle other: methyl cellulose in distilled water Details on exposure Dosing: N ew Zealand white rabbits (10/sex/dose) were treated dermally on clipped dorsal skin with 1.0 ml of vehicle (0.1% (w/v) methyl cellulose in distilled water), 50% CARBOWAX MPEG-350 (w/v dilution in 0.1% methyl cellulose in water) or 100% CARBOWAX MPEG-350, for six hours/day, five days per week for 90 days. Rabbits were fitted with Elizabethan collars after dosing to prevent ingestion of test material. After each 6-hour exposure the application site was wiped with a paper towel dampened with water and then dried using a towel. Rabbits were then uncollared until the next treatment. Analytical verification of doses or concentrations no data Duration of treatment / exposure 90 days Frequency of treatment daily, six hours/day, five days per week Doses / concentrations 1 ml of 50% and 100% material (approximately 169 and 338 mg/kg/day) Basis nominal conc. N o. of animals per sex per dose 10/sex/dose Control animals yes, concurrent vehicle Further details on study design A preliminary range-finding study in 15 rabbits dosed 6 hr/day for 9 days showed that daily administration of 1 ml of 50% or 100% test material only caused mild skin irritation. Therefore, these doses were chosen for the90-day study.
Based on weights of animals determined at weekly intervals and the reported density of test material (1.09 g/ml) doses can be calculated on average mg/kg/day basis. These doses are 169 mg/kg/day (for 50%) and 338 mg/kg/day (for 100%). Examinations Parental animals: Observations and examinations Observations: All rabbits were observed daily (weekdays) for death, clinical signs and dermal irritation. Body weights were recorded on the morning of the first day of dosing, weeklythereafter and prior to sacrifice. Food consumption was measured weekly. Urine was collected from 5 animals/sex/group during the last two weeks of dosing and subjected to standard analyses. Standard hematology and clinical chemistry parameters were evaluated for all animals j ust prior to sacrifice. Estrous cyclicity (Parental animals) no data Sperm parameters (Parental animals) no data Postmortem examinations (Parental animals) N ecropsy: All animals were sacrificed and necropsied after 13 weeks of treatment. Weights were recorded for liver, kidneys, brain and adrenals of all animals and testes of males. Histopathologic examinations were performed on tissues (including testes, epididymes, p rostate, accessorysex glands, uterus, ovaries and mammary gland) from high-dose and control animals. Results and discussions Effect levels Endpoint N OAEL Generation P

Sex male/female Effect level 338 mg/kg bw/day (nominal)

Basis for effect level / Remarks The NOAEL listed is for reproductive organ toxicity. The NOAEL for systemic effects was not listed by the investigators. Based on the data, this value is 100% (338 mg/kg/day). Observations: p arental animals Clinical signs ( p arental animals)
yes Body weight and food consumption ( p arental animals)
yes Test substance intake ( p arental animals)
yes Reproductive function: estrous cycle ( p arental animals) no data Reproductive function: sperm measures ( p arental animals)
yes Organ weights ( p arental animals)
yes Gross pathology ( p arental animals)
yes Histopathology ( p arental animals)
yes Details on results ( p arental animals) N o effects on any test animal sex organ were observed Observations: offspring Remarks on results including tables and figuresThe NOAEL listed is for reproductive organ toxicity. Further details of this study can be found in the summary for repeated dose toxicity dermal.002. The NOAEL for systemic effects was not listed by the investigators. Based on the data, this value is 100% (338 mg/kg/day).
7.8.2 Developmental toxicity / teratogenicity Developmental toxicity / teratogenicity Hoberman TGME Rats 1990.002 UUID IUC5-b7c1466f-70d0-481e-817f-c4f81d91cf44 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-24 17:15:27 EDT Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 90 Reliablility 1 (reliable without restriction) Rationale for reliability Robust study following GLP and standard protocol.

Data source Reference

Reference type study report

Author Hoberman AM. Year 1990 Title Triethylene glycol monomethyl ether (TGME): oral developmental toxicity study in Crl:CD(SD)BR pregnant rats. Bibliograp hic source Testing laboratory Argus Research Laboratories, Inc. Report

no. StudyNumber 503-005.

Owner company Company study no. Report date Materials and methods Limit test

no GLP compliance

no Test materials Test material equivalent to submission substance identityyes Test material identity Identifier CAS number Identity 112-35-6

Identifier EC number Identity 203-962-1

Identifier Common name Identity triethylene glycol methyl ether Details on test material no details Test animals Species
rat Strain Sprague-Dawley Details on test animals and environmental conditions 203 to 256 g Administration / exposure Route of administration oral: gavage Vehicle unchanged (no vehicle) Details on exposure Groups of 25 mated female rats (203 to 256 g) were given daily dosages of 4.8 ml of deionized water (control), or 0.6, 1.2, 2.4, and 4.8 ml/kg/day of triethylene glycol monomethyl ether (TGME) by gavage. These doses corresponded to 0, 625, 1250, 2500 or 5000 mg/kg/day. All doses were adjusted daily according to body weights recorded immediately prior to intubation. Analytical verification of doses or concentrations no data Duration of treatment / exposure Days 6 to 15 of gestation Frequency of treatment daily Duration of test 15 days Doses / concentrations 0, 625, 1250, 2500 or 5000 mg/kg/day Basis nominal conc. N o. of animals per sex per dose 25 females per dose Control animals yes, concurrent vehicle
yes, sham-exposedExaminations Maternal examinations Rats were observed at least twice daily during the dosage and postdosage periods for clinical signs, signs of resorption, p remature deliveries and death. Body weight and feed consumption were recorded on Day 0 of presumed gestation and from days 6 through 20 of gestation. Dams that were found dead were necropsied on day of death and subjected to the same procedures described for scheduled sacrifice. Ovaries and uterine content Rats were sacrificed on Day 20 of presumed gestation, and the thoracic and abdominal viscera were examined for gross lesions. The uterus was excised from each rat and weighed. The number and placement of implantations were recorded and sites were categorized as early or late resorptions, or live or dead fetuses. Each ovary was examined for the number of corpora lutea. Fetal examinations Fetuses were weighed, sexed, and examined for external alterations. One-half were examined for soft tissue alterations, and the remaining half were examined for skeletal alterations. Statistics Maternal and fetal incidence data were analyzed suing the variance test for homogeneity of the binomial distribution. Maternal body weight and feed consumption data, organ weight data, and litter averages for percent male fetuses, p ercent dead or resorbed conceptuses per litter, fetal body weights, fetal ossification sites, and percent fetal alterations were analyzed using Bartlett's Test of homogeneity of variances and the analysis of variance (when data were homogeneous). If the analysis of variance was significant, Dunnett's Test was used to identify the statistical significance of individual groups. If data were not homogeneous, the Kruskal-Wallis test was used when less than or equal to 75% ties were present; when more than 75% ties were present the Fisher's Exact Test was used. In cases where the Kruskal-Wallis Test was statistically significant, Dunn's Method of Multiple Comparisons was used to identify the statistical significance of individual groups.
All other Caesarean-sectioning data were evaluated using the procedures previously described for the Kruskal-Wallis Test. Results and discussions Effect levels Endpoint N OAEL Effect type maternal toxicity Effect level 1250 mg/kg bw/day (nominal) Basis for effect level / Remarks Reduced food consumption was observed at the next higher dose (2500 mg/kg bw).
Endpoint N OAEL Effect type teratogenicity

Effect level 625 mg/kg bw/day (nominal)

Basis for effect level Groups given 1250 mg/kg/day and higher doses of TGME had significant increases in the litter and/or fetal incidences of reversible delays in fetal ossification./ Remarks Maternal toxic effects
yes Details on maternal toxic effects One nonpregnant animal in the high dose group (5000 mg/kg/day) was found dead on day 13 of p resumed gestation. This was considered by the authors to be treatment-related. Significant numbers of rats treated with the high dose exhibited decreased motor activity, excess salivation, ataxia, and impaired righting reflex. Food consumption of high dose animals were reduced over the entire dosage period. Average maternal body weight gains of rats in the high dose group were reduced on days 6-9, 6-12, 12-16, and 6-16 of gestation. Consequently, average body weights of these animals were reduced on days 9, 12, and 16. Average gravid uterine weights of high-dose animals were also reduced.
Food consumption of rats receiving 2500 mg/kg/day was reduced during days 6-16, 6-18, and 12-16. Food consumption and average maternal body weights and body weight gains in rats receiving 1250 mg/kg/day were not significantly different from controls. Therefore, 1250 mg/kg/day was considered by study personnel to be the NOAEL for maternal toxicity.
There was no effect of TGME on the number of pregnant dams or number of copora lutea, implantations, live litter size or fetal sex ratios. Embryotoxic / teratogenic effects
yes Details on embryotoxic / teratogenic effects Fetal: Significant increases in embryo-fetal lethality (litter averages for total resorptions (1.6 versus 0.6 in control), late resorptions (0.3 versus 0 in controls), p ercentage of resorbed conceptuses (12.0 versus 4.4 incontrol) and dams with at least one resorption (81.8% versus 47.8 in control) occurred in the 5000 mg/kg group. Fetuses from rats treated with 2500 or 5000 mg/kg had lower body weights than controls (3.04 and 2.56 g (respectively) versus 3.32 in controls).
There was no effect of TGME on the incidences or types of gross external or internal soft tissue malformations. Groups given 1250 mg/kg/day and higher doses of TGME had significant increases in the litter and/or fetal incidences of reversible delays in fetal ossification. Fetuses from rats given 2500 or 5000 mg/kg/day also had a significant increase in the incidence of cervical ribs. The NOAEL for developmental toxicity was considered by study personnel to be 625 mg/kg/day. Remarks on results including tables and figures

The authors remarked that the skeletal variations noted were common observations in fetuses with reduced body weights. Since only reversible delays in fetal ossification were observed in the 1250 mg/kg/day group, the actual NOAEL may be close to this concentration. The NOAEL listed under teratogenicity is the NOAEL for developmental toxicity.
Developmental toxicity / teratogenicity Hoberman TGME Rabbits 1990.003 UUID IUC5-d2c695b2-ef8c-491e-b413-e22684b2304f Dossier UUID 0Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-24 17:15:28 EDT Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 90 Reliablility 1 (reliable without restriction) Rationale for reliability Robust study following GLP and standard methodology

Data source Reference

Reference type study report

Author Hoberman AM. Year 1990 Title Triethylene glycol monomethyl ether (TGME): oral developmental toxicity study in New Zealand White rabbits. Bibliograp hic source Testing laboratory Argus Research Laboratories, Inc. Report

no. 503-004

. Owner company Company study no. Report date Materials and methods Limit test

no Principles of method if other than guideline Study followed standard methodology GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 112-35-6

Identifier EC number Identity 203-962-1Identifier Common name Identity Triethylene glycol methyl ether (TGME) Details on test material no details Test animals Species rabbit Strain N ew Zealand White Details on test animals and environmental conditions no data Administration / exposure Route of administration oral: gavage Details on exposure Groups of 20 artificially inseminated female rabbits were given daily dosages of 0 (same volume of deionized water as the highest dose), 250, 500, 1000 or 1500 mg/kg/day of triethylene glycol monomethyl ether (TGME) by gavage. All doses were adjusted daily according to body weights recorded immediately prior to intubation. Analytical verification of doses or concentrations no data Details on analytical verification of doses or concentrations no data Details on mating procedure artificial insemination Duration of treatment / exposure days 6 to 18 of gestation Frequency of treatment daily Duration of test 24 days Doses / concentrations 0, 250, 500, 1000 or 1500 mg/kg/day Basis nominal conc. N o. of animals per sex per dose 20 artificially inseminated female rabbits Control animals yes, concurrent vehicle Examinations Maternal examinations Rabbits were observed daily during the course of the study for clinical signs, abortions, p remature deliveries and death. Body weights were recorded on Day 0, and Days 6 through 29 of presumed gestation. Food consumption was recorded daily. Ovaries and uterine content Rabbits were sacrificed on Day 29 of presumed gestation, and the thoracic and abdominalviscera were examined for gross lesions. The uterus was excised from each animal and weighed. The number and placement of implantations were recorded and sites were categorized as early or late resorptions, or live or dead fetuses. Each ovary was examined for the number of corpora lutea. Fetal examinations Fetuses were weighed, sexed, and examined for external and soft tissue or skeletal alterations. Statistics no data Results and discussions Effect levels Endpoint N OAEL Effect type maternal toxicity Effect level 500 mg/kg bw/day (nominal) Basis for effect level / Remarks Mortallity and maternal toxicity was observed for dose groups above 500 mg/kg bw, but effects and mortality did not occur at 500 mg/kg bw.

En dp oin

t N OAEL

Eff
ect typ

e teratogenicity

Eff
ect lev el 1000 mg/kg bw/day (nominal)

Ba sis for eff
ect lev el / Re

ma rks The authors concluded that the NOAEL for fetal toxicity was 1500 mg/kg/day because the skeletal abnormalities observed at this dose were not unique. However, in a similar study p erformed by the same laboratory in rats (see previous record), common skeletal abnormalities were considered to be adverse. On this basis, the NOAEL for developmental toxicity in rabbits should be the dose that did not produce an increase in any skeletal abnormalities (1000 mg/kg/day). The NOAEL listed under teratogenicity is the NOAEL for developmental toxicity.

Maternal toxic effects
yes Details on maternal toxic effects Maternal: Eight rabbits treated with the 1500 mg/kg/day dose died, and three aborted. A significant number of rabbits treated with this dose exhibited decreased motor activity, labored breathing, a red substance in the cage pan, dehydration, no feces, ataxia, gastriculceration,anogenital staining, mottled gallbladders, thin-walled stomach, reddened stomach, and fluid-filled or empty small intestines, and lower average gravid uterine weight. There was one death in the 1000 mg/kg/day group. This was considered to be possibly related to treatment. One rabbit in the low dose group aborted. Study personnel did not consider this to be related to test material because it was not dose-dependent.
There was no effect of treatment on the number of pregnant rabbits, average number of corpora lutea, implantations, live fetuses, resorptions, or fetal sex ratios.
Rabbits treated with all doses except 250 mg/kg/day gained more weight during the postdosage p eriod than controls, reflecting increased food consumption during this period. Study personnel did not consider this weight gain to be an adverse effect, as it is commonly seen in developmental studies after dosing is terminated. Details on embryotoxic / teratogenic effects Fetal: There was no effect of treatment on fetal body weight, or incidences or types of gross external or internal soft tissue malformations. The fetal and/or litter incidences of angulated hyoid alae and reversible delays in ossification of the xiphoid were increased in the 1500 mg/kg/day group. Developmental toxicity / teratogenicity Bates & deSerres TGME Rats 1992.004 UUID IUC5-77fa4421-7d6d-4f7c-8c44-5c5a55ab7755 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-24 17:15:29 EDT Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1 9 9 2 Reliablility 1 (reliable without restriction) Rationale for reliability Robust study following standard procedure and following GLP. Purity of test substance was provided. Data source Reference

Referen ce type Author Bates HK and de Serres FJ. Yea

r 1992

Title Developmental neurotoxicity evaluation of triethylene glycol monomethyl ether (CAS 112-35-6) administered by gavage to time-mated CD rats on gestational day 6 throughp ostnatal day 21. Bibliogr aphic

source CMA Reference Ge-43.0-DEV/ N EU-RTI

Testing laborato ry Rep
ort

no. Owner compan y Compan

y study

no. Rep
ort date 1992- 03-03

Materials and methods Limit test

no GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 112-35-6

Identifier EC number Identity 203-962-1

Identifier Common name Identity triethylene glycol methyl ether Details on test material The analyzed chemical purity was 99.2%. Test animals Species
rat Strain Sprague-Dawley Details on test animals and environmental conditions Timed pregnant CD" (Sprague-Dawley) rats, 64 sperm plug- p ositive females per group Administration / exposure Route of administration oral: gavage Vehicle unchanged (no vehicle) Details on exposureTimed pregnant CD" (Sprague-Dawley) rats, 64 sperm plug- p ositive females per group, were gavaged with the neat test material, triethylene glycol monomethyl ether (TGME), once daily, on gestational day (GD) 6 through postnatal day (PND) 21 at doses of 0, 300, 1650 or 3000 mg/kg/day. The volume of TGME administered was adjusted based on each animal's most recent body weight. Analytical verification of doses or concentrations no data Details on analytical verification of doses or concentrations no data Details on mating procedure no details other than the females were plug- p ositive females per group Duration of treatment / exposure day 6 of gestation through postnatal Day 21 Frequency of treatment daily Duration of test 38 days Doses / concentrations 300, 1650, 3000 Basis nominal conc. N o. of animals per sex per dose 64 p regnant females per dose. Control animals yes, concurrent vehicle Examinations Maternal examinations Clinical observations were made at least twice daily during the dosing period and daily otherwise. Maternal body weights were measured on GD 0, 6, 9, 12, 15, 18, 20, and on PND 0, 4, 7, 13, 17, and 21. Food consumption was measured for the intervals GD 0-6, 6-9, 9-12, 12-15, 15-18, 18-20, and PND 0-3, 3-6, 6-9, and 9-12. Maternal animals were allowed to deliver and rear their young.
On PND 22 the dams were evaluated for body weight, liver and kidney weight and the number of uterine implants (metrial glands). Fetal examinations Pups were counted, examined externally, weighed, and sexed on PND 0 and PND 4. After examination on PND 4, litter size was standardized by random culling to either a 4:4 or 5:3 sex ratio. Litters with insufficient numbers of pups were removed from the study after culling. Litters with sufficient numbers of pups remained on study, and pups wereexamined and weighed on PNDs 7, 13, 17, 21,35, 49, and 68. Male pups were examined daily starting at PND 17 for testicular descent, and females were examined daily starting on PND 30 for vaginal opening. One male and one female pup from each litter were assigned to each of three behavioral tests. Motor activity was assessed for one hour in a Figure-8 maze on PNDs 13, 17, 21, 47, and 58. Auditory startle response was assessed on PNDs 22 and 60, and learning and memory were assessed with an active avoidance paradigm run on PNDs 60-64. Three euthanizations occurred during the course of this study. The first took place after culling andinvolved those dams that had failed to deliver as well as the dams and pups from litters of insufficient size or sex ratio. The second took place on PND 22 and the third on PND 68.
On PND 22 and PND 68 one male and one female pup from each litter were weighed and killed. A total of 24 of these pups were perfused in situ at each euthanization (PND 22 and PND 68 i.e., 48 animals total) and were examined for histopathologic lesions of the central and p eripheral nervous system. The brains of the remaining animals at each sacrifice were removed and separated into the telencephalon, diencephalon, medulla oblongata/ p ons, and the cerebellum. These sections were all weighed separately. Statistics Data were analyzed using the FREQ, GLM, N PA R 1WAY and LIFETEST procedures in the SAS software package, in conjunction with a set of custom-designed analysis procedures. Results and discussions Effect levels

En dp oin

t N OAEL

Eff
ect typ

e maternal toxicity

Eff
ect lev el 1650 mg/kg bw/day (nominal)

Ba sis for eff
ect lev el / Re

ma rks Conclusion of summary preparer, EPA. The authors stated that “TGME administered by gavage to pregnant and lactating CD" (Sprague- Dawley) rats resulted in no overt signs of maternal toxicity”. However, they also stated that the increased kidney weights in the high dose animals occurred as a result of exposure to TGME. Based on this comment, a maternal NOAEL of 1650 was assigned by the summary preparer. This is in agreement with the maternal NOAEL derived by the EPA (Anderson, L. Triethylene glycol monomethyl, monoethyl and monobutyl ethers RM1 screening document (draft), Feb. 24, 1995).

Endpo int N OAEL

Effect

type teratogenicity

Effect level 300 mg/kg bw/day (nominal)

Basis for Conclusion of summary preparer, EPA. The authors arrived at a no observable effect level ( N OEL) of “equal to or greater than 300 mg/kg/day” based on decreased postnataleffect level / Remar ks weight gains at 1650 and 3000 mg/kg/day. The reviewer does not believe that a N OAEL can be assigned from this study due to the unclear significance of minor reductions in body weight gains of animals at various time points and changes in startle response at 1650 and 3000 mg/kg. A NOAEL for teratogenicity of 300 mg/kg/day has been derived by the EPA (Anderson, L. Triethylene glycol monomethyl, monoethyl and monobutyl ethers RM1 screening document (draft), Feb. 24, 1995). The NOAEL listed under teratogenicity is the NO(A)EL for developmental toxicity. Maternal toxic effects
yes Details on maternal toxic effects Of the 256 mated animals assigned to this study 33, 27, 28, and 31 litters in the control to high-dose group, respectively, had sufficient pups of both sexes to be used for the behavioral evaluations. Evaluation of data from the maternal animals revealed no dose- related patterns of clinical signs of toxicity or lethality. Maternal body weights were equivalent across all groups and for all time points. N o statistically significant effects on maternal weight gain or food consumption were noted. The length of gestation was significantly increased in the high-dose group animals compared to control although this finding was “of questionable biological significance since the difference between the groups was smaller than the 14-hour breeding time.” Necropsy of maternal animals in the high- dose group revealed significantly heavier kidneys than controls. Kidney weights increased in a dose-dependent manner.

N ecropsy of maternal animals revealed that kidneys from the maternal animals exposed to 3000 mg/kg/day of TGME were significantly heavier than controls Details on embryotoxic / teratogenic effects Analysis of pup in life data revealed no significant effects for PND 0/4 p up sex ratio or for pup survival during any period. Female pups from the mid- and high-dose groups (6.7 and 6.8 +/- 0.1 g) and male pups from the high- dose group (7.0 and 7.1 +/- 0.1 g) were significantly heavier than their control cohorts on PND O (6.2 and 6.7 +/- 0.1 g for females and males, respectively). Pups from these same groups gained significantly less weight in the period from PND 4 to PND 21. Although born heavier, the male pups from the high-dose group were significantly lighter than the control pups at the end of the study on PND 68 (440.7 +/- 6.0 vs. 462.4 +/- 4.8 g). Final body weights (PND 68) of mid and high dose females and mid-dose males were not significantly different from control.
Evaluation of pup development through the determination of vaginal opening revealed no differences between groups. Male pup development, as gauged by time of testes descent, was shown to be significantly advanced in the pups from the mid- and high-dose groups. Evaluation of the behavioral data generated during the course of this study indicated no dose-related effects on motor activity or active avoidance data. Significant effects on auditory startle response p arameters were noted. In particular, the auditory startle amplitude (magnitude of the startle reflex) was increased in male and female pups in the high-dose group on PND 22. Auditory startle amplitude was also increased for male pups on PND 60 and a similar trend of smaller magnitude was observed in PND 60 females. When startle latency (time to maximum startle reflex) was examined, the pups showed no consistent effect on PND 22, but both male and female pups demonstrated a decrease in the startle latency on PND 68.N ecropsy of weanling and adolescent pups revealed no findings that could be related to treatment. Histopathological assessment of the peripheral and central nervous systems of the p ups showed no treatment related lesions in any group. Applicant's summary and conclusion Conclusions“In conclusion, TGME administered by gavage to pregnant and lactating CD" (SpragueDawley) rats resulted in no overt signs of maternal toxicity. In addition, no discernible effects were noted in the offspring on motor activity, active avoidance, or neuropathology at exposures up to 3000 mg/kg/day. Exposure to TGME at 3000 mg/kg/day resulted inincreases in auditory startle amplitude and decreases in latency to maximum startle, but no changes in the habituation p rocess evaluated in the auditory startle test. The significance of these auditory startle observations with regard to the condition of the test animals is notclear. Exposure to TGME at levels of 1650 and 3000 mg/kg/day produced developmental toxicity evidenced by decreased p ostnatal weight gains. Therefore, the no observable effect level" ( N OEL) for this study is considered to be equal to or greater than 300 mg/kg/day.” Developmental toxicity / teratogenicity Taupin BF DOT 1993.005 UUID IUC5-79004ca6-0383-4857-9e88-728137a942cf Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-03-24 17:24:59 EDT Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1993

Reliablility 2 (reliable with restrictions) Rationale for reliability Pups were not examined for malformations. Statistical analyses were not p erforme d . Otherwise the study was well conducted according to GLP and standard procedures. Data source Reference Reference type study report

Author Taupin PJY Year 1993 Title Brake Fluid DOT 4: Chernoff and Kavlock (CKA) developmental toxicity screen in the rat Bibliographi

c source

Testing laboratory Shell Research Limited, Sittingbourne Research Centre Report

no. SBGR.92.2 33 Owner Shellcompany Company study no. Report date 1993-02-0 2 Materials and methods Limit test

no Test guideline Qualifier according to Guideline other guideline: Chernoff-Kavlok teratogenicity screening test Deviations GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 106008-94-0

Identifier Common name Identity Brake Fluid DOT 4 Details on test material Test material is a mixture containing 30-50% triethylene glycol monomethyl ether borate ester (CAS No. 106008-94-0), 3-30% triethylene glycol monobutyl ether borate ester, 20-30% triethylene glycol monomethyl ether (CAS No. 112-35-6), 2-10% triethylene glycol monobutyl ether (CAS No. 143-22-6), 20-30% tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 2-10% tetraethylene glycol monobutyl ether (CAS No. 1559-34-8), and < 1% minor additives. Test animals Species
rat Strain Sprague-Dawley Details on test animals and environmental conditions no data Administration / exposure Route of administration oral: gavage Vehicle unchanged (no vehicle) Details on exposure Groups of 10 female rats were dosed by oral gavage with 25, 150 or 1000 mg/kg/day test material on days 7-17 of gestation. Additional groups of females were sham dosed (negative control) or dosed with 1000 mg/kg/day ethylene glycol diethyl ether ( p ositive control). Analytical verification of doses or concentrations no dataDetails on analytical verification of doses or concentrations no data Details on mating procedure no data Duration of treatment / exposure days 7-17 of gestation Frequency of treatment daily Duration of test From Day 7 of gestation to Day 5 of lactation. Doses / concentrations 25, 150, 1000 mg/kg/day Basis nominal conc. N o. of animals per sex per dose 10 female rats. Control animals other: sham dosed (negative control) or dosed with 1000 mg/kg/day ethylene glycol diethyl ether ( p ositive control). Further details on study design Groups of 10 female rats were dosed by oral gavage with 25, 150 or 1000 mg/kg/day test material on days 7-17 of gestation. Additional groups of females were sham dosed (negative control) or dosed with 1000 mg/kg/day ethylene glycol diethyl ether ( p ositive control). Animals were allowed to litter naturally, and any that did not deliver by day 25 of gestation were killed. Dams and surviving pups were killed on day 5 of lactation. Examinations Maternal examinations Body weights were recorded on days 1, 7 and 21 of gestation and on day 5 of lactation (or at termination for animals that did not reproduce). Food intake was recorded over days 1 to 7 and 7 to 17 of gestation, day 17 of gestation to day 1 of lactation and days 1-5 of lactation. Ovaries and uterine content Uteri of all dams were examined for implantation sites. Fetal examinations The birth index [total number of pups born (live and dead) x 100/ number of implantation sites], live birth index (number of pups alive at day 1 of lactation/ total number of pups born x 100) and viability index (number of pups alive on day 5 of lactation/ number of pups alive on day 1 of lactation x 100) were calculated for each litter and group. Litter weights were recorded on days 1 and 5 of lactation and the uteri of all dams were examined for implantation sites. Pups were not necropsied. Statistics Statistical analyses were not performed. Results and discussions Effect levels Endpoint N OAEL Effect type maternal toxicity Effect level 1000 mg/kg bw/dayBasis for effect level / Remarks 1000 mg/kg bw was highest dose tested and showed no adverse effects.

Endpoint N OAEL Effect type teratogenicity Effect level 1000 mg/kg bw/day Basis for effect level / Remarks 1000 mg/kg bw was highest dose tested and showed no adverse effects.

Maternal toxic effects no effects Details on maternal toxic effects There was no effect of Brake Fluid DOT4 on maternal body weight of food intake. Embryotoxic / teratogenic effects no effects Details on embryotoxic / teratogenic effects Mean litter weights of low dose (25 mg/kg/day) animals were slightly lower than negative controls at birth (79 +/- 24 g vs. 90 +/- 23 g in sham control) and on day 5 of lactation (109 +/- 29 g vs. 133 +/- 34 g in sham control). In contrast, mean litter weights of high dose animals were higher than negative controls at birth (97 +/- 10 g) and on day 5 of lactation (150 +/- 24 g). The authors stated that the reduction at 25 mg/kg/day could be related to slightly smaller litter sizes (the birth index was 85 +/- 15 vs. 95 +/- 7 in the sham control). Two rats in this group had a lower number of implant sites (8 and 6) than the others (ranged from 15-19), which led to a decrease in the number of pups delivered(5 in each of the animals vs. 13-18 in the others). Another low dose animal that had 16 implant sites only delivered 9 p ups. The birth index of animals treated with 150 (94 +/- 6) or 1000 mg/kg/day test material (95 +/- 6) was similar to the sham control (95 +/- 7). There was no effect of treatment on the number of dead pups (4 in control vs. 1 in each treated group). There were no treatment-related necropsy findings. There was no effect of treatment with Brake Fluid DOT 4 of the duration of gestation, the number of females littering, the mean number of implant sites, or the live birth index or viability index. Based on these data, the authors concluded that 1000 mg/kg/day Brake Fluid DOT4 did not cause fetal growth retardation or embryolethality.
By contrast, the positive control animals lost weight from days 7 to 21 of gestation. All nine p regnant animals treated with ethylene glycol diethyl ether (EGDE) resorbed their litters. Most animals treated with EGDE had enlarged livers and/or spleens. Remarks on results including tables and figures

It is not known whether the decreased mean litter weights or birth index at 25 mg/kg/day or the increased mean litter weights at 1000 mg/kg/day are significantly different from control, since statistical analyses were not performed. However, these findings do not appear to be related to treatment since they are not dose-dependent. Since the investigators concluded that 1000 mg/kg/day Brake Fluid DOT4 did not cause fetal growth retardation or embryo or fetal lethality, the NOAEL for these effects is 1000 mg/kg/day. The NOAEL listed under teratogenicity is the NOAEL for developmental toxicity.

Overall remarks, attachments Overall remarksReference substance: 3,6,9,12-tetraoxatetradecan-1-ol UUID ECB5-2734aded-8007-4016-8c23-63e6ef180819 Dossier UUID 0 Author European Commision/Joint Research Centre/European Chemicals Bureau Date 2007-05-10 05:00:00 EDT Remarks Created General information Reference substance name 3,6,9,12-tetraoxatetradecan-1-ol EC inventory EC number 227-090-6 CAS number 5650-20-4 EC name 3,6,9,12-tetraoxatetradecan-1-ol Molecular formula C10H22O5 Reference substance information CAS information CAS number 5650-20-4 IUPAC name IUPAC name 3,6,9,12-tetraoxatetradecan-1-ol Synonyms N ame 3,6,9,12-tetraoxatetradecan-1-ol

N ame 3,6,9,12-Tetraoxatetradecan-1-ol

N ame 3,6,9,12-Tetraoxatetradecan-1-ol
DSL Category: Organics USEPA Category: Ethylene Glycol Ethers; N eutral Organics; N onionic Surfactants Molecular and structural information Molecular formula C10H22O5 Molecular weight range 222.2787 SMILES notation CCOCCOCCOCCOCCO InChI InChI=1/C10H22O5/c1-2-12-5- 6-14-9-10-15-8-7-13-4-3-11/h 11H,2-10H2,1H3 Structural formulaLegal entity: PCA Services, Inc. UUID IUC5-627340ec-79cf-4d47-86f0-902729c7a dc2 Dossier UUID 0 Author rgerwe / ( N o legal entity) Date 2008-11-16 11:49:37 EST Remarks General information Legal entity name PCA Services, Inc. Identifiers Other IT system identifiers IT system LEO ID 8869

Contact information Contact address Address 2704 Trail Wood Drive Postal code 27705 Town Durham Region / State N orth Carolina Country United States of America Phone (919) 382-8787 Fax (919) 382-8788 E-mail r.gerwe2@verizon.net Web site www. p caserve.comContact persons Organisation PCA Services, Inc. Title President First name Roderick Last name Gerwe Phone (919) 382-8787 Fax (919) 382-8788 E-mail r.gerwe2@verizon.net Address 2704 Trail Wood Drive Postal code 27705 Town Durham Region / State N orth Carolina Country United States of America

From: Saved by Windows Internet Explorer 7 <Saved by Windows Internet Explorer 7> Date: Fri, 3 Jul 2009 16:22:31 -0400 Subject: Substance: p entaethylene glycol butyl ether / 3,6,9,12,15,18-hexaoxaicosane / 3,6,9,12,15,18-hexaoxaicosane / 23601-39-0 / PCA Services, Inc. / Durham / United States of America Content-Type: multipart/related; boundary="

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_ "; type="multipart/alternative" Thread-Topic: Substance: p entaethylene glycol butyl ether / 3,6,9,12,15,18-hexaoxaicosane / 3,6,9,12,15,18-hexaoxaicosane / 23601-39-0 / PCA Services, Inc. / Durham / United States of America Thread-Index: AcrBZmuh+PbFY/FoSxSSSWNxTSgrPw== X-MS-Has-Attach: yes X-MS-TNEF-Correlator: MIME-Version: 1.0

Printing Date 2009-07-03 16:20:40 EDTRestriction of specific regulatory purposes

Confidentiality

N ame p entaethylene glycol butyl ether Legal entity owner PCA Services, Inc. / Durham / United States of America Substance: p entaethylene glycol butyl ether UUID IUC5-8071b42b-3df0-48d4-a57e-7b8904e12227 Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-06-14 11:23:45 EDT Remarks Created endpoint study record 4.11 Flash point 0 Related Information 0.1 Templates 0.2 Categories 0.3 Mixtures 1 General Information 1.1 Identification Substance identification Chemical name p entaethylene glycol butyl ether Legal entity PCA Services
, Inc . / Durham / United States of America Reference substance Reference substance 3,6,9,12,15,18

- hexaoxaicosane / 3,6,9,12,15,18

- hexaoxaicosane / 23601

- 39

- 0

EC number EC name 245-774-2 3,6,9,12,15,18-hexaoxaicosane CAS number CAS name 23601-39-0 IUPAC name 3,6,9,12,15,18-hexaoxaicosane

Type of substance Origin organic 1.2 Composition 1.3 Identifiers 1.4 Analytical information 1.5 Joint submission 1.6 Sponsors 1.7 Suppliers 1.8 Recipients 1.9 Product and process oriented research and development 2 Classification and Labelling 2.1 GHS2.2 DSD - DPD 3 Manufacture, use and exposure 3.1 Technological process 3.2 Estimated quantities 3.3 Sites 3.4 Form in the supply chain 3.5 Identified uses and exposure scenarios 3.6 Uses advised against 3.7 Waste from production and use 3.8 Exposure estimates 3.9 Biocidal information 3.10 Application for authorisation of uses 4 Physical and chemical properties 4.1 Appearance/ p hysical state/colour Appearance/ p hysical state/colour.001 UUID IUC5-9e513793-d036-459f-92e7-fb61e065feac Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-06-14 11:01:37 EDT Remarks

Administrative Data Purpose flag key study ( ) robust study summary ( ) used for classification ( ) used for MSDS Study result type other: visual observation and specification

Reliablility 2 (reliable with restrictions) Rationale for reliability Data come from manufacturer's material safety data sheet. Pentaethylene glycol butyl ether is available commercially only as a component in automotive brake and clutch fluid formulations. Data source Reference Reference type company data

Author Year Title Safety Data Sheet for Shell Brake and Clutch Fluid DOT 4 Super Bibliographic

source Available online at http://www.enerquip.com.au/brochures/shell /Shell%20PDFs/Brake%20&%20cl utch%20fluid%20Dot%204%20super. p df Testing laboratory Report no.

Owner company Company study no. Report dateMaterials and methods Test materials Test material equivalent to submission substance identity

no Test material identity Identifier Common name Identity Shell Brake and Clutch Fluid DOT 4 Super Details on test material Mixture typically containing 30-50% triethyleneglycol monomethyl ether borate ester (CAS No. 106008-94-0),3-30% triethylene glycol monobutyl ether borate ester, 20-30% triethylene glycol monomethyl ether (CAS No. 112-35-6), 2-10% triethylene glycol monobutyl ether (CAS No. 143-22-6), 20-30% tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 2-10% tetraethylene glycol monobutyl ether (CAS No. 1559-34-8), and < 1% minor additives. Borate esters have the general molecular formula of B(OR)3, where R = glycol ether, e.g., -O(CH2 CH2O)nCH3.or -O(CH2 CH2O)n CH2CH2CH2CH3.. Results and discussion Physical state at 20oC and 1013 hPa liquid Colour clear amber Odour other: ether like 4.2 Melting point/freezing point Melting point/freezing point.001 UUID IUC5-29924571-7d67-412a-a861-ec607567bb82 Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-06-14 11:10:05 EDT Remarks

Administrative Data Purpose flag key study ( ) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result

Reliablility 2 (reliable with restrictions) Rationale for reliability Data come from manufacturer's data sheet. Pentaethylene glycol butyl ether is available commercially only as a component in automotive brake and clutch fluid formulations. Data source Reference Reference type company data

Author YearTitle Pennzoil product data sheet for Pennzoil brake fluid Bibliograp hic source available online at http://www. p ennzoil.com.au/downloads/tds/Pennzoil

_ Brake

_ Fluid

_ Dot

_ 4. p df Testing laboratory Repo
rt no.

Owner company Company study no. Repo
rt date Materials and methods GLP compliance no data Test materials Test material equivalent to submission substance identity
yes Test material identity Identifier Common name Identity Pennzoil (trademark) Brake Fluid (DOT 4) Results and discussions Melting / freezing point Melt./Freez. p t. <= -40 °C

Atm. p ressure Decomposition no Decomp. temp. Sublimation no Subl. temp. Remarks 4.3 Boiling point Boiling point.001 UUID IUC5-6492d754-c5c8-4598-b5c2-daa652359436 Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-06-14 11:35:24 EDT Remarks

Administrative Data Purpose flag key study ( ) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result

Reliablility 2 (reliable with restrictions) Rationale for reliability Data come from manufacturer's product data sheet. Pentaethylene glycol butyl ether is available commercially only as a component in automotive brake andclutch fluid. Data source Reference Reference type company data Author Year Title Pennzoil brake fluid DOT 4 data sheet Bibliographic

source Available online at http://www. p ennzoil.com/documents/Super%20HD%20Dot%203and4%20Bra ke%20Fluid. p df Testing laboratory Report no.

Owner company Company study

no. Report date

Reference type company data

Author Year

Title Pennzoil Technical Data Sheet for Pennzoil (trademark) Brake Fluid (DOT 4) Bibliograp hic source available online at http://www. p ennzoil.com.au/downloads/tds/Pennzoil

_ Brake

_ Fluid

_ Dot

_ 4. p df Testing laboratory Repo
rt no.

Owner company Company study no. Repo
rt date Materials and methods Test materials Test material equivalent to submission substance identity

no Test material identity Identifier Common name

Identity Pennzoil DOT 4 and DOT 3 Motor Vehicle Brake Fluid Results and discussions Boiling point Boiling pt. >= 270 °C Atm. p ressure 1013 hPa Decomposition no Decomp. temp. Remarks Equilibrium Reflux Boiling Point 4.6 Vapour pressureVapour pressure.001 UUID IUC5-b6325ec7-8a6d-436a-aaf7-4171008d3210 Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-06-14 11:23:33 EDT Remarks

Administrative Data Purpose flag key study ( ) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result

Reliablility 2 (reliable with restrictions) Rationale for reliability Data come from manufacturer's safety data sheet. Pentaethylene glycol butyl ether is available commercially only as a component in automotive brake and clutch fluid formulations. Data source Reference Reference type company data

Author Year Title Safety Data Sheet for Shell Brake and Clutch Fluid DOT 4 Super Bibliographic

source Available online at http://www.enerquip.com.au/brochures/shell /Shell%20PDFs/Brake%20&%20cl utch%20fluid%20Dot%204%20super. p df Testing laboratory Report no.

Owner company Company study no. Report date

Materials and methods Test materials Test material equivalent to submission substance identity

no Test material identity Identifier Common name Identity Shell Brake and Clutch Fluid DOT 4 Super Details on test material Mixture typically containing 30-50% triethyleneglycol monomethyl ether borate ester (CAS No. 106008-94-0),3-30% triethylene glycol monobutyl ether borate ester, 20-30% triethylene glycol monomethyl ether (CAS No. 112-35-6), 2-10% triethylene glycol monobutyl ether (CAS No. 143-22-6), 20-30% tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 2-10% tetraethylene glycol monobutyl ether (CAS No. 1559-34-8), and < 1% minor additives. Borate esters have the general molecular formula of B(OR)3, where R = glycol ether, e.g., -O(CH2CH2O)nCH3.or -O(CH2 CH2O)n CH2CH2CH2CH3.. Results and discussions Vapour pressure < 0.005 hPa at 20 °C Remarks 4.7 Partition coefficient Partition coefficient.001 UUID IUC5-71252617-a792-4d34-8c84-dd8adbfb81fa Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-06-11 15:58:06 EDT Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type estimated by calculation Study p eriod 20 09 Reliablility 2 (reliable with restrictions) Rationale for reliability Data were obtained using a recognized, approved computer model program.

Data source Reference Reference type other: computer model program output Author Year 2009 Title EPIWIN KOWWIN Program (v.167) Bibliographic

source Testing laboratory Report no.

Owner company Company study

no. Report date 2009-06-08

Materials and methods Partition coefficient type octanol-water Test materials Test material equivalent to submission substance identity
yes Test material identity Identifier CAS number Identity 23601-39-0

Identifier EC numberIdentity 245-774-2

Identifier IUPAC name

Identity 3,6,9,12,15,18-hexaoxaicosane Details on methods EPIWIN KOWWIN Model input was CAS No. 23601-39-0, Results and discussions Partition coefficient Type log Pow Partition coefficient ca. -0.3228 Temp. p H 4.8 Water solubility Water solubility.001 UUID IUC5-462550a2-44ef-40e1-a53c-ceb370c8fdb3 Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-06-14 11:23:02 EDT Remarks

Administrative Data Purpose flag key study ( ) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result

Reliablility 2 (reliable with restrictions) Rationale for reliability Data come from manufacturer's safety data sheet. Pentaethylene glycol butyl ether is available commercially only as a component in automotive brake and clutch fluids. Data source Reference Reference type company data

Author Year Title Safety Data Sheet for Shell Brake and Clutch Fluid DOT 4 Super Bibliographic

source Available online at http://www.enerquip.com.au/brochures/shell /Shell%20PDFs/Brake%20&%20cl utch%20fluid%20Dot%204%20super. p df Testing laboratory Report no.

Owner company Company study no. Report date

Materials and methodsTest materials Test material equivalent to submission substance identity

no Test material identity Identifier Common name Identity Shell Brake and Clutch Fluid DOT 4 Super Details on test material Mixture typically containing 30-50% triethyleneglycol monomethyl ether borate ester (CAS No. 106008-94-0),3-30% triethylene glycol monobutyl ether borate ester, 20-30% triethylene glycol monomethyl ether (CAS No. 112-35-6), 2-10% triethylene glycol monobutyl ether (CAS No. 143-22-6), 20-30% tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 2-10% tetraethylene glycol monobutyl ether (CAS No. 1559-34-8), and < 1% minor additives. Borate esters have the general molecular formula of B(OR)3, where R = glycol ether, e.g., -O(CH2 CH2O)nCH3.or -O(CH2 CH2O)n CH2CH2CH2CH3.. Results and discussions Water solubility > 1000000 mg/L Temp. p H Details on results miscible in water 4.11 Flash point Flash point.001 UUID IUC5-3a8b17bf-6d63-462c-9383-54682284758b Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-06-14 11:27:09 EDT Remarks

Administrative Data Purpose flag key study ( ) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result

Reliablility 2 (reliable with restrictions) Rationale for reliability Data come from manufacturer's safety data sheet. Pentaethylene glycol butyl ether is available commercially only as a component in automotive brake and clutch fluid formulations. Data source Reference Reference type company data

Author Year Title Safety Data Sheet for Shell Brake and Clutch Fluid DOT 4 Super Bibliographic Available online atsource http://www.enerquip.com.au/brochures/ shell/Shell%20PDFs/Brake%20&%20cl utch%20fluid%20Dot%204%20super. p df Testing laboratory Report no.

Owner company Company study no. Report date

Materials and methods Test materials Test material equivalent to submission substance identity

no Test material identity Identifier Common name Identity Shell Brake and Clutch Fluid DOT 4 Super Details on test material Mixture typically containing 30-50% triethyleneglycol monomethyl ether borate ester (CAS No. 106008-94-0),3-30% triethylene glycol monobutyl ether borate ester, 20-30% triethylene glycol monomethyl ether (CAS No. 112-35-6), 2-10% triethylene glycol monobutyl ether (CAS No. 143-22-6), 20-30% tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 2-10% tetraethylene glycol monobutyl ether (CAS No. 1559-34-8), and < 1% minor additives. Borate esters have the general molecular formula of B(OR)3, where R = glycol ether, e.g., -O(CH2 CH2O)nCH3.or -O(CH2 CH2O)n CH2CH2CH2CH3.. Results and discussions Flash point ca. 155 °C
at 5 Environmental fate and pathways 5.1 Stability 5.1.1 Phototransformation in air Phototransformation in air.001 UUID IUC5-49e2caa6-bd40-4aa5-bc7f-cc8c64c91475 Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-06-14 12:13:11 EDT Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type estimated by calculation Study p eriod 20 09 Reliablility 2 (reliable with restrictions) Rationale for Data were obtained using a recognized, approved computer model program.reliability Data source Reference Reference type other: computer model program output. Author Year Title EPIWIN V4.00 Suite AOPWIN (v1.92) Bibliographic

source Testing laboratory Report no.

Owner company

Company study

no. Report date 2009-06-11

Materials and methods Test materials Test material equivalent to submission substance identity
yes Test material identity Identifier CAS number Identity 23601-39-0

Identifier EC number Identity 245-774-2

Identifier IUPAC name

Identity 3,6,9,12,15,18-hexaoxaicosane Study design Estimation method (if used) PHOTOCHEMICAL REACTION WITH OH RADICALS - Concentration of OH radicals: 1.5E6 OH/cm3 - Degradation rate constant: 82.4248 E-12 cm3/molecule-sec - Computer programme: EPIWIN V4.00 Suite AOPWIN (v1.92) - Other: Half-life 0.130 day 1.557 hours (12-hour day) Light source sunlight 5.2 Biodegradation 5.2.1 Biodegradation in water: screening tests Biodegradation in water: Waggy Union Carbide Screening TGBE 1987.001 UUID IUC5-4eca5cef-8d6f-4f38-aa1b-e45f5c219362 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 08:01:49 EST RemarksAdministrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 87

Reliablility 2 (reliable with restrictions) Rationale for reliability Purity of test material was not noted.

Data source Reference Reference type study report

Author Waggy GT. Year 1987 Title Glycol ethers: Summary of available ecological fate and effects data. Bibliographic

source Testing laboratory Report

no. Owner company Union Carbide

Company study no. File Number 35931 Report date 1987-11-19

Materials and methods Test guideline

Qualifier according to

Guidelin

e other guideline: "Standard Methods for the Examination of Water and Wastewater, 16th Ed., USPHA, Washington, D. C., 1985) Deviatio

ns GLP compliance no data Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 143-22-6

Identifier EC number Identity 205-592-6

Identifier Common name

Identity Triethylene glycol butyl etherDetails on test material N o details. Study design Oxygen conditions aerobic Inoculum or test system sewage, domestic, non-adapted Details on inoculum no data Duration of test (contact time) 20 d Details on analytical methods N o data Details on study design A modified version of the biochemical oxygen demand (BOD) method published in "Standard Methods for the Examination of Water and Wastewater," 16th edition, Am. Public Health Association, 1985 was used. N onacclimated domestic sewage organisms were used as seed in the test. The test period was extended to 20 days. Reaeration (if needed) wasaccomplished by dividing the BOD bottle contents between 2 BOD bottles, sealing, shaking twenty times, returning contents to the original BOD bottle, recording the oxygen level, resealing, and returning the BOD bottle to the incubator. A discussion of these modifications appears in Price et al., "Brine shrimp bioassay and seawater BOD of petrochemicals", J. Water Poll. Control Fed., Jan. 1974. Any other information on materials and methods incl. tables

Biological oxygen demand (BOD) of triethylene glycol monomethyl ether (TGME; CAS No. 112-35-6) and triethylene glycol monoethyl ether (CAS No. 112-50-5) were also tested in this study. The 20 day BOD of both of these chemicals (71%) was greater than that of triethylene glycol monobutyl ethe r . The concentration of test material and bacteria were not listed in the report.

Results and discussions % Degradation of test substance %Degr. 47 St. dev. Parameter Sampling time 20 d Remarks Details on results The calculated theoretical oxygen demand of TGBE was 2.10 mg/mg. After 10 and 20 days of incubation, the percent biooxidation was 5, and 47%. Biodegradation in water: screening tests.002 UUID IUC5-2eb7caf5-b30e-42a2-9c0b-19fc46a2911f Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 08:19:32 ESTRemarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study p eriod 1989

Reliablility 2 (reliable with restrictions) Rationale for reliability Original reference was not available. Information (including the reliability code) came from a previous IUCLID data set produced by the European Chemicals Bureau. Data source Reference Reference type company data Author Year 1989 Title Hoechst AG. 1989. Bibliographic

source Testing laboratory Report no.

Owner company Hoechst AG

Company study

no. Unpublished Study (Werk Gendorf; p 07/89). Report date

Materials and methods Test type inherent biodegradability Test guideline Qualifier according to Guideline OECD Guideline 302 B (Inherent biodegradability: Zahn-Wellens/EMPA Test)

Deviations GLP compliance no data Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 23783-42-8

Identifier EC number Identity 245-883-5

Identifier Common name

Identity tetraethylene glycol monomethyl etherStudy design Oxygen conditions aerobic Inoculum or test system sewage, industrial (adaptation not specified) Details on inoculum industrial activated sludge (Gendorf, Germany sewage treatment plant) Duration of test (contact time) 7 d Initial test substance concentration Initial conc. 573 mg/L Based on test mat. Details on analytical methods no data Any other information on materials and methods incl. tables
CSB = elimination (time sequence values versus initial concentration value): Elimination through non-biological processes = ca. 10%

Results and discussions % Degradation of test substance %Degr. 99 St. dev. Parameter Sampling time 8 d Remarks Includes both biological and non-biological degradation. Details on results 3 hour(s) = 10 %; 1 day = 19%; 3 days = 29%; 5 days = 52%; 7 days = 91% Biodegradation in water: screening tests.003 UUID IUC5-c89be75b-2b44-41fc-bb09-dfa6627bf72a Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 08:24:38 EST Remarks

Administrative Data Purpose flag weight of evidence (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 20 00

Reliablility 4 (not assignable) Rationale for Limited data from a secondary sourcereliability Data source Reference Reference type secondary source

Author Year 2000 Title European Chemicals Bureau Dossier for Tetraethylene glycol butyl ether CAS No. 1559-34-8 Bibliograph ic source Shell Nederland Chemie B.V. Rotterdam EUROPEAN COMMISSION - European Chemicals Bureau Ispra (VA) Testing laboratory Report

no. Owner company Company study no. Report date Materials and methods Test type other: BOD GLP compliance no data Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 1559-34-8

Identifier EC number Identity 216-322-1

Identifier Common name

Identity Tetraethylene glycol butyl ether Study design Oxygen conditions no data Inoculum or test system no data Details on inoculum no data Results and discussions Details on results ThOD= 2.05 g O2/g substance. 5.3 Bioaccumulation 5.3.1 Bioaccumulation: aquatic / sediment Bioaccumulation: aquatic / sediment.001UUID IUC5-917fe733-6309-4cca-b850-852e19b511da Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-06-13 17:27:18 EDT Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type estimated by calculation Study p eriod 20 09 Reliablility 2 (reliable with restrictions) Rationale for reliability Data were obtained using a recognized computer model program.

Data source Reference Reference type other: Computer model program output Author Year 2009 Title EPIWIN (v4.00) BCFBAF (v3.00) Bibliographic

source Testing laboratory Report no.

Owner company Company study

no. Report date 2009-06-11

Materials and methods Test materials Test material equivalent to submission substance identity
yes Test material identity Identifier CAS number Identity 23601-39-0

Identifier EC number Identity 245-774-2

Identifier IUPAC name Identity 3,6,9,12,15,18-hexaoxaicosane Test conditions Details on estimation of bioconcentration BASIS INFORMATION - Measured/calculated logPow: calculated, -0.32BASIS FOR CALCULATION OF BCF - Estimation software: EPIWIN V4.00 Suite BCFBAF (v3.00) - Result based on calculated log Pow of: -0.32 Results and discussions Bioaccumulation factor Conc. in environment / dose Type other: log BCF Value ca. 0.5 Basis Time of plateau Calculation basis Remarks 5.4 Transport and distribution 5.4.2 Henry's Law constant Henry's Law constant.001 UUID IUC5-d665a811-fec0-4356-ae90-07a081ec61a6 Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-06-11 16:25:33 EDT Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type estimated by calculation Study p eriod 20 09 Reliablility 2 (reliable with restrictions) Rationale for reliability Data were obtained using a recognized, approved computer model program.

Data source Reference Reference type other: computer model program output Author Year 2009 Title EPIWIN v4.00 HENRYWIN (v3.20) Bibliographic

source Testing laboratory Report no.

Owner company Company study

no. Report date 2009-06-11

Materials and methods Test materials Test material equivalent to submission substance identityyes Test material identity Identifier CAS number Identity 23601-39-0

Identifier EC number Identity 245-774-2

Identifier IUPAC name Identity 3,6,9,12,15,18-hexaoxaicosane Details on methods Input was CAS No. 023601-39-0 to the EPIWIN HENRYWIN program. Results and discussions Henry's Law constant H H ca. 0 atm m3/mol Temp. (°C) Atm. p ress. 5.4.3 Distribution modelling Distribution modelling.001 UUID IUC5-70b780d7-4f83-4484-af16-ac24ee681e56 Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-06-14 12:21:52 EDT Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type estimated by calculation Study p eriod 20 09 Reliablility 2 (reliable with restrictions) Rationale for reliability Data were obtained using a recognized, approved computer model program.

Data source Reference Reference type other: computer model program output Author Year 2009 Title EPIWIN V4.00 Fugacity Bibliographic

source Testing laboratory Report no.

Owner company Company study Report date 2009-06-11no. Materials and methods Calculation programme EPIWIN V4.00 Fugacity Release year 2009 Test materials Test material equivalent to submission substance identity
yes Test material identity Identifier CAS number Identity 23601-39-0

Identifier EC number Identity 245-774-2

Identifier IUPAC name Identity 3,6,9,12,15,18-hexaoxaicosane Test substance input data - Molar mass: 294.39 - Water solubility: 1,000,000 mg/L - log Pow: -.323 - Melting point: -40 deg C - Reaction half-life estimates for - Air: 3.12 hours - Water: 900 hours - Soil: 1,800 hours - Sediment: 8,100 hours Results and discussions Percent distribution in media Air (%) 0 Water (%) 35 Soil (%) 64.9 Sediment (%) 0.08 6 Ecotoxicological Information 6.1 Aquatic toxicity 6.1.1 Short-term toxicity to fish Short-term toxicity to fish-Wagy TGBE 1974.001 UUID IUC5-bcc78767-6824-4cb8-b3ee-a711b6d75d4e Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / UnitedStates of America Date 2009-02-12 08:30:40 EST Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 74 Reliablility 2 (reliable with restrictions) Rationale for reliability Purity of test material was not noted.

Data source Reference Reference type Author Waggy GT, Payne JR. Year 1974 Title Environmental impact product analysis: Acute aquatic toxicity testing. Bibliographic

source Testing laboratory Report

no. Owner company Union Carbide Corporation

Company study no. File number 19133 Report date 1974-01-25

Materials and methods Test guideline

Qualifier according to Guideline other guideline: as described in "Standard Methods for the Examination of Water and Wastewater, 13th Ed., 1971. Deviation

s GLP compliance no data Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 143-22-6

Identifier EC number Identity 205-592-6Identifier Common name Identity Triethylene glycol butyl ether Details on test material N o details Analytical monitoring no data Details on sampling no data Details on analytical methods no data Vehicle

no Test organisms Test organisms (species) Pimephales promelas Details on test organisms Gdn fish per concentration Study design Test type static Water media type no data Limit test

no Total exposure duration 96 h Remarks Post exposure observation period no data Test conditions Hardness total hardness from 30 to 60 mg/l Test temperature 71 to 76 degrees F
p H 7.2 to 7.6 Dissolved oxygen 7.5 to 9.0 mg/l. Salinity total alkalinity from 30-40 mg/l N ominal and measured concentrations concentrations ranging from 10 to 10000 mg/l Details on test conditions An initial range-finding test was conducted using 2 fish exposed to concentrations ranging from 10 to 10000 mg/l. Definitive tests were performed with 10 fish (2.5 to 5 cm) p er test concentration in vessels containing 18.5 liters of dilution water under minimal controlledaeration (after the first four hours of the test). Fish were exposed for up to 96 hours. The temperature of the water ranged from 71 to 76 degrees F, the pH from 7.2 to 7.6, the total alkalinity from 30-40 mg/l, the total hardness from 30 to 60 mg/l, and the dissolved oxygen from 7.5 to 9.0 mg/l. Results and discussions Effect concentrations Duration 96 h Endpoint LC50 Effect conc. 2400 mg/L N ominal/Measured nominal Conc. based on test mat. Basis for effect mortality Remarks (e.g. 95% CL) Details on results The 24-hr, 48-hr and 96-hr LC50 values were 2400 mg/l. Any other information on results incl. tables

Toxicity of triethylene glycol monomethyl ether (CAS No. 112-35-6) and of triethylene glycol monoethyl ether (CAS No. 112-50-5) were also tested in this study. LC50 values for both chemicals were > 10000 mg/l.
Short-term toxicity to fish-Konemann TGBE 1981.002 UUID IUC5-a32a87a6-bee4-4a70-9571-2528d05fdf5a Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 08:33:31 EST Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 81

Reliablility 2 (reliable with restrictions) Rationale for reliability Purity of test material was not noted.

Data source Reference Reference type p ublication

Author Konemann H. Year 1981 Title Quantitative structure-activity relationships in fish toxicity studies. Part 1.Relationship for 50 industrial pollutants. Bibliograp hic source Toxicology 19:209-221.

Testing laboratory Report

no. Owner company Company study no. Report date Materials and methods Test guideline Qualifier no guideline followed Guideline Deviations Principles of method if other than guideline Typical acute aquatic toxicity method. GLP compliance no data Test materials Test material equivalent to submission substance identity
yes Test material identity Identifier CAS number Identity 143-22-6

Identifier EC number Identity 205-592-6

Identifier Common name Identity triethylene glycol monobutyl ether Details on test material no data Analytical monitoring

no Vehicle

no Test organisms Test organisms (species) Poecilia reticulata Details on test organisms Two to three month old guppies (8 p er group) Study design Test type semi-static Water media type freshwaterLimit test

no Total exposure duration 7 d Remarks Post exposure observation period no data Test conditions Hardness 25 mg/l as CaCO3 Test temperature 22 +/- 1 degrees C
p H N o data Dissolved oxygen Oxygen content remained above 5 mg/l Salinity no data N ominal and measured concentrations test concentrations increased geometrically in ratios of 3.2 Details on test conditions Two to three month old guppies (8 p er group) were exposed to several concentrations of test material in 1.5 liter vessels for 7 days. Each vessel was filled with 1 liter of standard water (hardness 25 mg/l as CaCO3) and covered with glass. A stock solution of test material was made by dissolving it in either acetone or 2- p ropanol (not specified). Various volumes of stock solution were added to the test vessels to increase test concentrations geometrically (in increasing ratios of 3.2). Test solution was renewed daily. Guppies were fed 0.5 hours before each renewal with commercial fish food. Oxygen content, water temperature, and viability offish were monitored. Oxygen content remained above 5 mg/l, and temperature was 22 +/- 1 degrees C. Any other information on materials and methods incl. tables

LC50's were calculated according to the method of Litchfield and Wilcoxon (J Pharm Exp Ther 96:99, 1949), or by estimation from a log-probit- plot (if concentration-death relationship was too steep).

Results and discussions Effect concentrations Duration 7 d Endpoint LC50 Effect conc. 197 mg/L N ominal/Measured nominal Conc. based on test mat. Basis for effect mortality Remarks (e.g. 95% CL) Details on results The molecular weight of the test material (206 g/mole) was used to convert the log LC50 (in micromoles/liter) to the LC50 (in mg/l).The log of the LC50 was calculated to be 2.98 micromoles/l. Short-term toxicity to fish.003 UUID IUC5-ccf6f1ee-b67f-46d4-99b1-fc611ba2bcb1 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 08:35:28 EST Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1988

Reliablility 2 (reliable with restrictions) Rationale for reliability Original reference was not available. Information (including the reliability code) came from a previous IUCLID data set produced by the European Chemicals Bureau. Data source Reference

Reference type secondary source

Author Year 1988 Title Unpublished study Bibliogra p hic

source Original reference was not available. Information came from a previous IUCLID data set produced by the European Chemicals Bureau.

Testing laboratory Repor
t no.

Owner company Hoechst AG.

Company study no. 88.1713 Repor t date

Reference type Author Year Title Bibliograp hic source Hoechst AG Frankfurt/MainClariant GmbH Frankfurt/MainEUROPEAN COMMISSION - European Chemicals Bureau Ispra (VA) Testing laboratory Report

no.Owner company Company study no. Report date Materials and methods Test guideline Qualifier according to Guideline OECD Guideline 203 (Fish, Acute Toxicity Test) Deviations GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 23783-42-8

Identifier EC number Identity 245-883-5

Identifier Common name Identity tetraethylene glycol monomethyl ether Details on test material no data Analytical monitoring

no Details on sampling no data Details on analytical methods no data Vehicle

no Details on test solutions no data Test organisms Test organisms (species) Brachydanio rerio (new name: Danio rerio) Details on test organisms no data Study design Test type static Water media type no data Total exposure duration48 h Remarks Post exposure observation period no data Test conditions Hardness no data Test temperature no data
p H no data Dissolved oxygen no data Salinity no data N ominal and measured concentrations no data Details on test conditions no data Reference substance ( p ositive control) no data Results and discussions Effect concentrations Duration 48 h Endpoint LC50 Effect conc. > 10000 mg/L N ominal/Measured nominal Conc. based on test mat. Basis for effect mortality Remarks (e.g. 95% CL) Short-term toxicity to fish.004 UUID IUC5-b5fab8ac-ed8a-4786-93e1-8dda0122cfe7 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 08:40:30 EST Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study p eriod 1988

Reliablility 2 (reliable with restrictions) Rationale for Original reference was not available. Information (including the reliability code)reliability came from a previous IUCLID data set produced by the European Chemicals Bureau. Data source Reference Reference type secondary source

Author Year 1988 Title Bibliographic

source Hoechst AG Frankfurt/Main and European Chemicals Bureau 2000 IUCLID

Testing laboratory Report no.

Owner company Hoechst AG.

Company study no. Unpublished Study (88.1713). Report date Materials and methods Test guideline Qualifier according to Guideline OECD Guideline 203 (Fish, Acute Toxicity Test) Deviations GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 23783-42-8

Identifier EC number Identity 245-883-5

Identifier Common name

Identity Tetraethylene glycol methyl ether Details on test material no data Analytical monitoring

no Details on sampling no data Details on analytical methods no data Vehicle

no Details on test solutionsno data Test organisms Test organisms (species) Brachydanio rerio (new name: Danio rerio) Details on test organisms no data Study design Test type static Water media type no data Total exposure duration 96 h Remarks Post exposure observation period no data Test conditions Hardness no data Test temperature no data
p H no data Dissolved oxygen no data Salinity no data N ominal and measured concentrations no data Details on test conditions no data Reference substance ( p ositive control) no data Results and discussions Effect concentrations Duration 96 h Endpoint LC50 Effect conc. > 10000 mg/L N ominal/Measured nominal Conc. based on test mat. Basis for effect mortality Remarks (e.g. 95% CL) Short-term toxicity to fish-BASF TGBE 1989.005 UUID IUC5-a8fb3d6f-8c5d-4c5d-b2b7-a8b454cabe0c Dossier UUID 0Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 08:41:39 EST Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 89

Reliablility 2 (reliable with restrictions) Rationale for reliability Purity of test material was not high.

Data source Reference Reference type study report Author Year 1989 Title Bibliographic

source Testing laboratory Department of Toxicology Report no.

Owner company BASF Company study no. Project No. 10F0573/885281 Report date 1989-04-26 Materials and methods Test guideline Qualifier according to Guideline other guideline: DIN 38 412 Deviations GLP compliance no data Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 143-22-6

Identifier EC number Identity 205-592-6

Identifier Common name Identity Triethylene glycol butyl ether Details on test material Purity was 87.2%Details on properties of test surrogate or analogue material no data Analytical monitoring

no Details on sampling no data Details on analytical methods no data Vehicle

no Details on test solutions no data Test organisms Test organisms (species) Idus idus Details on test organisms The average length and weight of fish were 6.7 cm and 2.8 g, respectively. Study design Test type static Total exposure duration 96 h Remarks Post exposure observation period no data Test conditions Hardness 2.5 mmol/l Test temperature 20 degrees C
p H 8.0 Dissolved oxygen no data Salinity no data N ominal and measured concentrations 0, 1000, 2150, 4640 or 10000 mg/l test material Details on test conditions Ten fish/group were exposed to 0, 1000, 2150, 4640 or 10000 mg/l test material in glass aquariums (30 cm x 22 cm x 24 cm) containing 10 liters of water (2.8 g fish/liter water) after a 3 day acclimation period. Food was withdrawn 1 day before and during exposure. The average length and weight of fish were 6.7 cm and 2.8 g, respectively. The water had a total hardness, acid capacity, ratio Ca/Mg, ratio Na/K, p H and temperature of 2.5 mmol/l, 0.8 mmol/l, 4:1, 10:1, 8.0, and 20 degrees C. Water was continuously aerated with oil-free air. Reference substance ( p ositive control)no data Results and discussions Effect concentrations Duration 96 h Endpoint other: LD50 Effect conc. > 2150

—< 4640 mg/L N ominal/Measured nominal Conc. based on test mat. Basis for effect mortality Remarks (e.g. 95% CL) Details on results The 24-hr, 48-hr and 96-hr LD50 values were > 2150 and < 4640 mg/l. All fish exposed to 4640 mg/l died within 4 hours. N o deaths were observed at 2150 mg/l. Apathy and tumbling were noted at 2150 mg/l. N o symptoms of toxicity were observed at 1000 mg/l. Short-term toxicity to fish.006 UUID IUC5-064a7437-761b-4cc5-8dfb-e3a47e59b115 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 08:42:25 EST Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Reliablility 2 (reliable with restrictions) Rationale for reliability Original data from which MSDS was written were not available.

Data source Reference Reference type Author Year Title Bibliograph ic source Dow MSDS for CARBOWAX methoxypolyethylene glycol 350 (CAS No. 9004-74-4), N umbe r 870, Dated 7/5/2000. Testing laboratory Report

no. Owner company Dow Chemical Company

Company study no. N umbe r 870 Report date 2000-07- 05 Materials and methodsTest guideline Qualifier Guideline other guideline: no data on guideline Deviations GLP compliance no data Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 9004-74-4

Identifier IUPAC name Identity Carbowax MPEG-350 Details on test material Test material (CARBOWAX MPEG-350; CAS No. 9004-74-4) is a mixture of several methylated glycol ethers of differing molecular weight (ranging from diethylene glycol monomethyl ether (C2) to heptadecaethylene glycol monomethyl ether (C17)). The majority of the material is in the C5-C11 range (87.445%). It contains 4.347 % (by weight) tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 1.303% triethylene glycol monomethyl ether (CAS No. 112-35-6), 0.181% diethylene glycol monomethyl ether (CAS No. 111-77-3). Analytical monitoring no data Details on sampling no data Details on analytical methods no data Vehicle no data Details on test solutions no data Test organisms Test organisms (species) other: fathead minnow Details on test organisms no data Study design Test type no data Water media type no data Total exposure duration 96 h Remarks Post exposure observation period no dataTest conditions Hardness no data Test temperature no data
p H no data Dissolved oxygen no data Salinity no datano data N ominal and measured concentrations no data Details on test conditions no data Reference substance ( p ositive control) no data Results and discussions Effect concentrations Duration 96 h Endpoint LC50 Effect conc. > 10000 mg/L N ominal/Measured no data Conc. based on no data Basis for effect no data Remarks (e.g. 95% CL) 6.1.3 Short-term toxicity to aquatic invertebrates Short-term toxicity to aquatic invertebrates-Waggy TGBE 1987.001 UUID IUC5-bdd81a61-161c-4e79-bcc6-8fffe18a1102 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 08:49:58 EST Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 87

Reliablility 2 (reliable with restrictions) Rationale for reliability Purity of test material was not noted.Data source Reference Reference type study report

Author Waggy GT. Year Title Glycol ethers: Summary of available ecological fate and effects data. Bibliographic

source Testing laboratory Report

no. Owner company Union Carbide

Company study no. File Number 35931 Report date 1987-11-19

Materials and methods Test guideline Qualifier equivalent or similar to Guideline other guideline: Test practices followed those recommended by EPA and ASTM.

Deviations GLP compliance no data Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 143-22-6).

Identifier EC number Identity 245-774-2

Identifier Common name Identity triethylene glycol monobutyl ether Analytical monitoring

no Details on sampling no data Details on analytical methods no data Vehicle

no Details on test solutions no data Test organisms Test organisms (species)Daphnia magna Details on test organisms Daphnia magna stocks were originally obtained from the EPA laboratory at Duluth, MN. They were maintained at 20-22 degrees C in a series of 600 ml beakers filled with Kanawha River water obtained from the South Side Boat Ramp (Charleston, SC). Daphnia were fed three times a week with a laboratory- p repared food consisting of trout food, yeast and alfalfa powder. Daphnia used in the test were offspring of 20-50 gravid females isolated for 24 hours. Study design Test type static Water media type freshwater Limit test

no Total exposure duration 48 h Remarks Post exposure observation period no data Test conditions Hardness 55 mg/l as CaCO3 Test temperature 20-22 deg C
p H 6.7 Dissolved oxygen no data Salinity no data N ominal and measured concentrations A series of from 5-10 equidistant concentrations based on results of fish toxicity studies ( p lus control) were tested Details on test conditions Tests were conducted in 250 ml beakers containing 100 ml of test solution (in Kanawha River water) and 5 Daphnia (less than 24 hours old). Tests were run in duplicate. Dissolved oxygen and pH were determined initially and at 48 hours for all test solutions. Total hardness, alkalinity, p H and conductivity of the test and holding water were 55 mg/l as CaCO3, 36 mg/l as CaCO3, 6.7, and 250 micromhos/cm. Mortalities were recorded at 24 and 48 hours. Results and discussions Effect concentrations Duration 48 h Endpoint LC50 Effect conc. 2210 mg/L N ominal/Measured nominalConc. based on test mat. Basis for effect mortality Remarks (e.g. 95% CL) Remarks on results including tables and figures
Toxicity of triethylene glycol monomethyl ether (CAS No. 112-35-6) and of triethylene glycol monoethyl ether (CAS No. 112-50-5) also were tested in this study. LC50 values for both chemicals were > 10000 mg/l.
Short-term toxicity to aquatic invertebrates.002 UUID IUC5-4cd42ee1-3e42-4d80-9ff5-7bc8a28ef61c Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 08:52:52 EST Remarks

Administrative Data Purpose flag weight of evidence (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Reliablility 4 (not assignable) Rationale for reliability Study data were available only from a secondary source

Data source Reference Reference type company data

Author Year 2000 Title Dow MSDS for CARBOWAX methoxypolyethylene glycol 350 (CAS No. 9004-74-4), Bibliographic

source Testing laboratory Report

no. Owner company Dow Chemical Company

Company study no. N umbe r 870 Report date 2000-07-05

Materials and methods Principles of method if other than guideline N o data on guideline followed. Study probably conducted by typical method. GLP compliance no data Test materialsTest material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 9004-74-4

Identifier Common name Identity Carbowas MGEP-350 Details on test material Test material (CARBOWAX MPEG-350; CAS No. 9004-74-4) is a mixture of several methylated glycol ethers of differing molecular weight (ranging from diethylene glycol monomethyl ether (C2) to heptadecaethylene glycol monomethyl ether (C17)). The majority of the material is in the C5-C11 range (87.445%). It contains 4.347 % (by weight) tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 1.303% triethylene glycol monomethyl ether (CAS No. 112-35-6), 0.181% diethylene glycol monomethyl ether (CAS No. 111-77-3). Analytical monitoring no data Details on sampling no data Details on analytical methods no data Vehicle

no Details on test solutions no data Test organisms Test organisms (species) Daphnia magna Details on test organisms no data Study design Test type no data Water media type no data Total exposure duration 48 h Remarks Post exposure observation period no data Test conditions Hardness no data Test temperature no data
p Hno data Dissolved oxygen no data Salinity no data N ominal and measured concentrations no data Details on test conditions no data Reference substance ( p ositive control) no data Any other information on materials and methods incl. tables

no data

Results and discussions Effect concentrations Duration 48 h Endpoint LC50 Effect conc. > 10000 mg/L N ominal/Measured no data Conc. based on no data Basis for effect Remarks (e.g. 95% CL)

6.1.5 Toxicity to aquatic algae and cyanobacteria Toxicity to aquatic algae and cyanobacteria-BASF TGBE 1989.001 UUID IUC5-4a81a83b-81b1-476b-97bc-c7d5793e0f6e Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 08:59:44 EST Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 89 Reliablility 2 (reliable with restrictions) Rationale for reliability Test material purity is unknown. Details about study conduct are lacking.

Data source Reference Reference type study reportAuthor Year 1989 Title Algentest for Butyltriglykol Bibliographic

source Testing laboratory Report no.

Owner company BASF AG Company study no. 2/1022/88/t0 Report date 1989-09-25 Materials and methods Principles of method if other than guideline N o guideline referenced. Study was conducted according to typical procedure for acute toxicity to algae. GLP compliance no data Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 143-22-6

Identifier EC number Identity 205-592-6

Identifier Common name Identity Triethylene glycol butyl ether Details on test material no data Analytical monitoring

no Test organisms Test organisms (species) Scenedesmus subspicatus (new name: Desmodesmus subspicatus) Details on test organisms A SAG 86.81 culture of Scenedesmus subspicatus (10,000 cells/ml) was maintained in OECD medium at 20 degrees C. Study design Test type static Water media type no data Limit test

no Total exposure duration 72 h Remarks Test conditionsHardness no data Test temperature no data
p H no data Dissolved oxygen no data Salinity no data N ominal and measured concentrations 0 (control), 7.812, 15.625, 31.25, 62.5, 125, 250 or 500 mg/l test material in quadruplicate. Details on test conditions Ten ml of cells in suspension was treated with 0 (control), 7.812, 15.625, 31.25, 62.5, 125, 250 or 500 mg/l test material in quadruplicate. Fluorescence of vials containing treated cells was determined 0, 24, 48 and 72 hours after treatment in a fluorimeter with a gain setting of 1. Fluorescence of 2 blank vials containing test material (at each concentration) and medium without cells was subtracted from values obtained for test vials. The values for the four tests were averaged and a standard deviation was calculated. The average fluorescence value of each concentration was presented as a percentage of control values. Results and discussions Effect concentrations Duration 72 h Endpoint EC50 Effect conc. > 500 mg/L N ominal/Measured nominal Conc. based on test mat. Basis for effect biomass Remarks (e.g. 95% CL)

Duration 24 h Endpoint EC20 Effect conc. 235.7 mg/L N ominal/Measured nominal Conc. based on test mat. Basis for effect biomass Remarks (e.g. 95% CL)

Duration 48 h Endpoint EC20 Effect conc. 235.4 N ominal/Measured nominal Conc. based on test mat. Basis for effect biomass Remarks (e.g. 95% CL)Duration 72 h Endpoint EC20 Effect conc. 267.1 mg/L N ominal/Measured nominal Conc. based on test mat. Basis for effect biomass Remarks (e.g. 95% CL)

Duration 72 h Endpoint EC90 Effect conc. 500 mg/L N ominal/Measured nominal Conc. based on test mat. Basis for effect biomass Remarks (e.g. 95% CL) Details on results The EC20 value at 24, 48, and 72 hours was 235.7, 235.4, and 267.1 mg/l. The EC50 value was greater than the highest concentration tested (500 mg/l). At time 0, fluorescence values ranged from 94.37 % of control for cells treated with 7.812 and 31/25 mg/l to 103.09 % of control for cells treated with 500 mg/l. The fluorescence values for cells treated with all concentrations except 125 (86.08%) and 250 mg/l (79.21%) were greater than 90% at 24 hours. At 48 hours, cells treated with 250 or 500 mg/l began to exhibit slightly lower fluorescence values than control. At 72 hours, values for cells treated with 250 or 500 mg/l were 80.3% and 75.91% of control, respectively. Most values for the 4 replicates at each concentration varied by < = 5%. However, at 48 hours, variance of values for concentrations greater than or equal to 250 mg/l ranged from 5-10%. The EC90 value = 500 mg/L. Toxicity to aquatic algae and cyanobacteria.001 UUID IUC5-a5ab8123-81cc-479c-bfc9-95e2302027ee Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-02-15 16:52:11 EST Remarks

Administrative Data Purpose flag supporting study ( ) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1989

Reliablility 2 (reliable with restrictions) Rationale for reliability Original reference was not available. Information (including the reliability code) came from a previous IUCLID data set produced by the European Chemicals Bureau Data source ReferenceReference type company data Author Year 1989 Title Algentest for Methyltriglykol Bibliographic

source Testing laboratory Report no. 2/1017/88/t72 Owner company BASF AG Company study no. Report date 1990-03-09

Materials and methods Principles of method if other than guideline Typical acute aquatic toxicity procedure for algae. GLP compliance no data Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 112-35-6

Identifier EC number Identity 203-962-1

Identifier Common name Identity Triethylene Glycol Methyl Ether Details on test material no data Analytical monitoring

no Details on analytical methods no data Vehicle no data Details on test solutions no data Test organisms Test organisms (species) Scenedesmus subspicatus (new name: Desmodesmus subspicatus) Details on test organisms no data Study design Test type no data Water media type no dataTotal exposure duration 72 h Remarks Post exposure observation period no data Test conditions Hardness no data Test temperature no data
p H no data Dissolved oxygen no datano data N ominal and measured concentrations no data Details on test conditions no data Reference substance ( p ositive control) no data Results and discussions Effect concentrations Duration 72 h Endpoint EC20 Effect conc. > 500 mg/L N ominal/Measured no data Conc. based on no data Basis for effect biomass Remarks (e.g. 95% CL)

Duration 72 h Endpoint EC50 Effect conc. > 500 mg/L N ominal/Measured no data Conc. based on no data Basis for effect biomass Remarks (e.g. 95% CL)

Duration 72 h Endpoint EC90 Effect conc. > 500 mg/L N ominal/Measured no data Conc. based on no data Basis for effect biomass Remarks (e.g. 95% CL) 6.1.7 Toxicity to microorganismsToxicity to microorganisms-Waggy TGBE 1987.001 UUID IUC5-fe3e0213-d14d-4407-9024-b69c5d4f5e0d Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 09:01:22 EST Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 87

Reliablility 2 (reliable with restrictions) Rationale for reliability Purity of test material was not noted.

Data source Reference Reference type study report

Author Waggy GT. Year 1987 Title Glycol ethers: Summary of available ecological fate and effects data. Bibliographic

source Testing laboratory Report

no. Owner company Union Carbide

Company study no. File Number 35931 Report date 1987-11-19

Materials and methods Principles of method if other than guideline Typical method for acute toxictiy to microorganisms. Details of the test are published in: Alsop et al., "Bacterial Growth Inhibition Tests", J. Water Pollution Control Federation, Vol 52: N o. 10, October, 1980. GLP compliance no data Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 143-22-6Identifier EC number Identity 205-592-6

Identifier Common name Identity Triethylene glycol butyl ether Details on test material no data Analytical monitoring

no Details on sampling no data Details on analytical methods no data Vehicle

no Details on test solutions no data Test organisms Test organisms (species) other: "sewer microorganisms" Details on inoculum no data Study design Test type no data Water media type no data Limit test

no Total exposure duration 16 h Remarks Post exposure observation period no data Test conditions Hardness no data Test temperature 23 degrees C
p H no data Dissolved oxygen no data Salinity no dataN ominal and measured concentrations no data Details on test conditions Selected concentrations (not listed) were incubated for 16 hours at 23 degrees C on a shaker table in the presence of nutrients, buffer, growth substrate, and sewer-microorganisms. Toxicity was indicated when the resulting turbidity was at (or less than) 50% of the control (IC50). Details of the test are published in: Alsop et al., "Bacterial Growth Inhibition Tests", J. Water Pollution Control Federation, Vol 52: N o. 10, October, 1980. Reference substance ( p ositive control) no data Results and discussions Effect concentrations Duration 16 h Endpoint IC50 Effect conc. > 10000 mg/L N ominal/Measured nominal Conc. based on test mat. Basis for effect growth inhibition Remarks (e.g. 95% CL) Details on results no data Remarks on results including tables and figures

Toxicity of triethylene glycol monomethyl ether (TGME, CAS No. 112-35-6) and of triethylene glycol monoethyl ether (TGEE, CAS No. 112-50-5) were also tested in this study. The LD50 values for TGME and TGEE were > 5000 mg/l and > 10000 mg/l, respectively.
Toxicity to microorganisms.002 UUID IUC5-f5b68256-a69b-4afe-9364-dd59396f8fd5 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 09:02:18 EST Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1988

Reliablility 2 (reliable with restrictions) Rationale for reliability Original reference was not available. Information (including the reliability code) came from a previous IUCLID data set produced by the European Chemicals BureauData source Reference Reference type company data

Author Year 1988 Title Unpublished Stud Bibliographi

c source Hoechst AG Frankfurt/Main EUROPEAN COMMISSION- European Chemicals Bureau Ispra (VA) Testing laboratory Report

no. Owner company Hoechst AG.

Company study no. Werk Gendorf; P 07/89 Report date Materials and methods Test guideline Qualifier according to Guideline OECD Guideline 209 (Activated Sludge, Respiration Inhibition Test) Deviations GLP compliance no data Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 23783-42-8

Identifier EC number Identity 245-883-5

Identifier Common name Identity Tetraethylene glycol methyl ether Details on test material no data Analytical monitoring

no Details on sampling no data Details on analytical methods no data Vehicle

no Details on test solutions no data Test organismsTest organisms (species) activated sludge Study design Test type no data Water media type no data Total exposure duration 3 h Remarks Post exposure observation period no data Test conditions Hardness no data Test temperature no data
p H no data Dissolved oxygen no data Salinity no data N ominal and measured concentrations no data Details on test conditions no data Reference substance ( p ositive control) no data Results and discussions Effect concentrations Duration 3 h Endpoint EC0 Effect conc. > 12500 mg/L N ominal/Measured nominal Conc. based on test mat. Basis for effect respiration rate Remarks (e.g. 95% CL) Toxicity to microorganisms.003 UUID IUC5-e4be1fc1-a0ae-4110-a0c1-7dfeecafc2ee Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 09:03:33 ESTRemarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1988

Reliablility 2 (reliable with restrictions) Rationale for reliability Original reference was not available. Information (including the reliability code) came from a previous IUCLID data set produced by the European Chemicals Bureau. Data source Reference Reference type company data

Author Year 1988 Title Bibliographic

source 2000 IUCLID data set produced by the European Chemicals Bureau.

Testing laboratory Report no.

Owner company Hoechst AG.

Company study no. Unpublished Study (Werk Gendorf; P 07/89). Report date Materials and methods Test guideline

Qualifie

r according to

Guideli

ne other guideline: "ETAD Fermentation tube method "Determination of damage to effluent bacteria by the Fermentation Tube Method" Deviatio

ns GLP compliance no data Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 23783-42-8

Identifier EC number Identity 245-883-5Identifier IUPAC name Identity tetraethylene glycol monomethyl ether Details on test material no data Analytical monitoring

no Details on sampling no data Details on analytical methods no data Vehicle

no Details on test solutions no data Test organisms Test organisms (species) anaerobic bacteria from a domestic water treatment plant Details on inoculum no data Study design Test type no data Water media type no data Total exposure duration 24 h Remarks Post exposure observation period no data Test conditions Hardness no data Test temperature no data
p H no data Dissolved oxygen no data Salinity no data N ominal and measured concentrations no data Details on test conditions no data Reference substance ( p ositive control)no data Results and discussions Effect concentrations Duration 24 h Endpoint other: SG Effect conc. ca. 3000 mg/L N ominal/Measured no data Conc. based on no data Basis for effect Remarks (e.g. 95% CL) 7 Toxicological information 7.1 Toxicokinetics, metabolism and distribution 7.1.2 Dermal absorption Dermal absorption-Ward & Scott TGBE 1986.001 UUID IUC5-ef1f9a61-dfcd-43a4-8fa1-8ed33080f2ff Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 09:06:35 EST Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 198 6 Reliablility 2 (reliable with restrictions) Rationale for reliability Well designed and conducted study, comparing in vitro human skin absorption rates for triethylene glycol butyl ether and three analogous glycol ethers. However, no data were provided for radiolabeling test material and documenting the analysis. Data source Reference Reference type Author Ward RJ, Scott RC. Year 1986 Title Triethylene glycol ethers: Absorption through human epidermis in vitro Bibliographic

source Testing laboratory Report

no. CTL/P/160 0 Owner company . Imperial Chemical Industries

Company Report 1986-10-31study no. date Materials and methods Type of method in vitro Principles of method if other than guideline Typical in vitro dermal absorption rate determination procedure was followed. GLP compliance no data Test materials Radiolabelling no data Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 143-22-6

Identifier EC number Identity 205-592-6

Identifier Common name

Identity POLYSOLV-TB, triethylene glycol monobutyl ether Details on test material Purity of test material (POLYSOLV-TB, triethylene glycol monobutyl ether) was 96.91%. Test animals Species human Sex no data Administration / exposure Type of coverage occlusive Vehicle unchanged (no vehicle) Duration of exposure 12 hours N o. of animals per group N ot applicable Details on in vitro test system (if applicable) Human abdominal whole skin (2.54 cmE2) was mounted in a glass diffusion apparatus (at 30 +/- 1 degree C) and the diffusion of triethylene glycol monobutyl ether was monitored during a 12-hr period using gas chromatography (n=6). The integrity of the epidermal membranes was first assessed by measuring permeability of membranes to tritiated water. Epidermal membranes displaying permeability constants greater than 1.5 x 10E-3 cm/hr were deemed to have been damaged during preparation and were rejected. Results and discussionsSigns and symptoms of toxicity no effects Dermal irritation not examined Remarks on results including tables and figures

The mean steady state of absorption for triethylene glycol monobutyl ether was 22.2 micrograms/cm2/hr (SD +/- 8.59), which was 100-fold less than that of ethylene glycol monomethyl ether. Test material did not increase permeability of the membrane (damage ratio of 1.26).

Overall remarks, attachments Overall remarks

Absorption of ethylene glycol monomethyl ether (EGME), triethylene glycol monomethyl ether (TGME), and triethylene glycol monoethyl ether (TGEE) also were tested in this study. The rate of absorption of EGME was220 micrograms/cm2/hr. The rate of absorption of TGME was 34.0 micrograms/cm2/hr and the mean damage ratio was 3.36 (small increase in permeability). The rate of absorption of TGEE was 24.1 micrograms/cm2/hr, and the mean damage ratio was 1.37 (no increase in permeability).
7.2 Acute Toxicity 7.2.1 Acute toxicity: oral Acute toxicity: oral Moreno TGBE 1976.001 UUID IUC5-0044d9c9-7b50-44d9-9e8c-4edf6cd14889 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 09:08:32 EST Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 76

Reliablility 2 (reliable with restrictions) Rationale for reliability Predates GLP. Purity of substance not given.

Data source Reference Reference type Author Moreno OM. Year 1976 Title Report on oral LD50 in rats. Bibliographic

source EPA/OTS File 0206801.

Testing laboratory MB Research Laboratories, Inc. Report no.Owner company Olin Corporation Company study no. Project number MB 75-990 Report date 1976-01-25

Materials and methods Test type standard acute method Limit test

no GLP compliance no data Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 143-22-6

Identifier EC number Identity 205-592-6

Identifier Common name Identity triethylene glycol monobutyl ether Details on test material no data Test animals Species
rat Strain Wistar Sex male Details on test animals and environmental conditions Rats (200-250 g) were fasted for approximately 18 hours prior to test material administration. Administration / exposure Route of administration other: intubation Vehicle unchanged (no vehicle) Details on oral exposure The test animals were fasted for approximately 18 hours prior to test material administration. Test material was given by intubation at 3.2, 5.0, 7.73, and 12.18 g/kg to groups of 10 animals. Doses 3.2, 5.0, 7.73, and 12.18 g/kg N o. of animals per sex per dose 10 animals per dose. A total of forty animals were used in the study Control animalsno Details on study design Food and water were freely available after treatment. Rats were observed for toxicity and death for 14 days. Statistics The LD50 value and 95% confidence limits were determined by the method of Litchfield and Wilcoxon (J Pharm Exp Ther 96:99, 1949). Results and discussions Effect levels Sex male Endpoint LD50 Effect level 5300 mg/kg bw 95% CL >= 4100

—<= 6800 Remarks Mortality All animals given 12.18 g/kg died within 3 hours. Eight animals given 7.73 g/kg and 6 given 5.0 g/kg died within 1 day. There were no other deaths over the course of the experiment. Clinical signs Signs of toxicity at 5.0 g/kg included loss of righting reflex and flaccid muscle tone; at 7.73 g/kg included comatose (6/10), flaccid muscle tone, and heavy breathing. There were no signs of toxicity in rats given 3.2 g/kg. Body weight no data Acute toxicity: oral Smyth TGBE 1962.002 UUID IUC5-d045e4a1-9095-406c-9f23-cfe403e38763 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 09:12:53 EST Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 62

Reliablility 2 (reliable with restrictions) Rationale for reliability Purity of test material was not noted. Predates current guidelines and GLP

Data source Reference Reference type p ublication Author Smyth HF, Carpenter CP, Weil CS, Pozzani U, Year 1962Striegel JA. Title Range-finding toxicity data: List VI. Bibliographic

source Am Ind Hyg Assoc J 23:95-107

Testing laboratory Report no.

Owner company Company study

no. Report date

Reference type study report Author Carpenter CP and Striegel JA. Year 1960 Title Range finding tests on butoxy triglycol. Bibliographic

source Testing laboratory Melon Institute of Industrial Research Report no. Report 23-25

Owner company

Company study

no. Report date 1960-03-31

Materials and methods Test type standard acute method Limit test

no Test guideline Qualifier no guideline followed Guideline Deviations Principles of method if other than guideline Standard acute oral study procedure of the time period GLP compliance

no Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 143-22-6

Identifier EC number Identity 205-592-6

Identifier Common nameIdentity triethylene glycol monobutyl ether Details on test material no details Test animals Species
rat Strain other: Carworth-Wistar Sex male Details on test animals and environmental conditions (4-5 weeks of age; 90-120 g Administration / exposure Route of administration other: intubation Vehicle other: water, corn oil or semi-solid agar (vehicle specific for test compound was not listed) Details on oral exposure no data Doses 4, 8, and 16 ml/kg N o. of animals per sex per dose five males per dose Control animals no data Details on study design Groups of five non-fasted rats (4-5 weeks of age; 90-120 g) were intubated with log doses with test material at dose levels differing by a factor of 2.0 in a geometric series. Test compound was diluted in either water, corn oil or semi-solid agar (vehicle specific for test compound was not listed). Animals were observed up to 14 days after dosing for mortality. Autopsies were p erformed on rats that died. Surviving rats were weighed at study termination. Statistics The LD50 value and its fiducial range ( p lus or minus 1.96 standard deviations) were estimated by the method of Thompson (Bacteriol Rev 11: 115, 1947) using the Tables of Weil (Biometrics 8: 249, 1952). Results and discussions Effect levels Sex male Endpoint LD50 Effect level 6.73 mL/kg bw 95% CL Remarks Average value. Range of LD50 from 4.13 to 11.0 ml/kg Mortality The oral LD50 for rats averaged 6.73 ml/kg and ranged from 4.13 to 11.0 ml/kg. All animals receiving 16 ml/kg died, 3 out of 5 dosed with 8 ml /kg, and 1 out of 5 dosed with 4 ml/kg diedwithin 1 day of dosing. Autopsy of dead rats showed a generalized congestion of the abdominal viscera and lungs. Clinical signs no data Body weight no data Gross pathology no data Other findings no data Acute toxicity: oral.003 UUID IUC5-6d220dd0-0521-4c4f-affd-3b76af914eea Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 09:16:29 EST Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 88

Reliablility 1 (reliable without restriction) Rationale for reliability Well conducted, robust study following recognized procedure.

Data source Reference Reference type study report

Author Reid ME. Year 1988 Title Carbowax MPEG 350 N M W . Acute toxicity and primary irritancy studies. Bibliographi

c source Testing laboratory Bushy Run Research Center Project Report 51-41 Report

no. Project Report 51-41 Owner company Union Carbide

Company study no. Report date 1988-05-23

Materials and methods Test type standard acute methodLimit test

no Principles of method if other than guideline N o guideline mentioned. Study was conducted using typical standard protocol for acute oral
test. GLP compliance no data Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 9004-74-4

Identifier Common name Identity CARBOWAX MPEG-350 Details on test material Test material (CARBOWAX MPEG-350; CAS No. 9004-74-4) is a mixture of several methylated glycol ethers of differing molecular weight (ranging from diethylene glycol monomethyl ether (C2) to heptadecaethylene glycol monomethyl ether (C17)). The majority of the material is in the C5-C11 range (87.445%). It contains 4.347 % (by weight) tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 1.303% triethylene glycol monomethyl ether (CAS No. 112-35-6), 0.181% diethylene glycol monomethyl ether (CAS No. 111-77-3). Test animals Species
rat Strain Sprague-Dawley Sex male/female Details on test animals and environmental conditions Rats were fasted overnight before dosing. Male and female rats weighed approximately 250 and 200 g at study initiation. Administration / exposure Route of administration other: stomach intubation Vehicle unchanged (no vehicle) Details on oral exposure Rats (5/sex/dose) received 8.0 or 16.0 ml/kg test material by stomach intubation. Two male rats were also dosed with 4.0 ml/kg. A total of 22 animals were used in the study. Doses 8.0 or 16.0 ml/kg N o. of animals per sex per dose 5/sex/dose Control animalsno data Details on study design Rats (5/sex/dose) received 8.0 or 16.0 ml/kg test material by stomach intubation. Two male rats were also dosed with 4.0 ml/kg. Doses were varied by adjusting the volume of test material or its dilution. Rats were fasted overnight before dosing. Male and female rats weighed approximately 250 and 200 g at study initiation. Animals were weighed before dosing and at days 7 and 14 after dosing. At death or sacrifice, each animal was subjected to gross pathologic evaluation. Statistics no data Results and discussions Effect levels Sex male/female Endpoint LD50 Effect level > 16 mg/kg bw 95% CL Remarks Mortality N one of the animals treated with any dose of test material died. Clinical signs no data Body weight Animals were weighed before dosing and at days 7 and 14 after dosing. N one of the animals treated with any dose of test material died. Gross pathology At death or sacrifice, each animal was subjected to gross pathologic evaluation. Acute toxicity: oral.004 UUID IUC5-60d19c56-d5dc-4760-bd61-3d5b8d49a1d8 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 09:17:55 EST Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 47

Reliablility 2 (reliable with restrictions) Rationale for reliability Old study, conducted preguidelines and pre GLP

Data sourceReference Reference type study report

Author Carpenter CP Year 1947 Title Range finding tests on methoxy polyethylene glycols of approximate molecular weights 350, 550 and 750. Bibliograp hic source Melon Institute of Industrial Research, University of Pittsburgh.

Testing laboratory Report

no. Owner company Company study no. Report date 1947-05- 13 Materials and methods Test type standard acute method Limit test

no Principles of method if other than guideline Standard acute method conducted pre-guideline. GLP compliance

no Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 9004-74-4

Identifier Common name Identity MPEG-350 Details on test material Methoxy polyethylene glycol of approximately 350 molecular weight. Test animals Species
rat Strain other: common albino Sex male Administration / exposure Route of administration other: stomach tube Vehicle unchanged (no vehicle)Details on oral exposure no details Doses 10 ml/kg and 50 ml/kg N o. of animals per sex per dose Six male animals per dose. Twelve animals were used in the study. Control animals no data Details on study design Groups of 6 rats (91-106 g) were dosed with 10 ml/kg (approximately 1 ml) or 50 ml/kg (approximately 4.7-5.3 ml) undiluted test material by stomach tube. Body weight gain and deaths were observed over a period of 14 days. Statistics no data Results and discussions Effect levels Sex male Endpoint LD50 Effect level 22 mL/kg bw 95% CL Remarks Method of estimation not given. Mortality All animals dosed with 50 ml/kg died within 1 day. N one of the rats dosed with 10 ml/kg died. The LD50 was estimated to be 22 ml/kg (method of extrapolation not given). Clinical signs no data Body weight Animals dosed with 10 ml/kg gained from 23 to 68 grams over 14 days. Gross pathology no data Acute toxicity: oral.005 UUID IUC5-6c4163c9-77b2-43b3-9f94-7f7fa52fdfbc Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 09:19:15 EST Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1988

Reliablility 2 (reliable with restrictions)Rationale for reliability Original reference was not available. Information (including the reliability code) came from a previous IUCLID data set produced by the European Chemicals Bureau. Data source Reference

Reference type company data

Author Year 1988 Title Bibliograp hic source Hoechst AG Frankfurt/MainClariant GmbH Frankfurt/Main EUROPEAN COMMISSION-European Chemicals Bureau Ispra (VA) Testing laboratory Report

no. Owner company Hoechst AG

Company study no. Unpublished Study (77.0196). Report date Materials and methods Test type standard acute method Limit test
yes Principles of method if other than guideline Interne Richtlinie der Hoechst AG (Internal protocol of Hoechst AG) GLP compliance no data Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 23783-42-8

Identifier EC number Identity 245-774-2

Identifier Common name Identity tetraethylene glycol monomethyl ether Details on test material no data Test animals Species
rat Strain no data Sexno data Details on test animals and environmental conditions no data Administration / exposure Route of administration oral: unspecified Vehicle no data Details on oral exposure Probably used undiluted test material Doses no data N o. of animals per sex per dose no data Control animals no data Details on study design no data Statistics no data Results and discussions Effect levels Sex no data Endpoint LD50 Effect level > 15000 mg/kg bw 95% CL Remarks Mortality none at limit dose Clinical signs no data Body weight no data Gross pathology no data Other findings no data Acute toxicity: oral.006 UUID IUC5-254614e6-7242-4473-8612-c185f4246d57 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 09:20:35 EST RemarksAdministrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1988

Reliablility 2 (reliable with restrictions) Rationale for reliability Original reference was not available. Information (including the reliability code) came from a previous IUCLID data set produced by the European Chemicals Bureau. Data source Reference

Reference type company data

Author Year 1988 Title Bibliograp hic source Hoechst AG Frankfurt/MainClariant GmbH Frankfurt/Main EUROPEAN COMMISSION-European Chemicals Bureau Ispra (VA) Testing laboratory Report

no. Owner company Hoechst AG.

Company study no. Unpublished Study (88.1130) Report date Materials and methods Test type standard acute method Test guideline Qualifier according to Guideline OECD Guideline 401 (Acute Oral Toxicity) Deviations Principles of method if other than guideline Standard acute oral protocol used at the time. GLP compliance no data Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 23783-42-8

Identifier EC number Identity 245-883-5

Identifier Common nameIdentity tetraethylene glycol monomethyl ether Details on test material no data Test animals Species
rat Strain no data Sex no data Administration / exposure Route of administration oral: unspecified Details on oral exposure no data N o. of animals per sex per dose no data Control animals no data Details on study design no data Statistics no data Results and discussions Preliminary study (if fixed dose study) no data Effect levels Sex no data Endpoint LD50 Effect level > 2000 mg/kg bw 95% CL Remarks Acute toxicity: oral.007 UUID IUC5-02d53fa8-f9a6-470c-a8e6-08a99cf55033 Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-02-15 17:50:16 EST Remarks

Administrative Data Purpose flag supporting study ( ) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 58Reliablility 2 (reliable with restrictions) Rationale for reliability Older preguideline and pre GLP study. Purity of test material was not noted.

Data source Reference Reference type study report Author Carpenter CP. Year 1958 Title Range finding tests on methoxytriglycol. Bibliographic

source Testing laboratory Mellon Institute of Industrial Research Report no. 21-44

Owner company Company study

no. Report date 1958-06-12

Materials and methods Test type standard acute method Limit test

no Principles of method if other than guideline Standard acute oral toxicity study procedure. GLP compliance

no Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 112-35-6

Identifier EC number Identity 203-962-1

Identifier Common name Identity triethylene glycol monomethyl ether Details on test material no data Test animals Species
rat Strain other: Carworth Farms- N elson Sex maleDetails on test animals and environmental conditions 5-6 weeks old, 90-120 g Administration / exposure Route of administration other: stomach intubation Vehicle unchanged (no vehicle) Details on oral exposure stomach intubation Doses 4, 8, or 16 ml/kg N o. of animals per sex per dose 5 males per dose Control animals no data Details on study design Male rats (5-6 weeks old, 90-120 g) were dosed with 4, 8, or 16 ml/kg test material by stomach intubation. Rats were observed for 14 days. Surviving rats were weighed on day 14. Autopsies were performed on those that died. Statistics The method of moving average was used to calculate the LD50 value. Results and discussions Effect levels Sex male Endpoint LD50 Effect level 11300 mg/kg bw 95% CL Remarks Mortality All rats dosed with 16 ml/kg died within 1 day. N one of the other animals died. Clinical signs no data Body weight All animals except 1 dosed with 4 ml/kg gained weight. Gross pathology Autopsies on rats that died revealed congested lungs, mottled livers and kidneys, GI tractirritation, and congested adrenals. Acute toxicity: oral.008 UUID IUC5-e5c838af-1099-4d0a-9607-f2cbcb72734c Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-02-15 18:57:09 EST RemarksAdministrative Data Purpose flag supporting study ( ) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1 9 9 2 Reliablility 2 (reliable with restrictions) Rationale for reliability Test substance composition was well characterized, and study followed GLP. Few study details provided however. Data source Reference Reference type study report

Author Gardner JR. Year 1992 Title Brake fluid DOT 4: Acute oral and dermal toxicity in rat, skin and eye irritancy in rabbit. Bibliograph ic source Testing laboratory Shell Research Limited, Sittingbourne Research Centre Report

no. Owner company Shell

Company study no. DocumentNumber SBGR.92.011 Report date 1992-06-3 0 Materials and methods Test type standard acute method Principles of method if other than guideline standard acute oral toxicity procedure. GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 106008-94-0

Identifier Common name Identity Brake fluid DOT 4 Details on test material Test material is a mixture containing 30-50% triethyleneglycol monomethyl ether borate ester (CAS No. 106008-94-0),3-30% triethylene glycol monobutyl ether borate ester, 20-30% triethylene glycol monomethyl ether (CAS No. 112-35-6), 2-10% triethylene glycol monobutyl ether (CAS No. 143-22-6), 20-30% tetraethylene glycol monomethyl ether (CAS No.23783-42-8), 2-10% tetraethylene glycol monobutyl ether (CAS No. 1559-34-8), and < 1% minor additives Test animals Species
rat Strain Fischer 344 Sex male/female Details on test animals and environmental conditions no details Administration / exposure Route of administration oral: unspecified Vehicle unchanged (no vehicle) Details on oral exposure no data Doses 5000 mg/kg bw N o. of animals per sex per dose 10 Control animals

no Details on study design no data Statistics no data Results and discussions Effect levels Sex male/female Endpoint LD50 Effect level > 5000 mg/kg bw 95% CL Remarks 7.2.2 Acute toxicity: inhalation Acute toxicity: inhalation Smyth TGBE 1962.001 UUID IUC5-01baf344-0464-4b91-b377-af5dcc9969ee Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 09:23:18 EST RemarksAdministrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 60

Reliablility 2 (reliable with restrictions) Rationale for reliability Limited information on study details and test material provided.

Data source Reference Reference type Author Carpenter CP and Striegel JA Year 1960 Title Range finding tests on butoxy triglycol. Melon Institute of Industrial Research Bibliographi

c source

Testing laboratory Melon Institute of Industrial Research Report

no. Report 23-25 Owner company Company study no. Report date 1960-03-31

Reference type p ublication Author Smyth HF, Carpenter CP, Weil CS, Pozzani U, Striegel JA Year 1962

Title Range-finding toxicity data: List VI. Bibliographic

source Am Ind Hyg Assoc J 23:95-107.

Testing laboratory Report no.

Owner company Company study

no. Report date

Materials and methods Test type standard acute method Principles of method if other than guideline standard acute method of the period GLP compliance no data Test materials Test material equivalent to submission substance identity
yesTest material identity Identifier CAS number Identity 143-22-6

Identifier EC number Identity 205-592-6

Identifier Common name Identity triethylene glycol monobutyl ether Details on test material no data Test animals Species
rat Strain Wistar Sex female Details on test animals and environmental conditions no data Administration / exposure Route of administration inhalation: vapour Type of inhalation exposure no data probably whole body, since nose only not mentioned. Vehicle unchanged (no vehicle) Details on inhalation exposure no data Analytical verification of test atmosphere concentrations

no Duration of exposure 8 h Remarks From 15 minutes up to 8 h Concentrations not measured. N o. of animals per sex per dose six females per dose Control animals no data Details on study design Concentrated vapor (25 degrees C) was generated by passing air at 2.5 liters/min through a fritted glass disc immersed in 50 ml of butoxy triglycol. Rats were exposed for 8 hours to a flowing stream of this vapor and observed for 14 days.
Rats were exposed from time periods ranging from 15 minutes to 8 hours (until the inhalation p eriod killing about one half of the rats within 14 days was defined). The result is the longestinhalation period which permitted all rats to survive the14-day observation period. Results and discussions Preliminary study (if fixed dose study) no data Mortality All animals survived the eight hour exposure through the 14 day post exposure observation p eriod. Clinical signs no data. N o observations mentioned. Body weight no body weight observations mentioned in study. Gross pathology no data, p robably not conducted. Acute toxicity: inhalation Moreno TGBE 1976.002 UUID IUC5-5e7633c0-29b7-4419-9ef4-12f0e8f3f11c Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 09:35:07 EST Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 76

Reliablility 2 (reliable with restrictions) Rationale for reliability Good study, but preguideline and pre GLP and purity of test material was not noted. Data source Reference

Reference type study report Author Moreno OM. Year 1976 Title Report on inhalation toxicity in rats. Bibliographic

source EPA/OTS File 0206801.

Testing laboratory MB Research Laboratories, Inc. Report no. Project number MB 75-990 Owner company Olin Corporation

Company study

no. Report date 1976-01-25

Materials and methodsTest type standard acute method Principles of method if other than guideline standard acute inhalation toxicity method GLP compliance no data Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 143-22-6

Identifier EC number Identity 205-592-6

Identifier Common name Identity triethylene glycol monobutyl ether Details on test material no data Test animals Species
rat Strain Wistar Sex no data Details on test animals and environmental conditions 200-250 g weight for the test animals Administration / exposure Route of administration inhalation: vapour Type of inhalation exposure no data Vehicle unchanged (no vehicle) Analytical verification of test atmosphere concentrations no data Duration of exposure 1 h Remarks Concentrations 200 mg/liter of test material N o. of animals per sex per dose Ten rats of undetermined sex Control animals

noDetails on study design Ten rats (200-250 g, sex not stated) were placed in a 50 liter chamber and exposed to a nominal concentration of 200 mg/liter of test material for one hour. The rats were observed daily over 14 days for signs of toxicity. Statistics no data Results and discussions Effect levels Sex no data Endpoint LCLo Effect level > 200 mg/L air (nominal) 95% CL Exp. duration Remarks Mortality All animals survived the exposure. Clinical signs no data Body weight Bodyweights were recorded prior to and 14 days after treatment. Rats gained weight over the 14 day period. Gross pathology There were no signs of toxicity. Acute toxicity: inhalation.002 UUID IUC5-72623c1b-0a05-4549-b38c-357d47598a4e Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-02-15 18:07:08 EST Remarks

Administrative Data Purpose flag supporting study ( ) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 62

Reliablility 2 (reliable with restrictions) Rationale for reliability Purity of test material was not noted. Also older study predating guidelines or GLP. Data source Reference Reference type study report Author Year 1958 Title Range finding tests on methoxytriglycol.Bibliographic

source Testing laboratory Mellon Institute of Industrial Research Report no. 21-44

Owner company Company study

no. Report date 1958-06-12

Reference type p ublication Author Smyth HF, Carpenter CP, Weil CS, Pozzani U, Striegel JA Year 1962

Title Range-finding toxicity data: List VI Bibliographic

source Am Ind Hyg Assoc J 23:95-107.

Testing laboratory Report no.

Owner company Company study

no. Report date

Materials and methods Test type standard acute method Principles of method if other than guideline standard prodecure of the time for acute inhalation toxicology GLP compliance

no Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 112-35-6

Identifier EC number Identity 203-962-1

Identifier Common name Identity triethylene glycol monomethyl ether Details on test material no data Test animals Species
rat Strain other: Carworth-WistarSex female Administration / exposure Route of administration inhalation: vapour Type of inhalation exposure no data Vehicle unchanged (no vehicle) Details on inhalation exposure Six female rats were exposed to a flowing stream of vapor-ladened air generated by passing 2.5 l/min of dried air at room temperature through a fritted disc immersed to a depth of at least once inch in approximately 50 ml of test material contained in a gas-washing bottle. Rats were exposed from time periods ranging from 15 minutes to 8 hours (until the inhalation period killing about one half of the rats within 14 days was defined). The result is the longest inhalation period which permitted all rats to survive the14-day observation period. Analytical verification of test atmosphere concentrations no data Duration of exposure 8 h Remarks Concentrations not measured but probably saturated N o. of animals per sex per dose six females Control animals no data Results and discussions Mortality All animals survived an 8-hr exposure period to concentrated vapor and had normal weight gains. Clinical signs no data Body weight All animals had normal weight gains. Gross pathology no data Other findings no data 7.2.3 Acute toxicity: dermal Acute toxicity: dermal Smyth TGBE 1962.001 UUID IUC5-1abed54c-b863-4d49-9d2e-436387b80b92 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of AmericaDate 2009-02-12 09:38:46 EST Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1 9 6 2 Reliablility 2 (reliable with restrictions) Rationale for reliability 1962 study predating guidelines and GLP. Purity of test material not noted. Otherwise a good study. Data source Reference Reference type p ublication Author Smyth HF, Carpenter CP, Weil CS, Pozzani U, Striegel JA. Year 1962

Title Range-finding toxicity data: List VI. Bibliographic

source Am Ind Hyg Assoc J 23:95-107

Testing laboratory Report no.

Owner company Company study

no. Report date

Reference type study report Author Carpenter CP and Striegel JA. Year 1960 Title Range finding tests on butoxy triglycol. Bibliographic

source Testing laboratory Melon Institute of Industrial Research Report no. Report 23-25

Owner company Company study

no. Report date 1960-03-31

Materials and methods Test type other: variation of one-day cuff method of Draize Principles of method if other than guideline variation of one-day cuff method of Draize GLP compliance

noTest materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 143-22-6

Identifier EC number Identity 205-592-6

Identifier Common name Identity triethylene glycol monobutyl ether Details on test material no details Test animals Species rabbit Strain N ew Zealand White Sex male Details on test animals and environmental conditions Groups of 4 male rabbits (3-5 months, weighing between 2.5 to 3.5 kg Administration / exposure Type of coverage occlusive Vehicle no data Details on dermal exposure Groups of 4 male rabbits (3-5 months, weighing between 2.5 to 3.5 kg) were treated with 1.25, 2.5, 5.0 or 10 ml/kg dermally according to a variation of the one-day cuff method of Draize and associates (J Pharmacol Exper Ther 82: 377, 1944). Fur was clipped from the entire trunk. A VINYLITE sheeting was used to keep the test material in contact with the skin. Rabbits were immobilized during the 24-hour skin contact period. It is likely that no vehicle was used, but that was not stated. Duration of exposure 24 hours Doses N ot provided. N o. of animals per sex per dose four male rabbits per dose. Twelve animals total. Control animals

no Details on study design Groups of 4 male rabbits (3-5 months, weighing between 2.5 to 3.5 kg) were treated with 1.25, 2.5, 5.0 or 10 ml/kg dermally according to a variation of the one-day cuff method of Draize andassociates (J Pharmacol Exper Ther 82: 377, 1944). Fur was clipped from the entire trunk. A VINYLITE sheeting was used to keep the test material in contact with the skin. Rabbits were immobilized during the 24-hour skin contact period. After the dressing was removed, animals were observed for 14 days.
The LD50 value and its fiducial range ( p lus or minus 1.96 standard deviations) was estimated by the method of Thompson (Bacteriol Rev 11: 115, 1947) using the Tables of Weil (Biometrics 8: 249, 1952). Statistics The LD50 value and its fiducial range ( p lus or minus 1.96 standard deviations) was estimated by the method of Thompson (Bacteriol Rev 11: 115, 1947) using the Tables of Weil (Biometrics 8: 249, 1952). Results and discussions Effect levels Sex male Endpoint LD50 Effect level 3.54 mL/kg bw 95% CL >= 1.06

—<= 11.85 Remarks 1.96 standard deviations Mortality Three out of four rabbits treated with 10 ml/kg died within 3 days. The remaining animal in this group lost 110 g of weight over the 14-day recovery period. Two out of four rabbits treated with 5 ml/kg or 2.5 ml/kg, and 1 treated with 1.25 ml/kg died by day 9. Findings upon autopsy were cherry red and hemorrhaged lungs, dark livers mottled with prominent acini, and pale and mottled kidneys. The LD50 value was 3.54 (1.06 to 11.85) ml/kg. Clinical signs no data Body weight Surviving animal in the 10 ml/kg group lost 110 g of weight over the 14-day recovery period. Gross pathology Findings upon autopsy were cherry red and hemorrhaged lungs, dark livers mottled with p rominent acini, and pale and mottled kidneys. Other findings no data Acute toxicity: dermal Morena TGBE 1976.002 UUID IUC5-7e532477-b7c5-4907-b707-6b2c8d77e764 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 09:45:22 EST Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( )used for MSDS Study result type experimental result Study p eriod 19 76

Reliablility 2 (reliable with restrictions) Rationale for reliability A good study but non-current guideline. Test purity not provided.

Data source Reference Reference type study report Author Moreno OM. Year 1976 Title Report on acute dermal toxicity in rabbits. Bibliographic

source EPA/OTS Document File 0206801

Testing laboratory MB Research Laboratories, Inc. Report no.

Owner company Olin Corporation

Company study

no. Project Number MB 75-990 Report date 1976-01-25

Materials and methods Test type standard acute method Principles of method if other than guideline standard acute inhalation test procedure GLP compliance no data Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 143-22-6

Identifier EC number Identity 205-592-6

Identifier Common name Identity triethylene glycol monobutyl ether Details on test material no data Test animals Species rabbit Strain N ew Zealand White Sexno data Details on test animals and environmental conditions Ten rabbits were used with weights of 2.3 to 3.0 kg. Administration / exposure Type of coverage
open Vehicle no data Details on dermal exposure The animals were clipped free of abdominal hair. Epidermal abrasions were made longitudinally every 2 to 3 cm over the clipped area of 5 rabbits. The abrasions were deep enough to penetrate the stratum corneum, but not deep enough to produce bleeding. A single dose of 2.0 g/kg was applied to the exposed area. The area was covered with gauze and the trunk wrapped with impervious material for 24 hours. The dressing was then removed. It is likely that the test material was applied non-diluted, but that was not specified. Duration of exposure 24 hours Doses A single dose of 2.0 g/kg N o. of animals per sex per dose Ten rabbits Control animals

no Details on study design Ten rabbits (2.3 to 3.0 kg) were clipped free of abdominal hair. Epidermal abrasions were made longitudinally every 2 to 3 cm over the clipped area of 5 rabbits. The abrasions were deep enough to penetrate the stratum corneum, but not deep enough to produce bleeding. A single dose of 2.0 g/kg was applied to the exposed area. The area was covered with gauze and the trunk wrapped with impervious material for 24 hours. The dressing was removed, rabbits were cleaned, and animals were evaluated over 14 days. Statistics no data Results and discussions Effect levels Sex no data Endpoint LDLo Effect level > 2000 mg/kg bw 95% CL Remarks Mortality There were no deaths. Clinical signs N o signs of toxicity observed. Body weight no dataGross pathology no details Acute toxicity: dermal.003 UUID IUC5-15b639af-7701-4660-9a38-4677544c4e4a Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 09:47:04 EST Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1 9 8 8 Reliablility 1 (reliable without restriction) Rationale for reliability well conducted study with good documentation. Test material is well characterized as to composition. Data source Reference Reference type study report

Author Reid ME. Year 1988 Title Carbowax MPEG 350 N M W . Acute toxicity and primary irritancy studies. Bibliographi

c source Testing laboratory Bushy Run Research Center Report

no. Project Report 51-41 Owner company Company study no. Union Carbide Report date 1988-05-23

Materials and methods Test type standard acute method Principles of method if other than guideline standard acute inhalation test method GLP compliance no data Test materials Test material equivalent to submission substance identity

noTest material identity Identifier CAS number Identity 9004-74-4

Identifier Common name Identity CARBOWAX MPEG-350 Details on test material Test material (CARBOWAX MPEG-350)(CAS No. 9004-74-4) is a mixture of several methylated glycol ethers of differing molecular weight (ranging from diethylene glycol monomethyl ether (C2) to heptadecaethylene glycol monomethyl ether (C17)). The majority of the material is in the C5-C11 range (87.445%). It contains 4.347 % (by weight) tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 1.303% triethylene glycol monomethyl ether (CAS No. 112-35-6), 0.181% diethylene glycol monomethyl ether (CAS No. 111-77-3). Test animals Species rabbit Strain N ew Zealand White Sex male/female Details on test animals and environmental conditions Ten animals total were used in the study. Five rabbits of each sex (weighing between 2 and 3 kg). Administration / exposure Type of coverage occlusive Vehicle unchanged (no vehicle) Details on dermal exposure Five rabbits of each sex (weighing between 2 and 3 kg) were subjected to 24 hours of contact with the test material (16 ml/kg) , which was retained under impervious sheeting on the clipped, intact skin of the trunk. If necessary, gauze was wrapped around the trunk over the sample to p revent leakage. Bandaging tape was wrapped over the impervious sheeting. Excess fluid was removed after the contact period to diminish ingestion. Duration of exposure 24 hours of skin contact. Doses 16 ml/kg, single dose level N o. of animals per sex per dose five per sex per dose Control animals

no Details on study design Body weights were determined before and 7 and 14 days following test material application. Deaths were monitored for 14 days. Statisticsno data Results and discussions Preliminary study (if fixed dose study) no preliminary study Effect levels Sex male/female Endpoint LDLo Effect level > 16 mL/kg bw 95% CL Remarks Mortality N o animals died during the course of the study. Clinical signs N o signs of systemic toxicity or irritation were noted. Body weight no data Gross pathology no data Acute toxicity: dermal.004 UUID IUC5-39947494-db73-4033-ab8e-baf784e21445 Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-02-15 18:55:24 EST Remarks

Administrative Data Purpose flag supporting study ( ) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 92

Reliablility 2 (reliable with restrictions) Rationale for reliability few study details given

Data source Reference Reference type study report

Author Gardner JR. Year 1992 Title Brake fluid DOT 4: Acute oral and dermal toxicity in rat, skin and eye irritancy in rabbit Bibliographi

c source Testing Shell Research Limited, Sittingbourne Research Centre Reportlaboratory no. Owner company Shell

Company study no. DocumentNumber SBGR.92.011 Report date 1992-06-3 0 Materials and methods GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 106008-94-0

Identifier Common name Identity Brake fluid DOT 4 Details on test material Test material is a mixture containing 30-50% triethylene glycol monomethyl ether borate ester (CAS No. 106008-94-0), 3-30% triethylene glycol monobutyl ether borate ester, 20-30% triethylene glycol monomethyl ether (CAS No. 112-35-6), 2-10% triethylene glycol monobutyl ether (CAS No. 143-22-6), 20-30% tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 2-10% tetraethylene glycol monobutyl ether (CAS No. 1559-34-8), and < 1% minor additives Test animals Species
rat Strain Fischer 344 Sex male/female Administration / exposure Type of coverage no data Vehicle unchanged (no vehicle) Details on dermal exposure no data Duration of exposure no data Doses 2000 mg/kg bw N o. of animals per sex per dose 5 p er sex per dose Control animals no dataDetails on study design no data Statistics no data Results and discussions Effect levels Sex male/female Endpoint LD50 Effect level > 2000 mg/kg bw 95% CL Remarks Acute toxicity: dermal.005 UUID IUC5-7b14fc92-5c09-4a70-b7b8-ebde14a7b577 Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-02-15 19:21:01 EST Remarks

Administrative Data Purpose flag supporting study ( ) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 58

Reliablility 2 (reliable with restrictions) Rationale for reliability Well conducted study, but test substance purity was not provided.

Data source Reference Reference type p ublication Author Smyth HF, Carpenter CP, Weil CS, Pozzani U, Striegel JA. Year 1962

Title Range-finding toxicity data: List VI. Bibliographic

source Am Ind Hyg Assoc J 23:95-107.

Testing laboratory Report no.

Owner company Company study

no. Report date

Reference type study report Author Carpenter CP Year 1958Title Range finding tests on methoxytriglyco Bibliographic

source Testing laboratory Mellon Institute of Industrial Research Report no. 21-44

Owner company Company study

no. Report date 1958-06-12

Materials and methods Test type standard acute method Principles of method if other than guideline Standard acute dermal study procedure GLP compliance no data Test materials Test material equivalent to submission substance identity
yes Test material identity Identifier CAS number Identity 23601-39-0

Identifier EC number Identity 245-774-2

Identifier IUPAC name Identity 3,6,9,12,15,18-hexaoxaicosane Details on test material no data Test animals Species rabbit Strain N ew Zealand White Sex male Details on test animals and environmental conditions Male rabbits (3-5 months old) weighing between 2.5 to 3.5 kg Administration / exposure Type of coverage occlusive Vehicle unchanged (no vehicle) Details on dermal exposure Male rabbits were treated with 2.5 ml/kg ( N =2), 5 ml/kg ( N =4), or 10 ml/kg ( N =2) test material according to a variation of the one-day cuff method of Draize and associates (J PharmacolExper Ther 82: 377, 1944). Fur was clipped from the entire trunk, and doses were placed beneath an impervious plastic film (VINYLITE sheeting). Animals were immobilized for a 24-hour contact period and the film was removed. Rabbits were then observed for 14 days. The LD50 value and its fiducial range ( p lus or minus 1.96 standard deviations) was estimated by the method of Thompson (Bacteriol Rev 11: 115, 1947) using the Tables of Weil (Biometrics 8: 249, 1952). Duration of exposure 24-hour contact period Doses 2.5 ml/kg ( N =2), 5 ml/kg ( N =4), or 10 ml/kg ( N =2) N o. of animals per sex per dose 2 male animals at 2.5 ml/kg, 4 animals at 5.0 ml/kg and 2 animals at 10 ml/kg Control animals no data Statistics no data Results and discussions Effect levels Sex male Endpoint LD50 Effect level 7400 mg/kg bw 95% CL Remarks Mortality The two rabbits treated with 10 ml/kg died within 4 days. All other rabbits survived and appeared normal. The LD50 value was 7.13 ml/kg (7.4 g/kg). Clinical signs Marked erythema of skin was noted after removal of the dressing (doses and number affected was not noted). Gross pathology One of the rabbits treated with 10 ml/kg had internal hemorrhage as evidence by bloody exudate in the peritoneal cavity atautopsy. 7.3 Irritation / corrosion 7.3.1 Skin irritation / corrosion Skin irritation / corrosion Smyth TGBE 1962.001 UUID IUC5-daae3911-5f9b-4b90-bd8f-0ab0653581d9 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 09:48:45 EST Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used forMSDS Study result type experimental result Study p eriod 19 60 Reliablility 2 (reliable with restrictions) Rationale for reliability Predates current guidelines and GLP. Purity of substance not noted.

Data source Reference Reference type study report Author Carpenter CP and Striegel JA. Year 1960 Title Range finding tests on butoxy triglycol. Bibliographic

source Testing laboratory Melon Institute of Industrial Research Report no.

Owner company

Company study

no. Report 23-25 Report date 1960-03-31

Reference type p ublication Author Smyth HF, Carpenter CP, Weil CS, Pozzani U, Striegel JA Year 1962

Title Range-finding toxicity data: List VI. Bibliographic

source Am Ind Hyg Assoc J 23:95-107.

Testing laboratory Report no.

Owner company Company study

no. Report date

Materials and methods Type of method in vivo Principles of method if other than guideline Standard skin irritation procedure of the period. GLP compliance

no Test material equivalent to submission substance identity

no Test materials Test material identity Identifier CAS number Identity 143-22-6

Identifier EC numberIdentity 205-592-6

Identifier Common name Identity triethylene glycol monobutyl ether Details on test material no details Test animals Species rabbit Details on test animals and environmental conditions no data Test system Type of coverage
open Preparation of test site shaved Vehicle unchanged (no vehicle) Amount/concentration applied 0.01 ml (one concentraton) Duration of treatment / exposure 24 hours Observation period 24 hours after dosing N umber of animals five rabbits Control animals

no Details on study design Undiluted test solution (0.01 ml) was applied to the clipped belly skin of 5 rabbits. Irritation that occurred within 24 hours was scored in a graded fashion (from 1 to 10), with Grade 1 = no irritation, Grade 2 = the least visible capillary injection, Grade 6 = necrosis when undiluted. Results and discussions Irritation / corrosion results Irritation parameter overall irritation score Basis mean Time point 24 hours Score 3 Max. score Reversibility Remarks Irritant/corrosive response data An average irritation Grade of 3 was obtained with undiluted test material, indicating mild irritation. Marked capillary injection was noted on 4 animals and moderate injection on the 5th. Applicant's summary and conclusion Interpretation of resultsmoderately irritating Skin irritation / corrosion Carpenter & Striegel TGBE 1960.002 UUID IUC5-a3d0946a-40b2-45df-ab66-fd6527ff2bd7 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 09:50:22 EST Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1 9 6 0 Reliablility 2 (reliable with restrictions) Rationale for reliability Well conducted, older study predating GLP and current guidelines, and not stating purity of test material. Data source Reference Reference type study report Author Carpenter CP and Striegel JA. Year 1960 Title Range finding tests on butoxy triglycol. Bibliographic

source Testing laboratory Melon Institute of Industrial Research Report no. Report 23-25

Owner company Company study

no. Report date 1960-03-31

Materials and methods Type of method in vivo Principles of method if other than guideline Typical standard protocol of the time. GLP compliance no data Test material equivalent to submission substance identity

no Test materials Test material identity Identifier CAS number Identity 143-22-6Identifier EC number Identity 205-592-6

Identifier Common name Identity triethylene glycol monobutyl ether Details on test material no data Test animals Species rabbit Strain no data Details on test animals and environmental conditions male rabbits (3-5 months, 2.5 kg avg) Test system Type of coverage occlusive Preparation of test site shaved Vehicle unchanged (no vehicle) Amount/concentration applied 1.25, 2.5, 5.0 or 10 ml/kg Duration of treatment / exposure 24 hours skin contact Observation period 14 days N umber of animals four male rabbits per dose Control animals

no Details on study design Groups of 4 male rabbits (3-5 months, 2.5 kg avg) were treated with 1.25, 2.5, 5.0 or 10 ml/kg dermally (on clipped skin). A VINYLITE sheeting was used to keep the test material in contact with the skin. Rabbits were immobilized during the 24-hour skin contact period. After the dressing was removed, animals were observed for 14 days. Results and discussions Irritant/corrosive response data Listed here are dermal irritation results from an acute dermal toxicity study performed with high doses (1.25 to 10 ml/kg). Marked erythema of skin was found upon removal of the dressing (doses causing this effect were not stated). Some small scabs and extensive desquamation were p resent at Day 14. Skin irritation / corrosion Moreno TGBE 1976.003 UUID IUC5-9f06f0f3-1640-46cb-8120-a8bbc4d16825 Dossier UUID 0Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 09:52:08 EST Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 76 Reliablility 2 (reliable with restrictions) Data source Reference Reference type study report

Author Moreno OM. Year 1976 Title Report on primary dermal irritation in rabbits. Bibliographic

source Testing laboratory MB Research Laboratories, Inc. Report no. Project number MB 75-990 Owner company Olin Corporation

Company study no. Report date 1976-01-22

Materials and methods Type of method in vivo GLP compliance no data Test material equivalent to submission substance identity

no Test materials Test material identity Identifier CAS number Identity 143-22-6

Identifier EC number Identity 205-592-6

Identifier Common name Identity triethylene glycol monobutyl ether Details on test material no dataTest animals Species rabbit Strain no data Details on test animals and environmental conditions no data Test system Type of coverage occlusive Preparation of test site abraded Vehicle unchanged (no vehicle) Amount/concentration applied Six rabbits were clipped over the back and sides with an electric clipper. A site (1" x 1") to the left of the spinal column was abraded. Abrasions were minor incisions through the stratum corneum that did not disturb the derma or produce bleeding. Test material (0.5 ml) was applied to a surgical gauze (1" square, 2 layers thick). The patches were placed on test sites and secured with adhesive tape. The trunk was wrapped with impervious material. Patches were removed after 24 hours. Duration of treatment / exposure 24 hours Observation period 24 and 72 hours N umber of animals Six animals Control animals

no Details on study design Six rabbits were clipped over the back and sides with an electric clipper. A site (1" x 1") to the left of the spinal column was abraded. Abrasions were minor incisions through the stratum corneum that did not disturb the derma or produce bleeding. Test material (0.5 ml) was applied to a surgical gauze (1" square, 2 layers thick). The patches were placed on test sites and secured with adhesive tape. The trunk was wrapped with impervious material. Patches were removed after 24 hours. Dermal reactions were evaluated at 24 and 72 hours in accordance with the Consumer Product Safety Act, Title 16 CFR 1500.41. Results and discussions Irritation / corrosion results Irritation parameter overall irritation score Basis animal #1 Time point 24 hours Score ca. 1 Max. score 1 ReversibilityRemarks Irritant/corrosive response data An erythema score of 1 (barely perceptible) was observed in 1 rabbit at 24 hours (abraded skin) and another at 72 hours (intact skin). All others received erythema scores of 0. N o edema was observed at 24 or 72 hours. Applicant's summary and conclusion Interpretation of results not irritating Skin irritation / corrosion.004 UUID IUC5-71629c9f-77ab-4e58-ae8c-53e4c9cb9bcb Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 09:54:55 EST Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 88 Reliablility 1 (reliable without restriction) Rationale for reliability Well conducted study with strong detail documentation

Data source Reference Reference type study report

Author Reid ME. Year 1988 Title Carbowax MPEG 350 N M W . Acute toxicity and primary irritancy studies. Bibliographi

c source Testing laboratory Bushy Run Research Center Report

no. Project Report 51-41 Owner company Union Carbide

Company study no. Report date 1988-05-23

Materials and methods Type of method in vivo Principles of method if other than guideline Standard Draize procedure. GLP complianceno data Test material equivalent to submission substance identity

no Test materials Test material identity Identifier CAS number Identity 9004-74-4

Identifier Common name Identity CARBOWAX MPEG-350 Details on test material Test material (CARBOWAX MPEG-350, CAS No. 9004-74-4) is a mixture of several methylated glycol ethers of differing molecular weight (ranging from diethylene glycol monomethyl ether (C2) to heptadecaethylene glycol monomethyl ether (C17)). The majority of the material is in the C5-C11 range (87.445%). It contains 4.347 % (by weight) tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 1.303% triethylene glycol monomethyl ether (CAS No. 112-35-6), 0.181% diethylene glycol monomethyl ether (CAS No. 111-77-3). Test animals Species rabbit Strain no data Details on test animals and environmental conditions no data Test system Type of coverage occlusive Preparation of test site shaved Vehicle unchanged (no vehicle) Amount/concentration applied Test material (0.5 ml) was applied to the clipped, intact skin of six rabbits (3 of each sex). The material was loosely covered with a gauze patch an impervious sheeting. Rabbits were restrained for a 4-hour contact period. Excess material was removed after contact. Duration of treatment / exposure 4-hour contact period N umber of animals three of each sex Control animals

no Details on study design The skin reaction was scored by the method of Draize at one hour, and 1, 2, 3, and 7 days following dosing. Results and discussions Irritation / corrosion resultsIrritation parameter overall irritation score Basis mean Time point 1 hr, and 1, 2, 3 and 7 days Score ca. 0 Max. score 0 Reversibility Remarks Irritant/corrosive response data Scores of 0 were obtained for both erythema (and eschar formation) and edema. The material was therefore non-irritating. Applicant's summary and conclusion Interpretation of results not irritating Skin irritation / corrosion.005 UUID IUC5-9506b2f2-ca7f-4484-a3a2-0032d5db0671 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 09:55:40 EST Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1988

Reliablility 2 (reliable with restrictions) Rationale for reliability Original reference was not available. Information (including the reliability code) came from a previous IUCLID data set produced by the European Chemicals Bureau. Data source Reference Reference type company data

Author Year 1988 Title Bibliograp hic source Hoechst AG Frankfurt/MainClariant GmbH Frankfurt/Main EUROPEAN COMMISSION- European Chemicals Bureau Ispra (VA) Testing laboratory Report

no. Owner company Hoechst AG.

Company study no. Unpublished Study (88.1086). Report dateMaterials and methods Type of method in vivo Test guideline Qualifier according to Guideline OECD Guideline 404 (Acute Dermal Irritation / Corrosion) Deviations GLP compliance
yes Test material equivalent to submission substance identity

no Test materials Test material identity Identifier CAS number Identity 23783-42-8

Identifier IUPAC name Identity tetraethylene glycol monomethyl ether Test animals Species rabbit Strain no data Details on test animals and environmental conditions no data Test system Type of coverage no data Preparation of test site no data Vehicle no data Amount/concentration applied no data Duration of treatment / exposure four hours Observation period no data N umber of animals no data Details on study design no data Results and discussions Irritation / corrosion results Irritation parameter overall irritation score Basis meanTime point four hours Score ca. 0 Max. score Reversibility Remarks Irritant/corrosive response data Effect after 4 hours: none of recognizable significance.] Applicant's summary and conclusion Interpretation of results not irritating Skin irritation / corrosion.006 UUID IUC5-d25de863-f1f8-4b24-a48c-07127eb82083 Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-02-16 16:23:06 EST Remarks

Administrative Data Purpose flag supporting study ( ) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1992

Reliablility 2 (reliable with restrictions) Rationale for reliability Study well conducted following GLP and providing good data on test material p urity. Details provided in the study were somewhat limited as to methodology. Data source Reference Reference type study report

Author Gardner JR. Year 1992 Title Brake fluid DOT 4: Acute oral and dermal toxicity in rat, skin and eye irritancy in rabbit. Bibliograph ic source Testing laboratory Shell Research Limited, Sittingbourne Research Centre Report

no. SBGR.92. 011 Owner company Shell

Company study no. Report date 1992-06-3 0 Materials and methods Principles of method if other than guideline N o guideline specified, but study was conducted according to normally followed procedures for this type of study.GLP compliance
yes Test material equivalent to submission substance identity

no Test materials Test material identity Identifier CAS number Identity 106008-94-0

Identifier Common name Identity Brake fluid DOT 4 Details on test material Test material is a mixture containing 30-50% triethylene glycol monomethyl ether borate ester (CAS No. 106008-94-0), 3-30% triethylene glycol monobutyl ether borate ester, 20-30% triethylene glycol monomethyl ether (CAS No. 112-35-6), 2-10% triethylene glycol monobutyl ether (CASNo. 143-22-6), 20-30% tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 2-10% tetraethylene glycol monobutyl ether (CAS No. 1559-34-8), and < 1% minor additives. Test animals Species rabbit Strain no data Details on test animals and environmental conditions no data Test system Type of coverage semiocclusive Preparation of test site no data Vehicle unchanged (no vehicle) Amount/concentration applied applied undiluted Duration of treatment / exposure 4 hours Observation period no data N umber of animals six Control animals no data Details on study design no data Applicant's summary and conclusion Interpretation of resultsnot irritating Conclusions not irritating Skin irritation / corrosion.007 UUID IUC5-cf7333db-76dd-4280-8dc7-1b6acf9b6bdb Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-02-16 17:00:24 EST Remarks

Administrative Data Purpose flag supporting study ( ) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1 9 6 2 Reliablility 2 (reliable with restrictions) Rationale for reliability Some study details of test method animals and TS purity are lacking, but otherwise the study was well conducted. Data source Reference Reference type p ublication Author Smyth HF, Carpenter CP, Weil CS, Pozzani U, Striegel JA. Year 1962

Title . Range-finding toxicity data: List VI. Bibliographic

source Am Ind Hyg Assoc J 23:95-107.

Testing laboratory Report no.

Owner company Company study

no. Report date

Reference type study report Author Carpenter CP Year 1958 Title Range finding tests on methoxytriglycol. Bibliographic

source Testing laboratory Mellon Institute of Industrial Research Report no. 21-44

Owner company Company study Report date 1958-06-12no. Materials and methods Type of method in vivo Principles of method if other than guideline N o test guideline specified, but study was conducted according to procedure commonly used. GLP compliance no data Test material equivalent to submission substance identity

no Test materials Test material identity Identifier CAS number Identity 112-35-6

Identifier EC number Identity 203-962-1

Identifier Common name Identity triethylene glycol monomethyl ether Details on test material no data Test animals Species rabbit Strain no data Details on test animals and environmental conditions no data Test system Type of coverage
open Preparation of test site shaved Vehicle unchanged (no vehicle) Amount/concentration applied undiluted substance Duration of treatment / exposure 24 hours Observation period 24 hours N umber of animals 5 rabbits Control animals no dataDetails on study design Undiluted test solution (0.01 ml) was applied to the clipped belly skin of 5 rabbits. Irritation that occurred within 24 hours was scored in a graded fashion (from 1 to 10), with Grade 1 = no irritation, Grade 2 = the least visible capillary injection, Grade 6 = necrosis when undiluted. Results and discussions Irritation / corrosion results Irritation parameter overall irritation score Basis Time point 24 hours Score 2 Max. score Reversibility Remarks Applicant's summary and conclusion Interpretation of results slightly irritating Conclusions An irritation Grade of 2 was obtained with undiluted test material, indicating minimal irritation. 7.3.2 Eye irritation Eye irritation Moreno TGBE 1976.001 UUID IUC5-8ac0cca2-5b55-4466-876c-f551d7465383 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 10:08:38 EST Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 76

Reliablility 2 (reliable with restrictions) Rationale for reliability One dose was used. Purity of test substance was not provided. Otherwise satisfactory study. Data source Reference

Reference type study report Author Moreno OM. Year 1976 Title Report on rabbit eye irritation. Bibliographic

source EPA/OTS File 0206801

Testing MB Research Laboratories, Inc. Report no. Project number MB 75-990laboratory Owner company Olin Corporation

Company study

no. Report date 1976-01-24

Materials and methods Principles of method if other than guideline After installation of the undiluted test material in the eye, ocular reactions were graded in accordance with the Consumer Product Safety Act, Title 16 CFR 1500.42 at 1, 2, and 3 days after instillation of the test material. GLP compliance no data Test material equivalent to submission substance identity

no Test materials Test material identity Identifier CAS number Identity 143-22-6

Identifier EC number Identity 205-592-6

Identifier Common name Identity triethylene glycol monobutyl ether Details on test material no data Test animals Species rabbit Strain N ew Zealand White Details on test animals and environmental conditions no data Test system Vehicle unchanged (no vehicle) Amount/concentration applied .1 ml Duration of treatment / exposure Single exposure into the eye, that was presumably not rinsed out (rinse not specified). Observation period Oocular reactions were graded in accordance with the Consumer Product Safety Act, Title 16 CFR 1500.42 at 1, 2, and 3 days after instillation of the test material. N umber of animals six animals Control animalsno Details on study design Test material (0.1 ml) was instilled into the conjunctival sac of one eye of each rabbit on Day 0. Ocular reactions were graded in accordance with the Consumer Product Safety Act, Title 16 CFR 1500.42 at 1, 2, and 3 days after instillation of the test material. Results and discussions Overall irritation / corrosion results Irritation p aramete r other: total conjunctival: ((redness + chemosis + discharge) x 2)

Basis Time point 72 hours 10

—16 Max. score 20 Reversibility Remarks
Irritation parameter other: Highest overall Basis Time point 72 hours 21 Max. score 110 Reversibility Remarks Irritant/corrosive response data Conjunctival redness, chemosis and discharge scores of 2-3 (diffuse crimson to beefy red) were noted at all time points in all rabbits (except 1 rabbit that had a chemosis score of 1 at 72 hours). Iris scores of 1 (folds above normal, congestion, swelling, corneal injection, sluggish reaction to light) were observed in all animals at each time point. The total conjunctival score ((redness + chemosis + discharge) x 2) ranged from 10-16 out of a possible 20. The highest overall score was 21 out of a possible 110. Applicant's summary and conclusion Interpretation of results irritating Eye irritation Smyth TGBE 1962.002 UUID IUC5-afb41288-60f5-4da8-babb-f44e555e5409 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 10:11:36 EST Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDSStudy result type experimental result Study p eriod 19 60

Reliablility 2 (reliable with restrictions) Rationale for reliability Good study, but older preguideline. Purity of test substance not noted.

Data source Reference Reference type p ublication Author Smyth HF, Carpenter CP, Weil CS, Pozzani U, Striegel JA. Year 1962

Title Range-finding toxicity data: List VI. Bibliographic

source Am Ind Hyg Assoc J 23:95-107.

Testing laboratory Report no.

Owner company Company study

no. Report date

Reference type study report Author Carpenter CP and Striegel JA. Year Title Range finding tests on butoxy triglycol. Bibliographic

source Testing laboratory Melon Institute of Industrial Research Report no. 23-25

Owner company Company study

no. Report date 1960-03-31

Materials and methods Type of method in vivo Principles of method if other than guideline other method: Carpenter and Smyth (Am J Opthal 29:1363, 1946) GLP compliance no data Test material equivalent to submission substance identity

no Test materials Test material identity Identifier CAS number Identity 143-22-6

Identifier IUPAC nameIdentity Triethylene glycol butyl ether

Identifier EC number Identity 205-592-6 Details on test material no data Test animals Species rabbit Strain no data Details on test animals and environmental conditions no data Test system Vehicle no data Duration of treatment / exposure not noted Observation period not noted N umber of animals not noted Control animals no data Details on study design Various volumes and concentrations of test material ( p robably undiluted) were applied to rabbit eyes (number of rabbits and time of exposure was not indicated). Eye injury was scored on a 10 p oint scale according to the degree of corneal necrosis that resulted from instillation of the various concentrations. Grade 1 = very small area of necrosis from 0.5 ml undiluted material, Grade 5 = severe burn from 0.005 ml undiluted material, Grade 10 = severe burn from 0.5 ml of a 1% solution in water or propylene glycol. Results and discussions Overall irritation / corrosion results Irritation parameter overall irritation score Basis mean Time point ca. 5 Max. score 5 Reversibility Remarks Irritant/corrosive response data Rabbit eyes were necrosed by instillation of 0.02 ml. Minor to moderate injury resulted from the instillation of 0.005 ml. Overall remarks, attachments Attached full study report ()Applicant's summary and conclusion Interpretation of results highly irritating Eye irritation.003 UUID IUC5-78f71c39-96a5-4663-9e58-1a86cdce80fb Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 10:12:47 EST Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1 9 8 8 Reliablility 1 (reliable without restriction) Rationale for reliability Study was well conducted with detailed information. Test material was well characterized with regard to composition. Data source Reference Reference type Author Reid ME. 1988 Year 1988 Title MPEG 350 N M W . Acute toxicity and primary irritancy studies. Bibliographic

source Testing laboratory Bushy Run Research Center Report no. 51-41

Owner company Union Carbide

Company study no. Report date 1988-05-23

Materials and methods Principles of method if other than guideline N o guideline specified. GLP compliance no data Test material equivalent to submission substance identity

no Test materials Test material identityIdentifier CAS number Identity 9004-74-4

Identifier Common name Identity CARBOWAX MPEG-350 Details on test material Test material (CARBOWAX MPEG-350, CAS No. 9004-74-4) is a mixture of several methylated glycol ethers of differing molecular weight (ranging from diethylene glycol monomethyl ether (C2) to heptadecaethylene glycol monomethyl ether (C17)). The majority of the material is in the C5-C11 range (87.445%). It contains 4.347 % (by weight) tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 1.303% triethylene glycol monomethyl ether (CAS No. 112-35-6), 0.181% diethylene glycol monomethyl ether (CAS No. 111-77-3). Test animals Species rabbit Strain N ew Zealand White Details on test animals and environmental conditions no data Test system Vehicle unchanged (no vehicle) Amount/concentration applied 0.1 ml Duration of treatment / exposure N ot specified whether eye was rinsed at some point after instillation of test material. Observation period 1 and 4 hours, and 1, 2, 3, and 7 days after dosing N umber of animals Six Control animals yes, concurrent no treatment Details on study design Six male New Zealand white rabbits were dosed with 0.1 ml of test material. The test material was instilled into the lower conjunctival sac or placed directly on one eye per animal. The other eye served as a control. The eyes were scored at 1 and 4 hours, and 1, 2, 3, and 7 days after dosing. Florescein (2%) was added to the eyes before dosing and after 1 day of exposure to assess corneal injury. Results and discussions Irritant/corrosive response data Instillation of test material resulted in no corneal injury or iritis. Minor conjunctival irritation developed in all 6 rabbits. Moderate discharge was seen in several of the eyes. These effects resolved by 24 hours. Applicant's summary and conclusion Interpretation of results slightly irritatingEye irritation.004 UUID IUC5-c616a915-b5cd-4ae4-8aa0-1d3d4c7818cd Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 10:14:29 EST Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1988

Reliablility 2 (reliable with restrictions) Rationale for reliability Original reference was not available. Information (including the reliability code) came from a previous IUCLID data set produced by the European Chemicals Bureau. Data source Reference

Reference type company data

Author Year 1988 Title Bibliograp hic source Hoechst AG Frankfurt/MainClariant GmbH Frankfurt/Main EUROPEAN COMMISSION - European Chemicals Bureau Ispra (VA) Testing laboratory Report

no. Owner company Hoechst AG.

Company study no. Unpublished Study 88.1220. Report date Materials and methods Type of method in vivo Test guideline Qualifier according to Guideline OECD Guideline 405 (Acute Eye Irritation / Corrosion) Deviations GLP compliance
yes Test material equivalent to submission substance identity

no Test materials Test material identityIdentifier CAS number Identity 23783-42-8

Identifier Common name Identity tetraethylene glycol monomethyl ether Details on test material no data Test animals Species rabbit Strain N ew Zealand White Details on test animals and environmental conditions no data Test system Vehicle no data Amount/concentration applied no data. Probably undiluted test material applied. Duration of treatment / exposure no data Observation period 4 hours N umber of animals no data Control animals no data Details on study design no data Results and discussions Irritant/corrosive response data Effect after 4 hours: none of recognizable significance]. Applicant's summary and conclusion Interpretation of results not irritating Eye irritation.005 UUID IUC5-dcf774f2-5ca6-41d7-8180-979db71c1ff5 Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-02-17 12:28:06 EST Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) usedfor MSDS Study result type experimental result Study p eriod 19 92

Reliablility 1 (reliable without restriction) Rationale for reliability Well conducted study following GLP, with the composition of the test material well characterized. Data source Reference Reference type study report

Author Gardner JR. Year 1992 Title Brake fluid DOT 4: Acute oral and dermal toxicity in rat, skin and eye irritancy in rabbit Bibliograph ic source Testing laboratory Shell Research Limited, Sittingbourne Research Centre Report

no. SBGR.92. 011 Owner company Company study no. Report date 1992-06-3 0 Materials and methods Type of method in vivo Principles of method if other than guideline N o guideline specified, but study was conducted according to standard procedure for eye irritation. GLP compliance
yes Test material equivalent to submission substance identity

no Test materials Test material identity Identifier CAS number Identity 106008-94-0

Identifier Common name Identity Brake fluid DOT 4 Details on test material Test material is a mixture containing 30-50% triethylene glycol monomethyl ether borate ester (CAS No. 106008-94-0), 3-30% triethylene glycol monobutyl ether borate ester, (20-30% triethylene glycol monomethyl ether (CAS No. 112-35-6), 2-10% triethylene glycol monobutyl ether (CASNo. 143-22-6), 20-30% tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 2-10% tetraethylene glycol monobutyl ether (CAS No. 1559-34-8), and < 1% minor additivesTest animals Species rabbit Strain no data Details on test animals and environmental conditions no data Test system Vehicle unchanged (no vehicle) Amount/concentration applied .1 ml Duration of treatment / exposure 72 hours Observation period 72 hours N umber of animals six Control animals no data Details on study design no data Results and discussions Irritant/corrosive response data sllightly irritating Applicant's summary and conclusion Interpretation of results slightly irritating Eye irritation.006 UUID IUC5-20da953b-85c9-483d-bc3c-9822a5b1b5dc Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-02-17 13:00:07 EST Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1958

Reliablility 2 (reliable with restrictions) Rationale for reliability Rabbit strain not given. Details of number of animals exposed to each dose not given. GLP not specified. Purity of test substance not noted. Otherwise thie was a credible study.Data source Reference Reference type p ublication Author Smyth HF, Carpenter CP, Weil CS, Pozzani U, Striegel JA. Year 1962

Title Range-finding toxicity data: List VI. Bibliographic

source Am Ind Hyg Assoc J 23:95-107

Testing laboratory Report no.

Owner company Company study

no. Report date

Reference type study report Author Carpenter CP. Year 1958 Title Range finding tests on methoxytriglycol. Bibliographic

source Testing laboratory Mellon Institute of Industrial Research Report no. 21-44

Owner company Company study

no. Report date 1958-06-12

Materials and methods Type of method in vivo Principles of method if other than guideline N o guideline specified, but study was conducted according to typical procedure for eye irritation. GLP compliance no data Test material equivalent to submission substance identity

no Test materials Test material identity Identifier CAS number Identity 112-35-6

Identifier EC number Identity 203-962-1

Identifier Common name Identity triethylene glycol monomethyl ether Details on test materialno details. Test animals Species rabbit Strain no data Details on test animals and environmental conditions no data Test system Vehicle unchanged (no vehicle) Amount/concentration applied .5 ml Duration of treatment / exposure no data Observation period no data N umber of animals not specified Control animals no data Details on study design Various volumes and concentrations of test material were applied to rabbit eyes (number of rabbits and time of exposure was not indicated). Eye injury was scored on a 10 p oint scale according to the degree of corneal necrosis that resulted from instillation of the various concentrations. Grade 1 = very small area of necrosis from 0.5 ml undiluted material, Grade 5 = severe burn from 0.005 ml undiluted material, Grade 10 = severe burn from 0.5 ml of a 1% solution in water or propylene glycol. Results and discussions Overall irritation / corrosion results Irritation parameter overall irritation score Basis Time point

Max. score 1 Reversibility Remarks Irritant/corrosive response data Five rabbit eyes were not injured by 0.5 ml undiluted test material (grade 1). Applicant's summary and conclusion Interpretation of results slightly irritating 7.5 Repeated dose toxicity 7.5.1 Repeated dose toxicity: oral Repeated dose toxicity: oral.001UUID IUC5-eefddf90-38fc-44d8-98e5-428a21ee84f8 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 10:57:33 EST Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 90 Reliablility 1 (reliable without restriction) Rationale for reliability Guideline study performed following GLP

Data source Reference Reference type study report

Author Gill MW and Negley JE. Year 1990 Title Triethylene glycol monomethyl ether. N inety day subchronic drinking water inclusion neurotoxicity study in rats. Bibliograp hic source

Testing laboratory Bushy Run Research Center Report

no. Project Report 52-607,

Owner company Union Carbide

Company study no. Report date 1990-09-21

Reference type p ublication

Author Gill MW, Fowler EH, Gingell R, Lomax LG, Corely RA. Year 1998 Title Subchronic dermal toxicity and oral neurotoxicity of triethylene glycol monomethyl ether in CD rats. Bibliograph ic source Int J Toxicol 17:1-22.

Testing laboratory Report

no. Owner companyCompany study no. Report date Cross-reference to same study This study is also summarized as a fertility study in Toxicity to reproduction.003 Materials and methods Test type subchronic Limit test

no Test guideline Qualifier equivalent or similar to Guideline EPA OPPTS 870.3100 (90-Day Oral Toxicity in Rodents) Deviations Principles of method if other than guideline EPA. 1989. 40 CFR 799, Fed Reg 54:13470-13477 GLP compliance
yes Test materials Test material equivalent to submission substance identity
yes Test material identity Identifier CAS number Identity 112-35-6

Identifier EC number Identity 203-962-1

Identifier Common name Identity triethylene glycol monomethyl ether Details on test material The purity of the material was at least 98.7%. Test animals Species
rat Strain Sprague-Dawley Sex male/female Details on test animals and environmental conditions 8 weeks old Administration / exposure Route of administration oral: drinking water Vehicle unchanged (no vehicle) Details on oral exposureMale and female rats (8 weeks old, 15/sex/group) were treated with triethylene glycol monomethyl ether (TGME) for 91 days via drinking water at target doses of 0, 400, 1200 and 4000 mg/kg/day. Analytical verification of doses or concentrations no data Details on analytical verification of doses or concentrations It is assumed that test material of 98.7% p urity was diluted into the drinking water, such that the animals drinking an historically expected amount of water daily would ingest the target dose. Duration of treatment / exposure 91 days Frequency of treatment daily Doses/concentrations 0, 400, 1200 and 4000 mg/kg/day. Basis nominal in water N o. of animals per sex per dose 15/sex/group Control animals yes, concurrent no treatment Positive control no data Examinations Observations and examinations performed and frequency Rats were observed daily for clinical signs and weekly for body weight and water and food consumption. Ten rats/sex/group were observed periodically for behavior (functional observational battery) and motor activity. Sacrifice and pathology After 91 days of treatment, tissues of 10 animals/sex/group were fixed in situ, and brains were removed. These animals received complete necropsies, and tissues from 6 animals/sex/group were processed for evaluation of the nervous system by light microscopy. The 5 animals/sex/group not sacrificed and perfused in situ were killed by severing the brachial vessels to permitexsanguination. These animals received complete necropsies, and the liver, kidneys, brain, lungs, adrenals, and testes (males) were weighed. Liver and testes were examined by light microscopy. Statistics Data for continuous variables were analyzed with Levene's test for homogeneity of variance, analysis of variance (ANOVA), and by pooled variance t-tests. If Levene's test indicated heterogeneous variances, groups were analyzed with an ANOVA for unequal variances, followed by separate variance t-tests. Fisher's exact 2 x 2 groups comparisonswere used to analyze functional observational battery data. Motor activity counts were log transformed prior to analysis. Motor activity dose-effects, dose-sex interactions, and time-dose interactions were determined using repeated measures ANOVAs with dose and sex as grouping factors and time as a within-subject factor. Comparisons between treated and control groups were made for total test session activity (the sum of the counts across the 90-min test session) using ANOVA. To reduce the increased false positives associated with repeated significance testing, the correction p rocedure described by Mantel (Biometrics 36:381-399, 1980) was used when testing foroverall significance. The frequency data for anatomic pathology were analyzed as described by Sokal and Rohlf (Biometry, WHFreeman, 1981). Any other information on materials and methods incl. tables

No post obs. period was conducted.

Results and discussions Effect levels Endpoint N OAEL Effect level 400 mg/kg bw/day (nominal) Sex male Basis for effect level / Remarks Liver weight effects.
Endpoint LOAEL Effect level 1200 mg/kg bw/day (nominal) Sex male Basis for effect level / Remarks Liver weight effects.
Endpoint N OAEL Effect level 1200 mg/kg bw/day (nominal) Sex male Basis for effect level / Remarks Testicular effects.
Endpoint LOAEL Effect level 4000 mg/kg bw/day (nominal) Sex male Basis for effect level / Remarks Testicular effects. Observations Clinical signs and mortality
yes Body weight and weight gain
yes Food consumption and compound intake (if feeding study)
yes Food efficiency no data Water consumption and compound intake (if drinking water study)
yes Ophthalmoscopic examination no data Haematology no data Clinical chemistry no data Urinalysis no dataN eurobehaviour
yes Organ weights
yes Gross pathology
yes Histopathology: non-neoplastic
yes Histopathology: neoplastic no data Details on results The actual doses attained in the study (time weighted average) were 0, 420, 1240 and 4300 mg/kg/day for males and 0, 420, 1290 and 4100 mg/kg/day for females.
One female in the high dose treatment group (approximately 4000 mg/kg/day) died on Day 37. Males and females treated with the highest dose consumed less food and had lower body weights and body weight gains than control animals. Water consumption decreased in high-dose females (by an average of 17%).
Treatment with triethylene glycol monomethyl ether did not result in any clinical signs of toxicity, alterations in the functional observational battery, or gross microscopic lesions in the nervous system. Significant, small decreases in total test session motor activity were observed in the high-dose treatment group at the Day 60 (males only) and Day 90 (females) evaluation p eriods. Study personnel stated that “the decreases in motor activity were not considered to be neurotoxicologically significant based on the small magnitude of the changes, the parallel changes in body weights at the evaluation periods, and the lack of corroborative behavioral effects from the functional observational battery evaluations or histological changes in central or peripheral nervous system tissues.”
Increased relative liver weight was observed in males treated with 4000 mg/kg/day (5.229 ± 0.3984) and 1200 mg/kg/day (3.951 ± 0.4191) versus control (3.214 ± 0.1519). Absolute liver weights of males treated with 4000 mg/kg/day were significantly greater than controls (25.926 ± 3.1591 versus 18.978 ± 1.4925). Microscopic changes (hepatocellular cytoplasmic vacuolization and/or hypertrophy) were noted in livers of high-dose males (14/15). The severity of these liver lesions was minimal or mild (with the exception of moderate or marked vacuolization for 4 high dose males). Mild cholangiofibrosis was observed around a small number of bile ducts in high-dose males (7/15). This was not considered by study personnel to be physiologically significant due to the limited number of bile ducts affected and the mild nature of the effect (Gill et al., Int J Toxicol. 17:1-22, 1998). Minimal or mild hepatocellular hypertrophy was seen in 10/15 high dose females. Three males treated with 400 mg/kg/day and 4 treated with 1200 mg/kg/day also exhibited minimal-mild hepatocellular cytoplasmic vacuolization and/or cellular hypertrophy (not statistically different from the controls). One control male had mild hepatocellular cytoplasmic vacuolization. N one of the females treated with 400 or 1200 mg/kg/day exhibited these changes. Hepatocellular hypertrophy was considered by study personnel to be a possible adaptive change to accommodate increased demand to metabolize the test substance.The testes of males in the high dose group exhibited degeneration (12/15) and/or atrophy (5/5) of the seminiferous tubules (spermatocytes or developing spermatids). These effects were concluded to be related to treatment. The severity of the lesions was primarily mild to moderate for degeneration (11/12) and minimal to moderate for atrophy (5/5), indicating that not all tubules were affected and that a limited number of cells was affected within the affected tubules. One male treated with 1200 mg/kg had severe seminiferous tubule atrophy, a complete loss of cell types in the tubules (except for Sertoli cells) and moderate Leydig cell hypertrophy (not significant from control). This was not considered to be related to treatment because of the lack of a plausible explanation for the unusual dose-response relationship (the effect at this dose was more severe than that of a higher dose) and the low incidence of animals affected at this dose level (Gill et al., Int J Toxicol 17:1-22, 1998). N o testicular changes were noted in males treated with 400 mg/kg/day TGME. Remarks on results including tables and figures

Overall remarks, attachments Overall remarks

The route of administration and maximum dose level was specified in a testing consent order (EPA. 1989. 40 CFR 799, Fed Reg 54:13470-13477). The highest dose level was initially set at 5000 mg/kg/day, but was decreased to 4000 mg/kg/day based on results of a 14-day dose range-finding drinking water study that demonstrated signs of debilitationat levels greater than 4000 mg/kg/day (Gill and Hurley, 1990).

The authors state that a possible contributing factor in the development of testicular lesions at the high dose was low-level contamination of the test substance with the known testicular toxicant 2-methoxyethanol (EGME). EGME was present in the test substance at a concentration of 0.02  0.04 %, resulting in a EGME dose up to 1.7 mg/kg/day for animals in the high dose group. Given the length of the study, it is possible that EGME contributed to the testicular lesions. A comparison between the doses of EGME and TGME required to produce testicular toxicity indicated that TGME is 350 times less potent than EGME in producing testicular lesions in the rat. The dose of TGME that caused testicular toxicity (4200 mg/kg/day) is 4 times greater than the 1000 mg/kg/day limit dose generally recommended for subchronic studies.

Based on the results of the study, the summary preparer assigned a NOAEL for effects on the liver of 400 mg/kg/day, and a LOAEL of 1200 mg/kg/day (based on increased relative liver weight of males at this dose). The summary preparer-assigned NOAEL and LOAEL for testicular effects are 1200 and 4000 mg/kg/day, respectively. The EPA has determined the NOAEL for testicular effects is between 400 and 1200 mg/kg/day (Anderson, L. Triethylene glycol monomethyl, monoethyl and monobutyl ethers RM1 screening document (draft), Feb. 24, 1995).
Repeated dose toxicity: oral.002 UUID IUC5-57449644-ba3a-427c-96c4-d077a125d217 Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States ofAmerica Date 2009-02-17 13:56:47 EST Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1993

Reliablility 2 (reliable with restrictions) Rationale for reliability Well conducted study run according to GLP and with good characterization of test material composition. N umber of animals per dose not completely specified.

Data source Reference Reference type study report

Author Taupin PJY Year 1993 Title Brake fluid DOT 4: A 28 day oral (gavage) toxicity study in the rat. Bibliographic

source Testing laboratory Shell Research Limited, Sittingbourne Research Centre Report

no. Owner company Shell

Company study no. SBGR.92.180 Report date 1993-10-07

Materials and methods Test type subacute Limit test

no Principles of method if other than guideline Guideline was not specified, but study was conducted according to typical procedures for 28 day oral repeated dose testing. GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 106008-94-0

Identifier Common nameIdentity Brake fluid DOT 4 Details on test material Test material is a mixture containing 30-50% triethylene glycol monomethyl ether borate ester (CAS No. 106008-94-0), 3-30% triethylene glycol monobutyl ether borate ester, 20-30% triethylene glycol monomethyl ether (CAS No. 112-35-6), 2-10% triethylene glycol monobutyl ether (CAS No. 143-22-6), 20-30% tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 2-10% tetraethylene glycol monobutyl ether (CAS No. 1559-34-8), and < 1% minor additives. Test animals Species
rat Strain Sprague-Dawley Sex male/female Details on test animals and environmental conditions no data Administration / exposure Route of administration oral: gavage Vehicle unchanged (no vehicle) Details on oral exposure no data Analytical verification of doses or concentrations no data Details on analytical verification of doses or concentrations no data Duration of treatment / exposure 28 days Frequency of treatment daily Doses/concentrations 25, 150, 1000 mg/kg/day Basis N o. of animals per sex per dose not detailed Control animals
yes Details on study design no data Positive control no data Examinations Sacrifice and pathologyGross pathology examinations were performed Statistics no data Results and discussions Effect levels Endpoint N OEL Effect level 150 mg/kg bw/day (nominal) Sex male/female Basis for effect level / Remarks N o treatment related effects seen at 150 mg/kg bw per day. Effects were seen at the next higher dose

Observations Clinical signs and mortality
yes Body weight and weight gain
yes Food consumption and compound intake (if feeding study)
yes Food efficiency no data Water consumption and compound intake (if drinking water study) no data Ophthalmoscopic examination no data Haematology no data Clinical chemistry
yes Urinalysis no data N eurobehaviour no data Organ weights
yes Gross pathology
yes Histopathology: non-neoplastic no data Histopathology: neoplastic not examined Details on results Food intake of males dosed with 1000 mg/kg/day was slightly reduced for first 2 weeks of treatment. Livers of all 5 males and some females dosed with 1000 mg/kg/day showed slight centrilobular hypertrophy (which was considered by the investigators to be adaptive). N one o f the controls exhibited this effect. There was no significant effect of treatment on liver weight.N o effects on other organs (including ovaries and testes) were noted. A NOEL of 150 mg/kg/day was assigned by the investigator. 7.5.2 Repeated dose toxicity: dermal Repeated dose toxicity: dermal.001 UUID IUC5-96d5f766-7416-44bd-8188-b55cb9fb01a9 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 11:05:37 EST Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 90 Reliablility 1 (reliable without restriction) Rationale for reliability Well conducted guideline study per GLP, with purity of test substance p rovided. Data source Reference Reference type Author Corley RA, Ciesslak, Breslin WJ, Lomax LG. 13-Week dermal toxicity study in Sprague-Dawley rats Year 1990

Title 13-Week dermal toxicity study in Sprague-Dawley rats Bibliograp hic source Testing laboratory Report

no. Study ID K-005610-004 Owner company Dow Chemical Company

Company study no. Report date 1990-09-26

Reference type p ublication

Author Gill MW, Fowler EH, Gingell R, Lomax LG, Corely RA. Year Title Subchronic dermal toxicity and oral neurotoxicity of triethylene glycol monomethyl ether in CD rats. Bibliograph ic source Int J Toxicol 17:1-22.

Testing laboratory Report

no.Owner company Company study no. Report date Cross-reference to same study The same study is summarized as a fertility study in Sprague-Dawley rats. Materials and methods Test type subchronic Limit test

no Test guideline Qualifier according to Guideline other guideline: as specified in a testing consent order (EPA. 1989. 40 CFR 799, Fed Reg 54:13470-13477). Deviations

GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 112-35-6

Identifier EC number Identity 203-962-1

Identifier Common name Identity triethylene glycol monomethyl ether Details on test material The test substance was triethylene glycol monomethyl ether (CAS 112-35-6). Purity (as determined by gas chromatography) was 99.23 % at the onset of the study and 99.24% at completion of the in-life phase. Test animals Species
rat Strain Sprague-Dawley Sex male/female Details on test animals and environmental conditions 8 week-old rats Administration / exposure Type of coveragesemiocclusive Vehicle unchanged (no vehicle) Details on exposure Triethylene glycol monomethyl ether (TGME) was administered dermally to 8 week-old rats (10/sex/dose level) at 0 (sham control), 400, 1200 or 4000 mg/kg/day for 13 weeks. Test material was applied to shaved areas of skin on the back and sides of each rat (12 cm2 in area), uniformly spread, and covered with a semiocclusive dressing for 6 hours. After removal of the dressing, the application site was wiped with a dampened towel. Material was applied in this manner daily, 5 days/week for 13 weeks. Analytical verification of doses or concentrations
yes Details on analytical verification of doses or concentrations Purity (as determined by gas chromatography) was 99.23 % at the onset of the study and 99.24% at completion of the in-life phase. Duration of treatment / exposure Six hours daily, 5 days/week for 13 weeks, 91 days. There was no post exposure observation p eriod. Frequency of treatment 5 days/week for 13 weeks Doses/concentrations 0 (sham control), 400, 1200 or 4000 mg/kg/day Basis analytical per unit body weight N o. of animals per sex per dose 10/sex/dose level Control animals yes, sham-exposed Details on study design Triethylene glycol monomethyl ether (TGME) was administered dermally to 8 week-old rats (10/sex/dose level) at 0 (sham control), 400, 1200 or 4000 mg/kg/day for 13 weeks. Test material was applied to shaved areas of skin on the back and sides of each rat (12 cm2 in area), uniformly spread, and covered with a semiocclusive dressing for 6 hours. After removal of the dressing, the application site was wiped with a dampened towel. Material was applied in this manner daily, 5 days/week for 13 weeks. Parameters evaluated throughout the study included clinical and ophthalmic observations, dermal irritation, body weight, food consumption, clinical p athology, estrous cyclicity (daily vaginal smears during study weeks 12 and 13), hematology ( j ust prior to sacrifice), clinical chemistry ( j ust prior to sacrifice), and urinalysis ( j ust prior to dosing and during final week of dosing). Organ weight (standard set), gross pathology and histopathology (control and high dose group) were evaluated upon necropsy. The oocytes, corpora lutea, and follicles from each ovary were evaluated with regard to their normal development. Bone marrow smears were prepared from each animal from the shaft of the femur.The testes and epididymes also were examined microscopically for males in the intermediateand low-dose groups. Examinations Observations and examinations performed and frequency Parameters evaluated throughout the study included clinical and ophthalmic observations,dermal irritation, body weight, food consumption, clinical pathology, estrous cyclicity (daily vaginal smears during study weeks 12 and 13), hematology ( j ust prior to sacrifice), clinical chemistry ( j ust prior to sacrifice), and urinalysis ( j ust prior to dosing and during final week of dosing). Sacrifice and pathology Organ weight (standard set), gross pathology and histopathology (control and high dose group) were evaluated upon necropsy. The oocytes, corpora lutea, and follicles from each ovary were evaluated with regard to their normal development. Bone marrow smears were prepared from each animal from the shaft of the femur. The testes and epididymes also were examined microscopically for males in the intermediate- and low-dose groups. Other examinations Additional satellite groups of 5 rats/sex/dose level were administered TGME for 30 days for interim hematological (48 hr and 30 days), clinical chemistry (48 hr and 30 days), body weight determinations, clinical observations, and dermal irritation. Statistics For the main study group, the data for continuous variables were evaluated by Bartlett's test for equality of variances. Depending on the outcome of the test, data were analyzed using a p arametric or nonparametric analysis of variance (ANOVA), followed by a Dunnett's test ( p arametric data) or Wilcoxon rank-sum test (nonparametric data) with a Bonferroni correction for multiple comparisons when appropriate. Statistical outliers were identified by a sequential test, but were not excluded from analyses.
For the satellite group, all data (except those for differential leukocyte count and red blood cell p arameters) were first tested for equality of variance using Bartlett’s test. Hematologic and clinical chemistry parameters were evaluated during a two-way analysis of variance with the factors of sex and dose. Examinations were first made for a significant sex-dose interaction. If this existed, a one-way ANOVA was preformed separately for each sex. If no sex-dose interaction was identified and a dose effect was identified, or if in the subsequent ANOVA separated by sex a dose-effect was identified, then separate ANOVAs were used for each treatment group with the control. A Bonferroni correction was used to control for multiple comparisons. Any other information on materials and methods incl. tables

The route of administration and maximum dose level was specified in a testing consent order (EPA. 1989. 40 CFR 799, Fed Reg 54:13470-13477). The highest dose level (4000 mg/kg/day) represented the maximum amount of test substance that could be retained on the back and sides of the rat as determined in a preliminary 2-week study (Yano et al. 1987. Dow Chemical Company Study ID: K-005610-001, Dated Nov. 25, 1987). The EPA has determined that based on severe testicular toxicity in 1/10 rats given 4000 mg/kg/day and minimal decreases in developing germ cells (1-5% of seminiferous tubules affected) in 1/10 rats given 1,200 mg/kg/day, the NOAEL for systemic toxicity is between 400 and 1200 mg/kg/day (Anderson, L. Triethylene glycol monomethyl, monoethyl and monobutyl ethers RM1 screening document (draft), Feb. 24, 1995). This value was reached even though it was recognized that the testicular changes in the 1,200 mg/kg/day rat were within historical control limits for Sprague-Dawley rats (0-17%).

Results and discussions Effect levels Endpoint N OAELEffect level 4000 mg/kg bw/day (actual dose received)

Sex male/female Basis for effect level / Remarks N OAEL = 4000 mg/kg bw (summary preparer); > 400 and < 1200 mg/kg bw (EPA). A significant decrease (15%) in platelet counts was noted in females dosed with 4000 mg/kg for 13 weeks when compared to control.

Observations Clinical signs and mortality
yes Dermal irritation
yes Body weight and weight gain
yes Food consumption
yes Food efficiency no data Water consumption no data Ophthalmoscopic examination
yes Haematology
yes Clinical chemistry
yes Urinalysis
yes N eurobehaviour no data Organ weights
yes Gross pathology
yes Histopathology: non-neoplastic
yes Histopathology: neoplastic no data Details on results Mean body weight and food consumption were comparable to controls throughout the study. There were no treatment-related hematological changes in the interim groups or in males administered test material for 13 weeks. A significant decrease (15%) in platelet counts was noted in females dosed with 4000 mg/kg for 13 weeks when compared to control (1217 +/- 280x 103/cu mm); however, the value (1034 +/- 92 x 103/cu mm) was only slightly below the historical control range (1050 to 1262 +/- 93 to 294 x 103/cu m) Therefore, it was not considered to be toxicologically significant (Gill et al., Int J Toxicol 17:1-22, 1998). There were no other changes in any hematological parameters (hematocrit, hemoglobin, erythrocyte count, total leukocyte count, and red blood cell indices). There were no changes in clinical chemistries, urinalyses, organ weights, or estrous cyclicity measurements.
Bilaterally decreased spermatogenesis in seminiferous tubules and decreased spermatozoa in the epididymes (both were graded as severe) were noted in the testes of one high dose male rat. This animal had a complete lack of mature spermatids in greater than 41% of tubules in each testicle, few spermatids beyond stage 12 of development in the seminiferous epithelium, and decreased spermatic elements in the head and tail of greater than 41% of the tubules and ducts in the epididymides. The testes of one male treated with 1200 mg/kg exhibited different testicular changes [bilateral multifocal degeneration of spermatocytes and spermatids from germinal epithelium (graded as very slight), and multinucleated spermatids]. In this rat, all stages of the cycle of the seminiferous epithelium were observed in morphologically normal tubules. The epididymides of this rat had decreased spermatic elements in the head and tail of 1-5% of ducts. Some of the ducts also contained immature spermatids. Remarks on results including tables and figures

Study personnel concluded that the bilateral microscopic testicular changes observed in one high-dose and one mid-dose male rat were unrelated to treatment. Reasons given were that the dissimilarity of the lesions for the two animals suggested that they occurred spontaneously, and the incidence of animals with lesions (1/10 in each group) was well within that of historical controls (0-17%). Study personnel also stated that the degenerative changes in the testes of one mid-dose and one high-dose rat were not consistent with the types of lesions that have been attributed to 2-methoxyethanol (2-ME). The cell types that are most vulnerable to 2-ME are the pachytene spermatocytes and round spermatids (Chapin et al., Fund Appl. Toxicol 5:182-189, 1985). As the dose of 2-ME is increased, the number and types of cells affected increase up to the point that the germinal epithelium is significantly degenerated and all stages of spermatogenesis are affected (Chapin et al., Fund Appl. Toxicol 5:182-189, 1985; Miller et al., Fund Appl Toxicol 3:49-54, 1983.). In contrast, the testicular effects seen with the high dose animal treated with TGME consisted of a virtually complete lack of mature spermatids beyond stage 12. All other stages, including spermatogonia and spermatocytes, were present and appeared morphologically normal. In the mid-dose rat, the only effects noted consisted of very slight degeneration of spermatocytes and spermatids similar to those seen in historical control animals.

Study personnel also stated that the lymphoid tissues and hematologic parameters, which have been reported to be affected at doses of 2-methoxyethanol that have been associated with testicular changes (Miller et al., Fund. Appl. Toxicol. 3:49-54, 1983) were unattected in this TGME study. Taking all factors into considereation, the testicular lesions observed in this dermal study could not be directly attributed to TGME exposure.
Repeated dose toxicity: dermal.002 UUID IUC5-77e34cdc-e7a6-4d3e-8230-745fe4db1d2b Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of AmericaDate 2009-02-12 11:11:23 EST Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS

Study result type experimental result Study p eriod 198 5 Reliablility 1 (reliable without restriction) Data source Reference Reference type study report

Author Year 1985 Title N ine-day and ninety-day dermal toxicity studies of CARBOWAX MPEG-350 in rabbits Bibliographi

c source Testing laboratory Bushy Run Research Center Report

no. Owner company Union Carbide

Company study no. Report date 1985-05-3 0

Reference type Author Hermansky SJ, Leung HW. Year 1997 Title Cutaneous toxicity studies with methoxy polyethylene glycol-350 (MPEG-350) in rats and rabbits. Bibliograph ic source Testing laboratory Report

no. Owner company Company study no. Report date Cross-reference to same study The same study is summarized as a fertility study. This is toxicity to reproduction.002 Materials and methods GLP compliance
yes Test materials Test material equivalent to submission substance identityno Test material identity Identifier CAS number Identity 9004-74-4

Identifier Common name Identity CARBOWAX MPEG 350 Details on test material The test material (CARBOWAX MPEG 350, CAS No. 9004-74-4) was reported to be chemically inert (stable for > 6 months at room temperature) and 99.8% p ure. This material is a mixture of several methylated glycol ethers of differing molecular weight (ranging from diethylene glycol monomethyl ether (C2) to heptadecaethylene glycol monomethyl ether (C17)). The majority of the material is in the C5-C11 range (87.445%). It contains 4.347 % (by weight) tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 1.303% triethylene glycol monomethyl ether (CAS No. 112-35-6), 0.181% diethylene glycol monomethyl ether (CAS No. 111-77-3). Test animals Species rabbit Strain N ew Zealand White Sex male/female Details on test animals and environmental conditions Body weights of males and females ranged from 2.5 to 3.2 kg and 2.5 to 3.1 kg at study initiation Administration / exposure Type of coverage
open Vehicle other: methyl cellulose in distilled water Details on exposure Dosing: N ew Zealand white rabbits (10/sex/dose) were treated dermally on clipped dorsal skin with 1.0 ml of vehicle (0.1% (w/v) methyl cellulose in distilled water), 50% CARBOWAX MPEG-350 (w/v dilution in 0.1% methyl cellulose in water) or 100% CARBOWAX MPEG-350, for six hours/day, five days per week for 90 days. Body weights of males and females ranged from 2.5 to 3.2 kg and 2.5 to 3.1 kg at study initiation. Rabbits were fitted with Elizabethan collars after dosing to prevent ingestion of test material. After each 6-hour exposure the application site was wiped with a paper towel dampened with water and then dried using a towel. Rabbitswere then uncollared until the next treatment. Analytical verification of doses or concentrations
yes Details on analytical verification of doses or concentrations The test material (CARBOWAX MPEG 350, CAS No. 9004-74-4) was reported to be chemically inert (stable for > 6 months at room temperature) and 99.8% p ure. Duration of treatment / exposuresix hours/day, five days per week for 90 days. Frequency of treatment five days per week Doses/concentrations 1 ml of 50% and 100% material (approximately 169 and 338 mg/kg/day) Basis analytical per unit body weight N o. of animals per sex per dose 10/sex/dose Control animals yes, concurrent vehicle Examinations Observations and examinations performed and frequency Observations: All rabbits were observed daily (weekdays) for death, clinical signs and dermal irritation. Any irritation was scored immediately prior to dosing using the Draize system. Body weights were recorded on the morning of the first day of dosing, weekly thereafter and prior tosacrifice. Food consumption was measured weekly. Urine was collected from 5 animals/sex/group during the last two weeks of dosing and subjected to standard analyses. Standard hematology and clinical chemistry parameters were evaluated for all animals just prior to sacrifice. Sacrifice and pathology N ecropsy: All animals were sacrificed and necropsied after 13 weeks of treatment. Weights were recorded for liver, kidneys, brain and adrenals of all animals and testes of males. Histopathologic examinations were performed on tissues from high-dose and control animals. Statistics Statistical Analyses: Body weight, food consumption, organ weight and clinical pathology data from the three groups were compared using Levene's test for homogeneity of variance. An analysis of variance was performed on the groups when data were homogeneous. If significantdifferences were found, group differences were delineated by grouped variance Student t-tests. When data were heterogeneous, Welch and Brown-Forsyth analyses were p erformed and significant differences among groups were determined using separate variance Student t-tests. Draize skin irritation scores were analyzed using the Kruskal-Wallis test, and significant differences in groups were determined using the Wilcoxon rank sum test (as modified by Mann-Whitney). Frequency data (i.e. histological) were compared using Fisher's exact tests. The p value of 0.05 (two-tailed) was used as the critical level of significance for all analyses. Any other information on materials and methods incl. tables

A preliminary range-finding study in 15 rabbits dosed 6 hr /day for 9 days (Carpenter, Range finding tests on methoxy polyethylene glycols of approximate molecular weights 350, 550 and 750. Melon Institute of Industrial Research, University of Pittsburgh. Report dated 5-13-47.1947) showed that daily administration of 1 ml of 50% or 100% test material only caused mild skin irritation. Therefore, these doses were chosen for the 90-day study.

Results and discussions Effect levels Endpoint N OAEL Effect level 338 mg/kg bw/day (actual dose received)Sex female Basis for effect level / Remarks Mild acanthosis (epidermal thickening)

Observations Clinical signs and mortality
yes Dermal irritation
yes Body weight and weight gain
yes Food consumption
yes Food efficiency no data Water consumption no data Ophthalmoscopic examination no data Haematology
yes Clinical chemistry
yes Urinalysis
yes N eurobehaviour no data Organ weights
yes Gross pathology
yes Histopathology: non-neoplastic
yes Histopathology: neoplastic not examined Details on results Mild acanthosis (epidermal thickening) was found in 3 females dosed with 100% material. Transient, dose-related erythema (Grade 1) and desquamation of skin occurred. N o systemic effects were observed in rabbits treated with either 50% or 100% test material. Remarks on results including tables and figures

The NOAELs for local or systemic effects were not listed by the investigators. Based on the data, these values are 50% and 100%, respectively. Based on weights of animals determined at weekly intervals and the reported density of test material (1.09 g/ml) doses can be calculated on average mg/kg/day basis. These doses are 169 mg/kg/day (for 50 %) and 338 mg/kg/day (for 100%).
Repeated dose toxicity: dermal.003UUID IUC5-28a8564b-5675-47e2-bd3f-df2751cc0ae1 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 11:13:44 EST Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1987

Reliablility 1 (reliable without restriction) Rationale for reliability Robust study following GLP with test substance well characterized as to composition. N o guideline specified but study was conducted according to standard procedures. Data source Reference Reference type study report

Author Gray TM. Year 1987 Title A 28-day dermal toxicity study in rats on PEG-methyl ether (Medical Group N umbe r #85-166). Bibliograp hic source Testing laboratory Report

no. Document N umbe r 4257, Owner company Armour-Dial, Inc.

Company study no. Report date 1987-05-15

Reference type study report

Author Hermansky SJ, Leung HW. Year 1997 Title Cutaneous toxicity studies with methoxy polyethylene glycol-350 (MPEG-350) in rats and rabbits. Bibliograph ic source Testing laboratory Report

no. Owner company Company Reportstudy no. date Materials and methods Test type subacute Limit test

no Principles of method if other than guideline N o guideline specified but study was conducted according to standard procedures. GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 9004-74-4

Identifier Common name Identity Carbowax MPEG-350 ( Details on test material Test material was Carbowax MPEG-350 (CAS No. 9004-74-4) from Union Carbide. This material is a mixture of several methylated glycol ethers of differing molecular weight (ranging from diethylene glycol monomethyl ether (C2) to heptadecaethylene glycol monomethyl ether (C17)). The majority of the material is in the C5-C11 range (87.445%). It contains 4.347 % (by weight) tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 1.303% triethylene glycol monomethyl ether (CAS No. 112-35-6), 0.181% diethylene glycol monomethyl ether (CAS No. 111-77-3).

Test material also contained 1 p pm o f 2-methoxyethanol. Test animals Species
rat Strain Sprague-Dawley Sex male Details on test animals and environmental conditions The animals were 52 days old. Administration / exposure Type of coverage
open Vehicle unchanged (no vehicle) Details on exposure Male rats (52 days old) were divided into 4 groups of 15 animals (control, low-, mid-, and high-dose groups and were acclimated to Elizabethan collars for 7 days before treatment. Onemid-dose and 3 high-dose animals were dropped before treatment because they appeared dehydrated. Each group was treated with 0 (sham control), 1.25, 2.5 or 5 g/kg/day test material on shaved backs. Analytical verification of doses or concentrations no data Duration of treatment / exposure four weeks Frequency of treatment five days per week Doses/concentrations 0 (sham control), 1.25, 2.5 or 5 g/kg/day Basis no data N o. of animals per sex per dose 15 male animals per dose Control animals yes, sham-exposed Details on study design Rats were sacrificed 3 days after the last treatment. Positive control no data Examinations Observations and examinations performed and frequency Signs of irritation, body weights of animals Sacrifice and pathology Organ weights, gross pathology Statistics no data Results and discussions Effect levels Endpoint N OAEL Effect level 1250 mg/kg bw/day Sex male Basis for effect level / Remarks This value is based on significant effects on body weight or weight gain at higher doses. Observations Clinical signs and mortality
yes Dermal irritation
yes Body weight and weight gain
yes Food consumption no effects Food efficiency no dataWater consumption no data Ophthalmoscopic examination no data Haematology no data Clinical chemistry no data Urinalysis no data N eurobehaviour no data Organ weights
yes Gross pathology
yes Histopathology: non-neoplastic no data Histopathology: neoplastic not examined Details on results Minor, transient irritation was noted at the application site of all treated animals. Body weights of animals given 5.0 g/kg/day and body weight gains of animals given 2.5 g/kg/day were depressed. Absolute weights of the thymus and testes of rats treated with 1.25 g/kg/day were 83% and 93%, respectively of control weights (significantly different). Relative weights of these organs were not significantly different from control. There were no pathological abnormalities in either of these organs. Remarks on results including tables and figures

One, 3, and 2 animals in the low-, mid- and high-dose groups slipped their collars and therefore may have ingested the material during grooming. Results in these animals were not significantly different from those animals that did not slip their collars. Therefore, possible ingestion of material in these animals did not appear to affect the results of the study.

The investigators did not identify a NOAEL for the study. However, they stated that there were no indications of systemic toxicity secondary to repeated cutaneous exposure to MPEG-350 in this study. Based on the information given, the summary preparer assigned a NOAEL of 1250 mg/kg/day. This value is based on significant effects on body weight or weight gain at higher doses (although the authors stated that these effects may have been due to use of Elizabethan collars). Although the absolute weights of the thymus and testes of rats treated with 1.25 g/kg/day were significantly less than control, relative weights of these organs were not different from control, there were no histological changes in these organs, and these effects were not noted at higher doses. Therefore, they were considered by the summary preparer to be unrelated to treatment.
Repeated dose toxicity: dermal IRDC TGBE 1986.005 UUID IUC5-f6fc6210-aefc-4b84-b058-1787e38841bc Dossier UUID 0Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 11:16:15 EST Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 86

Reliablility 2 (reliable with restrictions) Rationale for reliability Well conducted, documented study, but duration less than 28 days.

Data source Reference Referenc e type study report

Author Year 1986

Title 21-Day dermal toxicity study in rabbits-limit test on triethylene glycol monobutyl ether, triethylene glycolmonoethyl ether and triethylene glycol monomethyl ether Bibliogr aphic

source Testing laborator
y International Research and Development Corporation (IRDC). Rep
ort

no. Owner company
Compan

y study

no. Rep
ort date 1986-0 7-22

Materials and methods Test type subacute Limit test
yes Principles of method if other than guideline Typical procedure followed for subacute dermal study. GLP compliance
yes Test materialsTest material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 143-22-6

Identifier EC number Identity 205-592-6

Identifier Common name Identity triethylene glycol monobutyl ether Details on test material no data Test animals Species rabbit Strain N ew Zealand White Sex male/female Details on test animals and environmental conditions Rabbits were observed over a 51-52 day pretest period for clinical abnormalities. Prior to randomization, rabbits were fasted (19-23 hours), and blood samples were taken from the central ear artery for control hematological and biochemical evaluations. Healthy rabbits (4- 4.5 months of age) were randomly divided into groups of 5 p er sex. Administration / exposure Type of coverage semiocclusive Vehicle unchanged (no vehicle) Details on exposure Prior to study initiation, hair was removed from the back of each rabbit with an electric clipper. Rabbits were shaved as necessary during the course of the study to prevent the test material from becoming matted in the hair and to facilitate accurate observations. One group of rabbits was left untreated and the other was treated with 1000 mg/kg test material, five days per week for 3 weeks. Dose volumes were calculated based on the specific gravity of test material (as determined at the study site) and the body weight of animals (determinedweekly). Test material was placed on the back using a 5 cc plastic syringe. A glass rod was used to evenly distribute the dose over the test site. Following dosing, test sites (of all animals, including controls) were wrapped with gauze bandaging and Dermiform tape and plastic restraint collars were attached to the rabbits. Collars were removed after 6 hours, and test sites (of all animals, including controls) were washed with tepid tap water and dried with paper towels. Analytical verification of doses or concentrations no data Details on analytical verification of doses or concentrations no dataDuration of treatment / exposure 21 days Frequency of treatment 6 hr/day, 5 days/week for 3 weeks Doses/concentrations limit dose of 1000 mg/kg Basis nominal per unit body weight N o. of animals per sex per dose five per sex per dose Control animals yes, sham-exposed Details on study design All animals were fasted for 19-23 hours before study termination. Positive control no data Examinations Observations and examinations performed and frequency Animals were observed once daily for clinical signs and twice daily for mortality. Food consumption was estimated daily based on a visual assessment of remaining food. Body weights were recorded weekly. Rabbits were scored immediately prior to each dosing for dermal irritation in accordance with the Draize method. Blood samples taken from the central ear artery of animals at study termination were analyzed for standard hematological (total and differential leukocyte count, erythrocyte count, hemoglobin, hematocrit, p latelet count, reticulocyte count, mean corpuscular volume, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration) and biochemical (sodium, p otassium, chloride, calcium, p hosphorus, total bilirubin, gamma glutamyltranspeptidase, aspartate aminotransferase, alanine aminotransferase, ornithine carbamoyltransferase, urea nitrogen, creatinine, total protein, albumin, globulin, cholesterol and glucose) p arameters. Sacrifice and pathology All animals were examined grossly upon study termination.
Weights of adrenals, brain, kidneys, liver, ovaries and testes were taken. A full complement of tissueswas examined microscopically. Body weights (weeks 1, 2, 3, and 4), clinical pathology p arameters and organ weights (absolute and relative) were analyzed. Statistics Body weights (weeks 1, 2, 3, and 4), clinical pathology parameters and organ weights (absolute and relative) were analyzed. using Bartlett’s test for homogeneity of variance and analysis of variance (one-way). The treatment groups were compared to the controls using the appropriate t-statistic (for equal or unequal variance). Dunnett’s multiple comparison tables were used to j udge the significance of the differences. Total bilirubin data were transformed to ranks and analyzed using a non- p arametric test. All tests were two-tailed, with p < 0.05 and p < 0.01 as levels of significance. Results and discussions Effect levels Endpoint N OAEL Effect level 1000 mg/kg bw/daySex male/female Basis for effect level / Remarks N o adverse effects seen at the limit dose of 1000 mg/kg bw

Observations Clinical signs and mortality
yes Dermal irritation
yes Body weight and weight gain
yes Food consumption
yes Food efficiency no data Water consumption no data Ophthalmoscopic examination no data Haematology
yes Clinical chemistry
yes Urinalysis no data N eurobehaviour no data Organ weights
yes Gross pathology
yes Histopathology: non-neoplastic
yes Histopathology: neoplastic no data Details on results There were no deaths or signs of overt toxicity over the study period. There were no significant differences in body weights or food consumption between treated or control groups. Some hematological and biochemical values from treated animals were different from controls at termination. However, since the same changes were noted in blood samples taken from the animals prior to treatment, they were not considered by the investigators to be related to treatment. Mild to moderate desquamation and fissuring of skin was noted in most rabbits after 2 to 3 weeks of treatment with test material. This was confirmed microscopically and consisted of trace acanthosis and trace to moderate dermatitis. Testicular degeneration (scored as trace in severity) , occurred in one rabbit each from the TGEE and TGME-treated groups. This lesion was characterized by the presence of spermatid giant cells, focal tubular hypospermatogenesis,or cytoplasmic vacuolization. The pathologist stated that “random occurrence of this lesion was suggestive of its spontaneous nature and was not test article related. A high incidence of similar changes of spontaneous nature in normal New Zealand White rabbits has been reported by Morton et al. in "Vet Pathol 23: 176-183, 1986 and Vet Pathol 23: 210-217, 1986.”
Based on the results, the investigators concluded that in this study, there was no systemic toxicity induced by treatment with 1000 mg/kg/day test material. Therefore, the NOAEL is 1000 mg/kg/day. Remarks on results including tables and figures

Toxicity of triethylene glycol monomethyl (TGME, CAS No. 112-35-6) and monoethyl ethers (TGEE, CAS No. 112-50-5) at 1000 mg/kg also was tested in this study. The skin effects noted for triethylene glycol butyl ether were more severe than those for TGME and TGEE.
Repeated dose toxicity: dermal.006 UUID IUC5-97e117c7-391c-488b-8f68-5364d9ce0a2e Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 11:19:32 EST Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 87

Reliablility 2 (reliable with restrictions) Rationale for reliability Well conducted study, but of only 2 week duration. Purity of test substance not stated. Data source Reference Reference type study report

Author Yano BL, Phillips JE, Battjes JE. Year 1987 Title Triethylene glycol monomethyl ether: 2-week dermal toxicity study in male and female Sprague-Dawley rats. Bibliograp hic source Testing laboratory Report

no. Owner company Dow Chemical Company

Company Study ID:K-005610-001, Report 1987-11-study no. date 25 Materials and methods Test type subacute Limit test

no Principles of method if other than guideline Standard procedure used at the time for a two week repeat dose dermal study. GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 112-35-6).

Identifier EC number Identity 203-962-1

Identifier Common name Identity triethylene glycol monomethyl ether Details on test material Purity is unknown. Test animals Species
rat Strain Sprague-Dawley Sex male/female Details on test animals and environmental conditions 200 to 350 g weight Administration / exposure Type of coverage semiocclusive Vehicle unchanged (no vehicle) Details on exposure Groups of five rats/sex (200 to 350 g)were dosed with 0, 1000, 2500, or 4000 mg/kg/day of test material on clipped back skin, 6 hours/day for a total of 9 applications during a 12 day period. Test material was held in place with a gauze patch and elastic bandage. Analytical verification of doses or concentrations no data Details on analytical verification of doses or concentrations no dataDuration of treatment / exposure two weeks, 9 dose applications Frequency of treatment daily Doses/concentrations 0, 1000, 2500, 4000 mg/kg/day Basis nominal per unit body weight N o. of animals per sex per dose five rats/sex Control animals yes, concurrent no treatment Examinations Observations and examinations performed and frequency Parameters evaluated included clinical observations (including skin evaluations), body weight, feed consumption, clinical chemistry, hematology, urinalysis, and fasted body weights. Sacrifice and pathology Organ weight measurement, gross pathology, and histopathology were conducted. Other examinations no data Statistics no data Results and discussions Effect levels Endpoint N OAEL Effect level 4000 mg/kg bw/day (nominal) Sex male/female Basis for effect level / Remarks N o significant obverse effects were observed at this or lower doses that were considered treatment related.

Observations Clinical signs and mortality
yes Body weight and weight gain
yes Food consumption
yes Food efficiency no data Water consumption no data Ophthalmoscopic examination no data Haematology
yes Clinical chemistryyes Urinalysis
yes N eurobehaviour no data Organ weights
yes Gross pathology
yes Histopathology: non-neoplastic
yes Histopathology: neoplastic not examined Details on results There were no treatment-related adverse systemic effects. A few males and females treated with either 1000 or 2500 mg/kg/day had a few small scabs or crusts at the test site. These alterations were slight in degree and did not adversely affect the rats.
A number of clinical chemistry, hematological and urinalysis variables were significantly different from control. The lower albumin concentration in females from the 1000 mg/kg/day group and higher urea nitrogen concentration in males from the 2500 mg/kg/day group were not considered by study personnel to be related to treatment because the effects were not noted at higher concentrations. The lower albumin concentration in males treated with 4000 mg/kg/day also was not attributed to treatment by study personnel because the value was within the range of individual animal values in the control group. A slightly higher alanine aminotransferase activity was also statistically identified in rats from the 4000 mg/kg/day group. As the value was only marginally different from control and was not associated with any histologic changes in the liver, study personnel did not consider this to be related to treatment. A slightly higher red blood cell count and hemoglobin concentration was observed in rats given 4000 mg/kg/day. Since these were only slightly higher than control values, study personnel did not consider them to be related to treatment. A few of therats given 2500 or 4000 mg/kg/day had watery cecal contents and/or hemolyzed blood in the stomach. These gross pathologic observations were not associated with any histologic abnormalities in these tissues or alterations in hematologic and clinical chemistry parameters. Therefore, they were not attributed by study personnel to be related to treatment. 7.5.4 Repeated dose toxicity: other routes Repeated dose toxicity: other routes.001 UUID IUC5-303a73fc-8959-46fb-acd3-c853a3fecb22 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 14:06:20 EST RemarksAdministrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 97

Reliablility 1 (reliable without restriction) Rationale for reliability well conducted, thorough study following GLP. Test substance was well defined. Data source Reference Reference type study report

Author Year 1997 Title Subchronic intravenous toxicity study in the rat. Carbowax Sentry M-PEG 350- N F and Carbowax Sentry PEG 400 N F and FCC. Bibliograp hic source

Testing laboratory N orth American Science Associates, Inc ( N AMSA). Repor
t no. Report TS064-900/S

. Owner company Company study no. Repor t date Materials and methods Test type subchronic Limit test

no Principles of method if other than guideline One i.v. dose plus concurrent control. Typical battery of observations for a two week study. GLP compliance

no Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 9004-74-4

Identifier Common name Identity CARBOWAX Sentry MPEG-350 Details on test material Test material was CARBOWAX Sentry MPEG-350 (CAS No. 9004-74-4), N F grade. Thismaterial is a mixture of several methylated glycol ethers of differing molecular weight (ranging from diethylene glycol monomethyl ether (C2) to heptadecaethylene glycol monomethyl ether (C17)). The majority of the material is in the C5-C11 range (87.445%). It contains 4.347 % (by weight) tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 1.303% triethylene glycol monomethyl ether (CAS No. 112-35-6), 0.181% diethylene glycol monomethyl ether (CAS No. 111-77-3). Test animals Species
rat Strain Sprague-Dawley Sex male/female Details on test animals and environmental conditions Groups of six rats/sex (6-8 weeks of age, 114 g to 189 g Administration / exposure Route of administration intraveneous Vehicle other: Details on exposure Groups of six rats/sex (6-8 weeks of age, 114 g to 189 g) were dosed intravenously for 14 consecutive days with either vehicle (0.9% sodium chloride, USP), or 1 g/kg/day test material. Analytical verification of doses or concentrations
yes Duration of treatment / exposure fourteen days Frequency of treatment daily for fourteen consecutive days Doses / concentrations either vehicle (0.9% sodium chloride, USP), or 1 g/kg/day test material. N o. of animals per sex per dose six rats/sex Control animals yes, concurrent vehicle Examinations Observations and examinations performed and frequency Animals were observed daily for general health. Body weights were recorded on days 1, 8 and 15 of treatment. Sacrifice and pathology All animals were euthanized on day 15. Blood was collected from the posterior vena cava and standard hematological and clinical chemistries were performed. The heart, liver, spleen, kidneys, adrenal glands and gonads were weighed, fixed, and processed for microscopic evaluation. The data were analyzed using a standard BMDP Statistical Software Package.Statistics The data were analyzed using a standard BMDP Statistical Software Package. Results and discussions Effect levels Endpoint N OAEL Effect level 1000 mg/kg bw/day (actual dose received) Sex male/female Basis for effect level / Remarks N o adverse effects were observed at the single dose tested.

Observations Clinical signs and mortality
yes Body weight and weight gain
yes Food consumption no data Food efficiency no data Water consumption no data Ophthalmoscopic examination no data Haematology
yes Clinical chemistry
yes Urinalysis no data N eurobehaviour no data Organ weights
yes Gross pathology
yes Histopathology: non-neoplastic
yes Histopathology: neoplastic not examined Details on results There was no effect of treatment on body or organ weights or hematological values. Tissues (including testes) from treated animals were histologically similar to those of controls. There was a significant difference in aspartate aminotransferase activity in control (95 +/- 13 IU/L) and treated males (81 +/- 6 IU/L) that was not considered by the investigators to be related to treatment since the values for both groups were within the normal expected range. An increase in aspartate aminotransferase activity, rather than a decrease would be indicative of livertoxicity. 7.6 Genetic toxicity 7.6.1 Genetic toxicity in vitro Genetic toxicity in vitro BASF TGBE 1989.001 UUID IUC5-978d151e-c7ca-41a4-be56-3ee011a61a3a Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 14:10:39 EST Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1 9 8 9 Reliablility 2 (reliable with restrictions) Rationale for reliability This was an OECD guideline study, but only 4 strains were tested. Purity of test material is not high. Data source Reference Reference type study report Author Year 1989 Title Bibliographic

source Testing laboratory Department of Toxicology Report no. Owner company BASF AG Company study no. Project No. 40M0573/884365 Report date 1989-02-24 Materials and methods Type of genotoxicity gene mutation Type of study bacterial reverse mutation assay (e.g. Ames test) Test guideline Qualifier according to Guideline OECD Guideline 471 (Bacterial Reverse Mutation Assay) Deviations GLP compliance
yes Test materials Test material equivalent to submission substance identityno Test material identity Identifier CAS number Identity 143-22-6

Identifier EC number Identity 205-592-6

Identifier Common name Identity Triethylene glycol butyl ether Details on test material Test material purity was 87.2%. Method Species/strain Species/strain S. typhimurium TA 1535, TA 1537, TA 98 and TA 100 Details on mammalian cell lines (if applicable) Additional strain characteristics Metabolic activation with and without Metabolic activation system S-9 Test concentrations 20-5000 micrograms/ p late Controls N egativ

e controls yes

Solvent / vehicle controls

True negativ

e controls

Positive controls yes

Positive

control substan

ce other: Positive controls were N-methyl- N ’-nitro- N -nitroso-guanidine MNNG), 4-nitro-o- p henylenediamine, 9-aminoacridine chloride monohydrate (AACM) and 2-aminoanthracene (AA)

Remarks Details on test system and conditions Standard test: Test tubes containing 2 ml of soft agar, bacteria (0.1 ml of > = 10E8 S. typhimurium TA98, TA100, TA1535, or TA1537), test chemical (0.1 ml of test solution, p ositive control, or aqua dest. solvent) and either buffer or S-9 mix from Aroclor 1254-induced, male, Sprague Dawley rats (0.5 ml) were prepared. After mixing, the samples were poured onto minimal glucose agar plates within 30 seconds.
Preincubation test: Test tubes containing bacteria (0.1 ml of > = 10E8 S. typhimurium TA98, TA100, TA1535, or TA1537), test chemical (0.1 ml of test solution, p ositive control, or aqua dest. solvent) and either buffer or S-9 mix from Aroclor 1254-induced, male, Sprague Dawley rats (0.5 ml) were incubated at 37 degrees C for 20 minutes. Supplemented top agar (2 ml) was then added. After mixing, the overlay was poured onto minimal glucose agar plates. Plates were incubated at 37 degrees C for 48 hours in the dark. All dose levels (including positive and negative controls) were assayed in triplicate. The method of colony counting was not specified. Positive controls were 5 micrograms N-methyl- N ’-nitro- N -nitroso-guanidine MNNG) for strains TA100 and TA1535, 10 micrograms 4-nitro-o- p henylenediamine for strain TA98, and 100 micrograms 9-aminoacridine chloride monohydrate (AACM) for strain TA 1537 (all in the absence of S-9), and 10 micrograms 2-aminoanthracene (AA) for all strains in the presence of S-9. All positive control chemicals were dissolved in DMSO. Evaluation criteria Evaluation Criteria: The test material was considered a mutagen if both the mean number of revertant colonies was at least 2 times higher than the mean of the negative (solvent) control and it induced a reproducible dose-response relationship over several concentrations. If the dose-response was not definitive, it was considered to be a presumptive mutagen. If the reversion rates were between 2 and 3 times that of negative controls, the results were considered equivocal or inconclusive. Results and discussions Test results Species/strain S. typhimurium TA 1535, TA 1537, TA 98 and TA 100 Metabolic activation with and without Test system all strains/cell types tested Genotoxicity negative Cytotoxicity yes Vehicle controls valid no data N egative controls valid no data Positive controls valid yes Additional information on results Standard test: The average number of revertant in the controls for strains TA98, TA100, TA1535, and TA1537 in the absence of S-9 were 23, 114, 16, and 9. Addition of S-9 to strain TA98 increased the control mutation frequency to 34. S-9 had no effect on the frequency of mutations in the other strains. Positive controls induced an average of from 152 revertants in TA1535 to 1690 revertants in TA100. The number of revertants induced by test material was not increased from that of control at any concentration. The average number of revertants in cultures treated with test material (in the absence or presence of S-9) ranged from 109-140 in TA100, 12-21 in TA1535, and 8-11 in TA1537. Similar to control TA98 cultures, the averagenumber of revertants in TA98 cultures treated with test material in the presence of S-9 (33-36) were higher than in the absence of S-9 (19-24).
Preincubation test: The average number of revertant in the controls for strains TA98, TA100, TA1535, and TA1537 in the absence of S-9 were 24, 111, 17, and 8. Addition of S-9 to strains TA98 and TA1535 increased the control mutation frequency to 33 and 23, respectively. S-9 had nosubstantial effect on the frequency of mutations in the other strains. Positive controls induced an average of from 94 revertants in TA1537 to 1127 revertants in TA100. The number of revertants induced by test material was not increased from that of control at any concentration. The average number of revertants in cultures treated with test material (in the absence or p resence of S-9) ranged from 108-135 in TA100 and 7-11 in TA1537. Similar to control TA98 cultures, the average number of revertants in TA98 and TA1535 cultures treated with test material in the presence of S-9 (35-41 and 18-26, respectively) were higher than in the absence of S-9 (19-24 and 14-18, respectively).
The tests were valid, as positive controls induced at least a two-fold increase in frequency of mutations. Remarks on results including tables and figures

Cytotoxic concentration: > 5000 micrograms/plate
Applicant's summary and conclusion Interpretation of results negative Genetic toxicity in vitro.002 UUID IUC5-40906c59-da97-4ed9-9440-38381aa79661 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 14:12:27 EST Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 90

Reliablility 2 (reliable with restrictions) Rationale for reliability Only four strains of bacteria were used in the test.

Data source Reference Referenc e type study reportAuthor Samson YE and Gollapudi BB. Yea

r 1990

Title Evaluation of triethylene glycol monomethyl ether (TGME) in the Ames Salmonella/mammalian-microsome bacterial mutagenicity assay. Bibliogr aphic

source Testing laborator
y Rep
ort

no. Study ID TXT:K-00561 0-005, Owner company Dow Chemical Company

Compan y study

no. Rep
ort date 1990-03-07

Materials and methods Type of genotoxicity gene mutation Type of study bacterial reverse mutation assay (e.g. Ames test) Test guideline Qualifier equivalent or similar to Guideline other guideline: Test Standard 40 CFR 798.5265 Deviations GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 112-35-6

Identifier EC number Identity 203-962-1

Identifier Common name Identity triethylene glycol monomethyl ether Details on test material Purity was 99.23%. Method Species/strain Species/strain S. typhimurium TA 1535, TA 1537, TA 98 and TA 100 Details on mammalian celllines (if applicable) Additional strain characteristics Metabolic activation with and without Metabolic activation system not stated Test concentrations up to 5000 micrograms/ p late Vehicle DMSO and water Controls N egative controls yes Solvent / vehicle controls True negative controls Positive controls yes Positive control substance other: 2-nitrofluorene, ICR-191, 2-anthramine and sodium azide

Remarks Details on test system and conditions Test Concentrations: The test material was dissolved in distilled water at stock concentrations of 50, 16.67, 5, 1.667, and 0.5 mg/ml. Concentrations were verified by HPLC to be: 51.4, 18.3, 4.91, 1.75 and 0.523 mg/ml. All positive control solutions (1 mg/ml 2-nitrofluorene, 100 micrograms/ml ICR-191, 30 micrograms/ml 2-anthramine) were prepared in DMSO (with the exception of 250 micrograms/ml sodium azide dissolved in water).
Test: Bacteria (0.1 ml of 10E8 or 10E9 S. typhimurium TA 98, TA100, TA1535, or TA1537), test chemical (0.1 ml of test solution, p ositive control, or solvent) and either buffer or S-9 mix (0.5 ml) were pre-incubated in sterile 12 x 75 mm tightly-capped culture tubes in a gyratory incubator (300rpm) at 30 degrees C for 30 minutes. Supplemented top agar (2 ml) was then added, the overlay was poured onto plates, and plates were incubated at 37 degrees C for 2 days. All dose levels (including positive and negative controls) were assayed in triplicate.
Revertant colonies were counted manually or with an automatic colony counter. The counter was calibrated periodically. A correction factor was used to compensate for the area not scanned by the counter (i.e. dish edge) and overlapping colonies. Evaluation criteria Evaluation Criteria: The test material was considered a mutagen if both the mean number of revertant colonies was at least 3 times higher than the mean of the negative (solvent) control and it induced a reproducible dose-response relationship over several concentrations. If the dose-response was not definitive, it was considered to be a presumptive mutagen. If the reversion rates were between 2 and 3 times that of negative controls, the results were considered equivocal or inconclusive. Statistics no data Results and discussionsTest results Species/strain S. typhimurium TA 1535, TA 1537, TA 98 and TA 100 Metabolic activation with and without Test system all strains/cell types tested Genotoxicity negative Cytotoxicity yes Vehicle controls valid yes N egative controls valid Positive controls valid yes Additional information on results Concentrations up to 5000 micrograms/ p late did not cause toxicity or cause an increase in mutagenicity above that of negative controls.
The study was valid, as the positive controls induced at least 3 times the number of revertants as the negative controls in each tested strain. Remarks on results including tables and figures

Cytotoxic concentration = > 5000 micrograms/plate
Genetic toxicity in vitro.003 UUID IUC5-ce827574-5411-44b5-8a40-c69cc933392e Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 14:13:31 EST Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 84

Reliablility 1 (reliable without restriction) Rationale for reliability Well conducted study per GLP and with test substance well characterized as to composition. Data source Reference Reference type study report

Author Year 1984 Title Carbowax methoxy polyethylene glycol 350 Salmonella/microsome (Ames) bacterial mutagenicity assay. Bibliographic source Testing laboratory Bushy Run Research Center. Report

no. Owner company Union Carbide

Company study no. Report date 1984-10-2 3 Materials and methods Type of genotoxicity gene mutation Type of study bacterial reverse mutation assay (e.g. Ames test) Principles of method if other than guideline N o guideline was referenced in the study, but the study method followed conventional p rocedure for Ames studies. GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 9004-74-4

Identifier Common name Identity Carbowax MPEG-350 Details on test material The test material (CARBOWAX MPEG-350; CAS No. 9004-74-4) is a mixture of several methylated glycol ethers of differing molecular weight (ranging from diethylene glycol monomethyl ether (C2) to heptadecaethylene glycol monomethyl ether (C17)). The majority of the material is in the C5-C11 range (87.445%). It contains 4.347 % (by weight) tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 1.303% triethylene glycol monomethyl ether (CAS No. 112-35-6), 0.181% diethylene glycol monomethyl ether (CAS No. 111-77-3).Purity of test material was 99.8%. Impurities included 0.1% water, 0.05% ethylene glycol, 0.05% diethylene glycol, and 50-150 p pm BHT. Method Species/strain Species/strain other: S. typhimurium TA98, TA100, TA1535, TA1537, TA1538 Details on mammalian cell lines (if applicable) Additional strain characteristics Metabolic activation with and without

Metabolic 0.5 ml of S9 mix containing 50 microliters of S9 liver homogenate fromactivation system Aroclor 1254-induced, Sprague-Dawley male rats Test concentrations 1, 3, 10, 30 and 110 mg/ p late Vehicle
water Controls N egative controls yes Solvent / vehicle controls yes
True negative controls no
Positive controls yes Positive control substance other: 4-nitro-o- p henylenediamine, sodium azide, 9-aminoacridine and 2-aminoanthracene Remarks Details on test system and conditions Test material was dissolved in water to a concentration of 300 mg/ml for doses of 30 mg/ p late and below. All subsequent dilutions were made in the same solvent. Dilutions of test substance were made fresh each day and were gravimetrically analyzed. The volume of test material used in each test was 100 microliters. If necessary, p hosphate buffered saline was added to adjust the volume.
A preliminary toxicity test was performed in strain TA100 to determine concentrations to use on other strains (TA98, TA1535, TA1537, TA1538). N one of the doses used (up to 100 mg/ p late) were toxic. Test material was tested in the Ames assay in triplicate at five doses (1, 3, 10, 30 and 110 mg/ p late). Testing was performed with and without metabolic activation (0.5 ml of S9 mix containing 50 microliters of S9 liver homogenate from Aroclor 1254-induced, Sprague-Dawley male rats). Concurrent water and positive controls (4-nitro-o- p henylenediamine for TA98 and TA 1538, sodium azide for TA100 and TA1535 and 9-aminoacridine for TA1537 in the absence of S9 and 2-aminoanthracene for all stains in the p resence of S9) were run with each test. Evaluation criteria The test was considered valid, if positive controls caused mutagenicity and negative controls exhibited spontaneous reversion rates that were within historical range. Statistics no data Results and discussions Test results Species/strain other: S. typhimurium TA98, TA100, TA1535, TA1537, TA1538 Metabolic activation with and without Test system all strains/cell types tested Genotoxicity negative Cytotoxicity yes Vehicle controls valid yes N egative controls validPositive controls valid yes Additional information on results The test was valid, as positive controls caused mutagenicity and negative controls exhibited spontaneous reversion rates that were within historical range.
Cycotoxic concentration: > 110 mg/ p late Applicant's summary and conclusion Interpretation of results negative Conclusions Mutagenic activity was not observed with any concentration in any of the strains (with or without bacterial activation). Genetic toxicity in vitro.004 UUID IUC5-648e5cf6-6065-4214-96ec-1e4eb36f9cbd Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 14:14:48 EST Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 90

Reliablility 1 (reliable without restriction) Rationale for reliability Guideline study following GLP. Purity of test substance stated.

Data source Reference Reference type study report

Author Liscombe VA, Gollapudi BB. Year 1990 Title Evaluation of triethylene glycol monomethyl ether in the Chinese hamster ovary cell/hypoxanthine-guanine- p hosphoribosyl-transferase(CHO/HGPRT) forward mutation assay Bibliographi

c source Testing laboratory Report

no. Owner company Dow Chemical Company

Company ID TXT:K-005610-006 Report 1990-03-0study no. date 7 Materials and methods Type of genotoxicity gene mutation Type of study mammalian cell gene mutation assay Test guideline Qualifier according to Guideline other guideline: Test Standard 40 CFR 798.5300 Deviations Principles of method if other than guideline HGPRT Assay using Chinese hamster ovary cell GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 112-35-6

Identifier EC number Identity 203-962-1

Identifier Common name Identity triethylene glycol monomethyl ether Details on test material Purity was 99.23%. Method Target gene the gene locus for the enzyme (hypoxanthine-guanine phosphoribosyl transferase) Species/strain Species/strain Chinese hamster Ovary (CHO) Details on mammalian cell lines (if applicable) Additional strain characteristics Metabolic activation with and without Metabolic activation system S-9 Test concentrations 2000 to 5000 micrograms/ p late Vehicle water and DMSO Controls N egative controls yes Solvent / vehicle controls yes True negative controls no dataPositive controls yes Positive control substance other: EMS or 20-MC Remarks Details on test system and conditions Indicator cells: The CHO-K1-BH4 cell line was used in the study. Periodic examinations revealed no mycoplasma contamination. Cells were grown as a monolayer in Ham's F-12 nutrient mix supplemented with 5% heat-inactivated, dialyzed fetal bovine serum, 25 mM HEPES, 0.25 micrograms/ml Fungizone, 100 units/ml penicillin G and 0.1 mg/ml streptomycin sulfate. The selection medium used for the detection of mutants was Ham's F-12 nutrient mix without hypoxanthine, and supplemented with 10 micromolar 6-thioguanine, 5% serum, 25 mM HEPES, 2 mM L-glutamine and the antibiotics mentioned above.

Test materials: Test material was dissolved in water and further diluted (1:100) in culture medium. The concentrations of test material in stock solutions (200, 300, 400, 500 mg/ml)were verified by analytical methods.20-methylchlolanthrene (20-MC) was initially dissolved in DMSO, and further diluted in culture medium. Ethyl methanesulfonate (EMS) was dissolved in culture medium.
Preliminary test : The cytotoxicity of the test material was assessed by determining the ability of the treated cells to form colonies. The cultures (3 p er dose level) were treated with test material in the absence or presence of S-9, incubated for up to 7 days, fixed with methanol and stained with crystal violet. The number of colonies/dish was counted and the mean colonies/dish/treatment were expressed relative to the negative control value. The test material was not cytotoxic at up to 5000 micrograms/ml. Based on this result, this was the highest concentration used for the genemutation assay.
Mutation test: Cells in logarithmic growth phase were trypsinized and plated in medium containing 5% serum at a standard density (200 cells/100 mm dish for toxicity assay and 1 x 10E6 cells/100 mm dish for gene mutation assay) p rior to treatment. Approximately 24 hours after plating,the medium was replaced with Ham's medium without serum, S-9 mix prepared from liver homogenate of Aroclor-1254 treated (500 mg/kg) male, Sprague Dawley rats (when applicable) and test material (2000 to 5000 micrograms/ml), p ositive control (either 621 micrograms/ml EMS or 4 micrograms/ml 20-MC) or water. The total volume of the treatment medium was 10 ml/100 mm dish. The number of dishes treated at each dose level was based on the expected degree of toxicity that would yield at least 1 x 10E6 surviving cells. Cells were treated for 4 hours at 37 degrees C. Exposure was terminated by washing the cells with p hosphate-buffered saline. Cells were trypsinized 18-24 hours after termination of the treatment and replated at a density of 1 x 10E6 cells/100 mm dish. This step was repeated on the third and sixth days following treatment. On Day 8, cultures were trypsinized and plated at a density of 2 x 10E5 cells/100 mm dish (5 dishes per treatment) in selection medium for the determination of HGPRT-mutants and 200 cells/60 mm dish (5 dishes/treatment) in Ham's medium without hypoxanthine for determination of cloning efficiency. Dishes were incubated for 7-9 days, fixed with methanol and stained with crystal violet. The mutation frequency per 10E6 clonable cells was calculated as the total number of mutant colonies/cloning efficiency(number of colonies per number of cells plated). Evaluation criteriaThe assay was considered valid, if the positive control chemicals induced significant increased in mutation frequencies in assays with and without S-9 (EMS: 142.0-153.6; 20-MCA: 64.7-86.3). Statistics Statistical analysis: The frequencies of mutants per 10E6 clonable cells were statistically evaluated by pairwise tests (treatment vs. negative control) and by linear and quadratic trend analysis over the dose range. Results and discussions Test results Species/strain Chinese hamster Ovary (CHO) Metabolic activation with and without Test system all strains/cell types tested Genotoxicity negative Cytotoxicity yes Vehicle controls valid yes N egative controls valid yes Positive controls valid yes Additional information on results The mutation frequencies observed in cultures treated with the test chemical in the absence (1.4 to 7.1) and presence of S-9 (0 to 7.1) were not significantly different from the concurrent negative control values (1.4 to 9.6) and were within the laboratory historical negative control range.
Cytotoxic concentration: > 5000 micrograms
The assay was valid, since the positive control chemicals induced significant increased in mutation frequencies in assays with and without S-9 (EMS: 142.0-153.6; 20-MCA: 64.7-86.3). Applicant's summary and conclusion Interpretation of results negative Genetic toxicity in vitro.005 UUID IUC5-83cfdf6e-9c06-4310-b95d-65c1363a0e78 Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-02-17 14:18:00 EST Remarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1 9 9 2Reliablility 1 (reliable without restriction) Rationale for reliability well conducted study run according to glp, with good characterization of test material composition. Data source Reference Reference type study report Author Brooks TM, Wiggins DE. Year 1992 Title Brake fluid Dot 4: Bacterial mutagenicity studies Bibliographic

source Testing laboratory Shell Research Limited, Sittingbourne Research Centre Report no. SBGR.92.022

Owner company Shell

Company study

no. Report date 1992-04-09

Materials and methods Type of genotoxicity gene mutation Type of study bacterial reverse mutation assay (e.g. Ames test) Principles of method if other than guideline Guideline not specified, but study was run according to standard Ames study procedure GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 106008-94-0

Identifier Common name Identity Brake fluid Dot 4 Details on test material Test material is a mixture containing 30-50% triethylene glycol monomethyl ether borate ester (CAS No. 106008-94-0), 3-30% triethylene glycol monobutyl ether borate ester, 20-30% triethylene glycol monomethyl ether (CAS No. 112-35-6), 2-10% triethylene glycol monobutyl ether (CAS No. 143-22-6), 20-30% tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 2-10% tetraethylene glycol monobutyl ether (CAS No. 1559-34-8), and < 1% minor additives. Method Species/strain Species/strain other: TA98, TA100, TA1535, TA1537, TA1538 and E. coli WP2uvrA pKM101 Details on mammaliancell lines (if applicable) Additional strain characteristics Metabolic activation with and without Metabolic activation system Test concentrations up to 5000 micrograms per plate Vehicle no vehicle Controls N egative controls no data Solvent / vehicle controls no data True negative controls no data Positive controls no data Positive control substance no data Remarks Details on test system and conditions no data Evaluation criteria no data Statistics no data Any other information on materials and methods incl. tables

Results and discussions Test results Species/strain other: TA98, TA100, TA1535, TA1537, TA1538 Metabolic activation with and without Test system Genotoxicity negative Cytotoxicity no, but tested up to limit concentrations Vehicle controls valid no data N egative controls valid no data Positive controls valid no data Remarks on results including tables and figures
Cytotoxic concentration = > 5000 micrograms per plate
Genetic toxicity in vitro.006 UUID IUC5-95832cad-6a4b-4a42-8aec-f6afdd347855 Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of AmericaDate 2009-02-17 20:26:54 EST Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1 9 9 2 Reliablility 1 (reliable without restriction) Rationale for reliability Robust well conducted study following GLP, with good characterization of the test substance composition. Data source Reference Reference type study report

Author Brooks TM, Wiggins DE Year 1992 Title Brake fluid Dot 4: In vitro chromosome studies using cultured Chinese hamster ovary cells. Bibliograph ic source Testing laboratory Shell Research Limited, Sittingbourne Research Centre Report

no. SBGR.92. 090 Owner company Shell

Company study no. Report date 1992-07-2 3 Materials and methods Type of genotoxicity chromosome aberration Type of study in vitro mammalian chromosome aberration test Principles of method if other than guideline Guideline was not specified, but study was carried out following standard procedures for this type of study. GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 106008-94-0Identifier Common name Identity Brake fluid Dot 4 Details on test material Test material is a mixture containing 30-50% triethylene glycol monomethyl ether borate ester (CAS No. 106008-94-0), 3-30% triethylene glycol monobutyl ether borate ester, 20-30% triethylene glycol monomethyl ether (CAS No. 112-35-6), 2-10% triethylene glycol monobutyl ether (CAS No. 143-22-6), 20-30% tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 2-10% tetraethylene glycol monobutyl ether (CAS No. 1559-34-8), and < 1% minor additives. Method Species/strain Species/strain Chinese hamster Ovary (CHO) Details on mammalian cell lines (if applicable) no details

Additional strain characteristics Metabolic activation with and without Metabolic activation system S-9 Test concentrations The concentrations of test material used (from 10 to 5000 micrograms/ml without S-9 and 100 to 5000 micrograms/ml with S-9). Vehicle no vehicle Controls N egative controls yes Solvent / vehicle controls yes

True negative controls Positive controls yes Positive control substance other: methyl methanesulphonate and benzo(a) p yrene

Remarks Details on test system and conditions Cells (2 x 10E5) were incubated with medium containing the test compound or relevant controls [untreated control, solvent control and positive controls methyl methanesulphonate (20 micrograms/ml without S-9) and benzo(a) p yrene (25 micrograms/ml with S-9)] for either 3 hours in the presence of S9 mix (from Aroclor 1254-induced rat liver) or 24 hours in the absence of S9 mix. The concentrations of test material used (from 10 to 5000 micrograms/ml without S-9 and 100 to 5000 micrograms/ml with S-9) were chosen based on the results of p reliminary miscibility and mitotic index studies. Duplicate cultures were prepared for each test condition. Two separate experiments were conducted using different concentrations. Metaphase cells were prepared on glass microscope slides for the analysis of chromosome aberrations 24 hours following exposure for the cultures with or without S9 mix. All slides were coded. Where p ossible, 200 metaphases were scored for each dose group. Only those cells showing the modal chromosome number (20) +/- 2 were analyzed for chromosome damage. Chromosome aberrations were classified according to the scheme described by Savage (J Med Genetics 12:103-122, 1976).Evaluation criteria N ot specified. Statistics The mitotic index of each group was assessed by counting the number of metaphases in a total of 1000 cells. Data were assessed for heterogeneity using the Fisher’s exact test. The number of aberrations excluding gaps, aberrations including gaps, isogaps and/or chromatid gaps and p olyploidy and/or endoreduplication of treated cells was compared to controls using the Fisher’s exact test. A Cochran-Armitage trend test was carried out on the dose/response. The test was p erformed twice, once excluding control data and the other including the solvent control. Results and discussions Test results Species/strain Chinese hamster Ovary (CHO) Metabolic activation with and without Test system all strains/cell types tested Genotoxicity negative Cytotoxicity no, but tested up to limit concentrations Vehicle controls valid N egative controls valid Positive controls valid Additional information on results Cells exposed to test material at concentrations up to 5000 micrograms/ml showed no increase in chromosome damage or no linear trend compared to negative controls in either experiment. The positive control induced significantly more cells with aberrations compared to the negative controls (for untreated control and for solvent control). In the first experiment with S-9 (up to 1875 micrograms/ml test material), there was no effect of treatment on the incidence of type of aberration observed. However, there was a significant difference in the number of cells with chromatid gaps and/or isogaps between the untreated control (7/200) and solvent control cultures (1/200). In the second experiment with S-9 (cells were treated with 1500, 3000 or 5000 micrograms/ml test material), there was a significant difference in the number of cells with aberrations including gaps (11/200) and cells with chromatid gaps and/or isogaps (8/200) at the 1500 micrograms/ml compared to the solvent control (2/199 and 0/199, respectively). There also was a significant increase in the number of cells with chromatid gaps and/or isogaps at the high concentration (5/200) compared to control, and between both controls (untreated control had 7/200). N o linear trend was observed either by including or excluding the solvent control from the analysis. The positive control caused increases in aberrations with and without gaps compared to the solvent control in both studies.
The cytotoxic concentration was > 5000 micrograms/ml. Remarks on results including tables and figures
The small random increases in the number of chromatid gaps and/or isogaps in one experiment with S-9, which were not dose-dependent and not different from the untreated controls were not considered to be compound-related effects by study personnel.

Overall remarks, attachments Overall remarksApplicant's summary and conclusion Interpretation of results negative Conclusions Study personnel concluded that under the test conditions, the test material did not induce chromosomal aberrations either in the presence or absence of S9 mix. 7.6.2 Genetic toxicity in vivo Genetic toxicity in vivo.001 UUID IUC5-96adfb9f-af92-454b-a840-6b78eea9c1ae Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 14:16:12 EST Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 90 Reliablility 1 (reliable without restriction) Rationale for reliability Guideline study following GLP with test substance purity noted.

Data source Reference Reference type study report

Author McClintock ML and Gollapudi B. Year 1990 Title Evaluation of triethylene glycol monomethyl ether in the mouse bone marrow micronucleus test. Bibliograph ic source Testing laboratory Report

no. Owner company Dow Chemical Company

Company study no. Study ID TXT:K-005610-007 Report date 1990-03-0 7 Materials and methods Type of study micronucleus assayTest guideline Qualifier according to Guideline EPA OPPTS 870.5200 (Mouse Visible Specific Locus Test) Deviations Principles of method if other than guideline Study reference for protocol used is: Test Standard 40 CFR 798.5395 GLP compliance
yes Test materials Test material equivalent to submission substance identity
yes Test material identity Identifier CAS number Identity 112-35-6

Identifier EC number Identity 203-962-1

Identifier Common name Identity triethylene glycol monomethyl ether Details on test material Purity was 99.23%. Test animals Species

mouse Strain CD-1 Sex male/female Details on test animals and environmental conditions Strain specifically denoted to be CD-1 (ICR)BR. The animals were approximately 8 weeks old. Administration / exposure Route of administration oral: gavage Vehicle(s)
water Details on exposure Test material was dissolved in water and administered to mice (approximately 8 weeks old) by single oral gavage at dose levels of 0 (water), 500, 1667 and 5000 mg/kg body weight (10 ml/kg). A previous study revealed that 5000 mg/kg did not affect survival. Concentrations of test material in dosing solutions were verified by HPLC. Groups of animals(5/sex/dose/sacrifice time) were sacrificed by cervical dislocation 24, 48 and 72 hours after treatment. Mice (5/sex) treated with 120 mg/kg cyclophosphamide and sacrificed after 24 hours of treatment served as p ositive controls. Duration of treatment / exposure Single doseFrequency of treatment Single dose Post exposure period up to 72 hours Doses / concentrations 500, 1667, 5000 mg/kg bw Basis nominal in water N o. of animals per sex per dose 5 animals per sex per dose Control animals yes, concurrent vehicle Positive control(s) Mice (5/sex) treated with 120 mg/kg cyclophosphamide and sacrificed after 24 hours of treatment served as positive controls. Examinations Tissues and cell types examined Bone marrow samples were obtained from both femurs at sacrifice. Cell smears were prepared from cell suspensions. Details of tissue and slide preparation The slides were air dried, fixed in methanol and stained in 5% Giemsa. Slides were coded and scored blindly. One thousand polychromatic erythrocytes (PCE) were evaluated from each surviving animal and the frequencies of micronucleated polychromatic erythrocytes (MN-PCE) were recorded. Micronuclei were identified as darkly stained bodies with sharp contours and varying shapes such as round, almond, or ring. The ratio of PCE- N CE (normochromatic erythrocytes) in the bone marrow was determined by examining 100 erythrocytes. Evaluation criteria The test was valid if positive controls had significantly more MN-PCE than controls (62.2 in males and 34.6 in females). Statistics Statistical Analysis: The raw data on the counts of MN-PCE for each animal were transformed by adding 1 to each count and then taking the natural log of the adjusted number. The transformed MN-PCE data and the data on percent PCE were analyzed by a three-way analysis of variance looking only at main effects. Pairwise comparisons between treated vs. negative controls were done (if necessary) by a t-test usingBonferroni correction for multiple comparisons. Results and discussions Test results Sex male/female Genotoxicity negative Toxicity Vehicle controls valid yes N egative controls valid Positive controls valid yes Additional information on results One female dose with 1667 mg/kg test material died prior to scheduled sacrifice. The cause ofdeath was not determined. There were no significant increases in the frequencies of micronucleated polychromatic erythrocytes (MN-PCE) in groups treated with test material (range from 0.2 to 1.6) versus negative controls (range 0.4 to 1.2). The ratios of polychromatic erythrocytes (PCE) to normochromatic erythrocytes ( N CE) (% PCE) in test animals (67.3 to 82.0) also were similar to those of negative controls (70.6 to 78.7).
The test was valid as positive controls had significantly more MN-PCE than controls (62.2 in males and 34.6 in females). Applicant's summary and conclusion Interpretation of results negative 7.8 Toxicity to reproduction 7.8.1 Toxicity to reproduction Toxicity to reproduction.001 UUID IUC5-8cc5d3b2-1dd1-4d9b-b4f3-db6f453d4482 Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-02-17 21:07:51 EST Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1 9 9 0 Reliablility 2 (reliable with restrictions) Rationale for reliability Effect on mating was not characterized. Otherwise study was robust per current protocol following GLP. Data source Reference Reference type study report Author Corley RA, Ciesslak, Breslin WJ, Lomax LG. Year 1990 Title 13-Week dermal toxicity study in Sprague-Dawley rats. Bibliographic

source Testing laboratory Report no.

Owner company Dow Chemical Company

Company study

no. Study ID K-005610-004 Report date 1990-09-26Reference type p ublication

Author Gill MW, Fowler EH, Gingell R, Lomax LG, Corely RA. Year 1998 Title Subchronic dermal toxicity and oral neurotoxicity of triethylene glycol monomethyl ether in CD rats Bibliograph ic source Int J Toxicol 17:1-22.

Testing laboratory Report

no. Owner company Company study no. Report date Cross-reference to same study The same study is summarized as a 91 day dermal repeat dose study in Sprague-Dawley rats. This is repeated dose toxicity dermal.001 Materials and methods Test type fertility Limit test

no Test guideline Qualifier according to Guideline other guideline: EPA. 1989. 40 CFR 799, Fed Reg 54:13470-13477). Deviations GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 112-35-6

Identifier EC number Identity 203-962-1

Identifier Common name Identity triethylene glycol monomethyl ether Details on test material Purity (as determined by gas chromatography) was 99.23 % at the onset of the study and 99.24% at completion of the in-life phase. Test animals Species
rat StrainSprague-Dawley Sex male/female Details on test animals and environmental conditions 8 week-old rats Administration / exposure Route of administration dermal Vehicle unchanged (no vehicle) Details on exposure Triethylene glycol monomethyl ether (TGME) was administered dermally to 8 week-old rats (10/sex/dose level) at 0 (sham control), 400, 1200 or 400 mg/kg/day for 13 weeks. Test material was applied to shaved areas of skin on the back and sides of each rat (12 cm2 in area), uniformly spread, and covered with a semiocclusive dressing for 6 hours. After removal of the dressing, the application site was wiped with a dampened towel. Material was applied in this manner daily, 5 days/week for 13 weeks. Details on mating procedure N o mating Analytical verification of doses or concentrations
yes Details on analytical verification of doses or concentrations Purity of test substance as administered (as determined by gas chromatography) was 99.23 % at the onset of the study and 99.24% at completion of the in-life phase. Duration of treatment / exposure 91 days Frequency of treatment daily, 6 hr/day, 5 days/week Doses / concentrations 0 (sham control), 400, 1200 or 400 mg/kg/day Basis analytical conc. N o. of animals per sex per dose 10/sex/dose level Control animals yes, sham-exposed Examinations Parental animals: Observations and examinations Upon necropsy the test animals were examined. The oocytes, corpora lutea, and follicles from each ovary were evaluated with regard to their normal development. The testes and epididymes also were examined microscopically for males in the intermediate- and low-dose groups. Postmortem examinations (Parental animals) See Repeated dose dermal study.001 for details Results and discussions Effect levels Endpoint N OAELGeneration P Sex male/female Effect level 4000 mg/kg bw/day (actual dose received) Basis for effect level / Remarks N OAEL for systemic effects on test animals. Conclusion of summary preparer; no adverse systemic effects seen at highest dose.

Endpoint N OAEL Generatio

n P

Sex male/female Effect level >= 400

—< 1200 mg/kg bw/day (actual dose received)

Basis for effect level / Remarks Interpretation of EPA, based on bilaterally decreased spermatogenesis observed in one male treated with the highest dose (4000 mg/kg bw) and testicular changes observed in one male treated with 1200 mg/kg.

Observations: p arental animals Clinical signs ( p arental animals)
yes Body weight and food consumption ( p arental animals)
yes Reproductive function: estrous cycle ( p arental animals)
yes Reproductive function: sperm measures ( p arental animals)
yes Reproductive performance ( p arental animals) not examined Organ weights ( p arental animals)
yes Gross pathology ( p arental animals)
yes Histopathology ( p arental animals)
yes Details on results ( p arental animals) There were no indications of systemic toxicity at any dose. Mean body weight and food consumption were comparable to controls throughout the study. Bilaterally decreased spermatogenesis in seminiferous tubules and decreased spermatozoa in the epididymes (both were graded as severe) were noted in the testes of one high dose male rat. This animal had a complete lack of mature spermatids in greater than 41% of tubules in each testicle, few spermatids beyond stage 12 of development in the seminiferous epithelium, and decreased spermatic elements in the head and tail of greater than 41% of the tubules and ducts in the epididymides. The testes of one male treated with 1200 mg/kg exhibited different testicular changes [bilateral multifocal degeneration of spermatocytes and spermatids from germinal epithelium (graded as very slight), and multinucleated spermatids]. In this rat, all stages of the cycle of the seminiferous epithelium were observed in morphologically normal tubules. Theepididymides of this rat had decreased spermatic elements in the head and tail of 1-5% of ducts. Some of the ducts also contained immature spermatids. There were no effects on estrous cyclicity or ovaries of females. Observations: offspring Remarks on results including tables and figures

Study personnel concluded that the bilateral microscopic testicular changes observed in one high-dose and one mid-dose male rat were unrelated to treatment. Reasons given were that the dissimilarity of the lesions for the two animals suggested that they occurred spontaneously, and the incidence of animals with lesions (1/10 in each group) was well within that of historical controls (0-17%). Study personnel also stated that the degenerative changes in the testes of one mid-dose and one high-dose rat were not consistent with the types of lesions that have been attributed to 2-methoxyethanol (2-ME). The cell types that are most vulnerable to 2-ME are the pachytene spermatocytes and round spermatids (Chapin et al., Fund Appl. Toxicol 5:182-189, 1985). As the dose of 2-ME is increased, the number and types of cells affected increase up to the point that the germinal epithelium is significantly degenerated and all stages of spermatogenesis are affected (Chapin et al., Fund Appl. Toxicol 5:182-189, 1985; Miller et al., Fund Appl Toxicol 3:49-54, 1983.). In contrast, the testicular effects seen with the high dose animal treated with TGME consisted of a virtually complete lack of mature spermatids beyond stage 12. All other stages, including spermatogonia and spermatocytes, were present and appeared morphologically normal. In the mid-dose rat, the only effects noted consisted of very slight degeneration of spermatocytes and spermatids similar to those seen in historical control animals.

Study personnel also stated that the lymphoid tissues and hematologic parameters, which have been reported to be affected at doses of 2-methoxyethanol that have been associated with testicular changes (Miller et al., Fund. Appl. Toxicol. 3:49-54, 1983) were unaffected in this TGME study. Taking all factors into consideration, the testicular lesions observed in this dermal study could not be directly attributed to TGME exposure.

Overall remarks, attachments Overall remarks

Additional details for this study can be found in the Repeated dose dermal study.001 summary.

The EPA has determined that based on severe testicular toxicity in 1/10 rats given 4000 mg/kg/day and minimal decreases in developing germ cells (1-5% of semiferous tubules affected) in 1/10 rats given 1,200 mg/kg/day, the NOAEL for testicular toxicity is between 400 and 1200 mg/kg/day (Anderson, L. Triethylene glycol monomethyl, monoethyl and monobutyl ethers RM1 screening document (draft), Feb. 24, 1995). This value was reached even though it was recognized that the testicular changes in the 1,200 mg/kg/day rat were within historical control limits for Sprague-Dawley rats (0 1 7 %).
Toxicity to reproduction.002 UUID IUC5-276c6a8f-4917-473b-93d3-cef7c9bc2e2f Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 14:20:24 EST RemarksAdministrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1985

Reliablility 2 (reliable with restrictions) Rationale for reliability Well conducted, robust study with test substance well characterized as to composition. Study conducted following GLP. N o guideline specified Data source Reference Reference type study report

Author Year 1985 Title N ine-day and ninety-day dermal toxicity studies of CARBOWAX MPEG-350 in rabbits. Bibliographi

c source Testing laboratory Bushy Run Research Center Report

no. Owner company Union Carbide

Company study no. Report date 1985-05-3 0

Reference type Author Hermansky SJ, Leung HW. Year 1997 Title Cutaneous toxicity studies with methoxy polyethylene glycol-350 (MPEG-350) in rats and rabbits. Bibliograph ic source Testing laboratory Report

no. Owner company Company study no. Report date Cross-reference to same study This study is also summarized as a 90 day repeated dose dermal study. See repeated dose toxicity dermal.002 for further details. Materials and methods Test type fertility Limit testno Principles of method if other than guideline N o guideline specified, but study was conducted following standard procedures and principles. GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 9004-74-4

Identifier Common name Identity CARBOWAX MPEG 350 Details on test material The test material (CARBOWAX MPEG 350, CAS No. 9004-74-4) wasreported to be chemically inert (stable for > 6 months at room temperature) and 99.8% p ure. This material is a mixture of several methylated glycol ethers of differing molecular weight (ranging from diethylene glycol monomethyl ether (C2) to heptadecaethylene glycol monomethyl ether (C17)). The majority of the material is in the C5-C11 range (87.445%). It contains 4.347 % (by weight) tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 1.303% triethylene glycol monomethyl ether (CAS No. 112-35-6), 0.181% diethylene glycol monomethyl ether (CAS No. 111-77-3). Test animals Species rabbit Strain N ew Zealand White Sex male/female Details on test animals and environmental conditions Body weights of males and females ranged from 2.5 to 3.2 kg and 2.5 to 3.1 kg at study initiation. Administration / exposure Route of administration dermal Vehicle other: methyl cellulose in distilled water Details on exposure Dosing: N ew Zealand white rabbits (10/sex/dose) were treated dermally on clipped dorsal skin with 1.0 ml of vehicle (0.1% (w/v) methyl cellulose in distilled water), 50% CARBOWAX MPEG-350 (w/v dilution in 0.1% methyl cellulose in water) or 100% CARBOWAX MPEG-350, for six hours/day, five days per week for 90 days. Rabbits were fitted with Elizabethan collars after dosing to prevent ingestion of test material. After each 6-hour exposure the application site was wiped with a paper towel dampened with water and then dried using a towel. Rabbits were then uncollared until the next treatment.Analytical verification of doses or concentrations no data Duration of treatment / exposure 90 days Frequency of treatment daily, six hours/day, five days per week Doses / concentrations 1 ml of 50% and 100% material (approximately 169 and 338 mg/kg/day) Basis nominal conc. N o. of animals per sex per dose 10/sex/dose Control animals yes, concurrent vehicle Further details on study design A preliminary range-finding study in 15 rabbits dosed 6 hr/day for 9 days showed that daily administration of 1 ml of 50% or 100% test material only caused mild skin irritation. Therefore, these doses were chosen for the90-day study.
Based on weights of animals determined at weekly intervals and the reported density of test material (1.09 g/ml) doses can be calculated on average mg/kg/day basis. These doses are 169 mg/kg/day (for 50%) and 338 mg/kg/day (for 100%). Examinations Parental animals: Observations and examinations Observations: All rabbits were observed daily (weekdays) for death, clinical signs and dermal irritation. Body weights were recorded on the morning of the first day of dosing, weekly thereafter and prior to sacrifice. Food consumption was measured weekly. Urine was collected from 5 animals/sex/group during the last two weeks of dosing and subjected to standard analyses. Standard hematology and clinical chemistry parameters were evaluated for all animals j ust prior to sacrifice. Estrous cyclicity (Parental animals) no data Sperm parameters (Parental animals) no data Postmortem examinations (Parental animals) N ecropsy: All animals were sacrificed and necropsied after 13 weeks of treatment. Weights were recorded for liver, kidneys, brain and adrenals of all animals and testes of males. Histopathologic examinations were performed on tissues (including testes, epididymes, p rostate, accessorysex glands, uterus, ovaries and mammary gland) from high-dose and control animals. Results and discussions Effect levels Endpoint N OAEL Generation P

Sex male/female Effect level 338 mg/kg bw/day (nominal)Basis for effect level / Remarks The NOAEL listed is for reproductive organ toxicity. The NOAEL for systemic effects was not listed by the investigators. Based on the data, this value is 100% (338 mg/kg/day). Observations: p arental animals Clinical signs ( p arental animals)
yes Body weight and food consumption ( p arental animals)
yes Test substance intake ( p arental animals)
yes Reproductive function: estrous cycle ( p arental animals) no data Reproductive function: sperm measures ( p arental animals)
yes Organ weights ( p arental animals)
yes Gross pathology ( p arental animals)
yes Histopathology ( p arental animals)
yes Details on results ( p arental animals) N o effects on any test animal sex organ were observed Observations: offspring Remarks on results including tables and figures

The NOAEL listed is for reproductive organ toxicity. Further details of this study can be found in the summary for repeated dose toxicity dermal.002. The NOAEL for systemic effects was not listed by the investigators. Based on the data, this value is 100% (338 mg/kg/day).
Toxicity to reproduction.003 UUID IUC5-24f457bd-0cd8-42e3-ae5f-c4397b1732b1 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 14:22:10 EST Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 90

Reliablility 2 (reliable with restrictions)Rationale for reliability Well conducted, robust study, following GLP, but the effect on mating was not characterized. Data source Reference Reference type Author Gill MW and Negley JE. Year 1990 Title Triethylene glycol monomethyl ether. N inety day subchronic drinking water inclusion neurotoxicity study in rats. Bibliograp hic source Testing laboratory Bushy Run Research Center Report

no. Owner company Union Carbide

Company study no. Project Report 52-607, Report date 1990-09- 21 Cross-reference to same study This study is also summarized as a repeated dose study in Repeated dose study oral.001 Materials and methods Test type fertility Limit test

no Principles of method if other than guideline The route of administration and maximum dose level was specified in a testing consent order (EPA. 1989. 40 CFR 799, Fed Reg 54:13470-13477). GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 112-35-6

Identifier EC number Identity 203-962-1

Identifier Common name Identity triethylene glycol monomethyl ether Details on test material The purity was at least 98.7%. Test animals Species
ratStrain Sprague-Dawley Sex male/female Details on test animals and environmental conditions no data Administration / exposure Route of administration oral: drinking water Vehicle unchanged (no vehicle) Details on exposure Rats were treated with triethylene glycol monomethyl ether (TGME) for 91 days via drinking water at target doses of 0, 400, 1200 and 4000 mg/kg/day. Details on mating procedure Study did not include mating. Study examined male reproductive organs. Analytical verification of doses or concentrations no data Duration of treatment / exposure 91 days Frequency of treatment daily Doses / concentrations 0, 400, 1200 and 4000 mg/kg/day. Basis nominal in water N o. of animals per sex per dose 15/sex/group Control animals other: concurrent water Positive control no data Examinations Parental animals: Observations and examinations Rats were observed daily for clinical signs and weekly for body weight and water and food consumption. Rats were also observed periodically for behavior (functional observational battery) and motor activity. Estrous cyclicity (Parental animals) no data Sperm parameters (Parental animals) Yes, see results section. Litter observations

no Postmortem examinations (Parental animals) Gross lesions and organ weights were recorded at necropsy. Microscopic analyses of liver, testes and the nervous system also were performed.Postmortem examinations (Offspring)

no Statistics no data Reproductive indices no data Offspring viability indices no data Any other information on materials and methods incl. tables

The authors state that a possible contributing factor in the development of testicular lesions at the high dose was low-level contamination of the test substance with the known testicular toxicant 2-methoxyethanol (EGME). EGME was present in the test substance at a concentration of 0.02  0.04 %, resulting in a EGME dose up to 1.7 mg/kg/day for animals in the high dose group. Given the length of the study, it is possible that EGME contributed to the testicular lesions. A comparison between the doses of EGME and TGME required to produce testicular toxicity indicated that TGME is 350 times less potent than EGME in producing testicular lesions in the rat. The dose of TGME that caused testicular toxicity (4000 mg/kg/day) is 4 times greater than the 1000 mg/kg/day limit dose generally recommended for subchronic studies.

Results and discussions Effect levels Endpoint N OAEL Generation P Sex male/female Effect level 1200 mg/kg bw/day (nominal) Basis for effect level / Remarks Interpretation by summary preparer for reproduction organ toxicity.

Endpoint N OAEL Generation P Sex male/female Effect level > 400

—< 1200 mg/kg bw/day (nominal) Basis for effect level / Remarks Interpretation by the Environmental Protection Agency for testicular effects. Observations: p arental animals Clinical signs ( p arental animals)
yes Body weight and food consumption ( p arental animals)
yes Test substance intake ( p arental animals)
yes Reproductive function: estrous cycle ( p arental animals) no data Reproductive function: sperm measures ( p arental animals)
yes Reproductive performance ( p arental animals)no data Organ weights ( p arental animals)
yes Gross pathology ( p arental animals)
yes Histopathology ( p arental animals)
yes Details on results ( p arental animals) The testes of males in the high dose group exhibited degeneration (12/15) and/or atrophy (5/5) of the seminiferous tubules (spermatocytes or developing spermatids). The authors concluded that these effects were related to treatment. The severity of the lesions was primarily mild to moderate for degeneration (11/12) and minimal to moderate for atrophy (5/5), indicating that not all tubules were affected and that a limited number of cells was affected within the affected tubules. One male treated with 1200 mg/kg had severe seminiferous tubule atrophy, a complete loss of cell types in the tubules (except for Sertoli cells) and moderate Leydig cell hypertrophy (not significant from control). This was not considered to be related to treatment because of the lack of a plausible explanation for the unusual dose-response relationship (the effect at this dose was more severe than that of a higher dose) and the low incidence of animals affected at this dose level (Gill et al., Int J Toxicol 17:1-22, 1998) One male treated with 1200 mg/kg had severe seminiferous tubule atrophy and moderate Leydig cell hypertrophy (not significant from control). N o testicular changes were noted in males treated with 400 mg/kg/day TGME. Observations: offspring Viability (offspring) not examined Clinical signs (offspring) not examined Body weight (offspring) not examined Sexual maturation (offspring) not examined Organ weights (offspring) not examined Gross pathology (offspring) not examined Histopathology (offspring) not examined Details on results (offspring) 91 Day repeated dose study did not include mating, but examined male testes. Remarks on results including tables and figures

The NOAEL listed is for reproductive organ toxicity. Other results are shown in section 5.4. The summary preparer-assigned NOAEL and LOAEL for testicular effects is 1200 and 4000 mg/kg/day, respectively. By contrast, the EPA has determined that the NOAEL for testicular effects is between 400 and 1200 mg/kg/day (Anderson, L. Triethylene glycol monomethyl, monoethyl and monobutyl ethers RM1 screening document (draft), Feb. 24, 1995).
7.8.2 Developmental toxicity / teratogenicityDevelopmental toxicity / teratogenicity Leber TGBE 1990.001 UUID IUC5-82fde93b-9ed8-454d-9884-2393680f4a38 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 14:25:07 EST Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 86 Reliablility 1 (reliable without restriction) Rationale for reliability Established protocol followed with GLP.

Data source Reference

Referenc e type p ublication

Author Leber A.P. et al. Year 1990

Title Triethylene glycol ethers. Evaluation of in vitro absorption through human epidermis, 21-dermal toxicity in rabbits and a developmental toxicity screen in rats. Bibliogra p hic

source J Am Coll Toxicol 9:507-515, 1990.

Testing laborator
y Repo
rt no.

Owner company
Compan

y study

no. Repo
rt date

Reference type study report

Author Wason SM, Hodge MCE Year 1986 Title Triethylene glycol ethers: An evaluation of teratogenic potential and developmental toxicity using an in vivo screen in rats. Bibliograp hic sourceTesting laboratory Repor
t no. CTL/P/ 1584

Owner company Imperial Chemical Industries PLC.

Company study no. Repor t date Materials and methods Limit test

no Test guideline

Qualifier according to Guideline other guideline: modified Chernoff-Kavlok assay (Schuler RL et al. Environ Health Persp 57:141-146, 1984) Deviations

GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 143-22-6

Identifier EC number Identity 205-592-6

Identifier Common name Identity triethylene glycol monobutyl ether Details on test material Purity was 96.91% according to manufacturer (Olin Corporation). Test animals Species
rat Strain other: other:Alpk:AP (Wistar) Details on test animals and environmental conditions approximately 11-13 weeks of age Administration / exposure Route of administration oral: gavage Vehicle unchanged (no vehicle) Analytical verification of doses or concentrationsno data Duration of treatment / exposure days 7-16 of gestation Frequency of treatment daily Duration of test until Day 5 of parturition Doses / concentrations deionized water, 250 mg/kg triethylene glycol monobutyl ether (TGBE), 1000 mg/kg TGBE, 50 mg/kg ethylene glycol monomethyl ether (EGME), or 250 mg/kg EGME. Basis nominal conc. N o. of animals per sex per dose N ot stated. Control animals other: both negative (water) and positive (50 and 250 mg/kg ethylene glycol monomethyl ether) Further details on study design Female rats were mated with males of the same strain when they were approximately 11-13 weeks of age. The first day spermatozoa were detected in vaginal smears was counted as Day 1 of gestation. Ten gestating animals per group were dosed with deionized water, 250 mg/kg triethylene glycol monobutyl ether (TGBE), 1000 mg/kg TGBE, 50 mg/kg ethylene glycol monomethyl ether (EGME), or 250 mg/kg EGME. Dose levels of TGBE were selected based on the results of a previous range finding study. EGME was administered at levels known to p roduce toxicity in the assay. All animals were dosed by gavage from Days 7-16 (inclusive) of gestation with 1 ml of dosing solution per 100 g body weight using a 5ml glass syringe and stainless steel (16 gauge cannula). Dosing solutions were prepared immediately prior to dosing and stored in a refrigerator until use. The volume given to each animal was adjusted daily according to body weight. Examinations Maternal examinations Rats were observed each day for clinical condition and signs of illness. Body weights were recorded on Days 1, 7 through 17, 19, and 22 of gestation and on Day 5 p ost partum.
Maternal body weight gains were measured during treatment and pregnancy. Ovaries and uterine content The uteri of females which failed to litter were grossly examined for implantation sites on or shortly after Day 25 of gestation to ascertain if the animals had been pregnant. Fetal examinations Litters were weighed and sexed on Days 1 (within 24 hours of birth) and 5 p ost partum. Dead p ups were not weighed. Mortality on Day 1 and Day 5 p ost partum was recorded.
Animals which littered and their offspring were killed and discarded without postmortem examination after Day 5 p ost partum. Statistics Litters produced/number pregnant, number of viable litters on Days 1 and 5, total number of live pups/litter, total number of dead pups/litter, mean total litter size (live and dead pups), survival percentage, number of dead pups per group, mean pup weight (Days 1 and 5), meanp up weight gain and mean % weight gain/litter datafrom treated and control animals were compared using the Student's t-test. All comparisons were two-tailed. Results and discussions Effect levels Endpoint N OAEL Effect type maternal toxicity Effect level 1000 mg/kg bw/day (nominal) Basis for effect level / Remarks Data are for trieth;ylene glycol butyl ether

Endpoint N OAEL Effect type teratogenicity Effect level 1000 mg/kg bw/day (nominal) Basis for effect level / Remarks Data are for trieth;ylene glycol butyl ether

Details on maternal toxic effects Maternal Data: Dams dosed with either dose of TGBE appeared normal throughout the study and gained a similar amount of weight as negative controls. Administration of 50 or 250 mg/kg EGME was associated with piloerection. Four animals in the 250 mg/kg EGME group had slight vaginal bleeding between Days 17 and 19 of gestation. Details on embryotoxic / teratogenic effects Litter Data: The pregnancy rate was high with 9/10 p regnancies in the negative control group, and 10/10 p regnancies in the groups dosed with TGBE. N o litters were produced in either EGME group (although implantation sites were present in all animals). There were no effects on any litter parameter measured in rats treated with either dose of TGBE. Remarks on results including tables and figures

At the dose levels tested (250 or 1000 mg/kg/day), TGBE was not embryotoxic or teratogenic (in contrast to EGME).

Triethylene glycol monomethyl ether and triethylene glycol monoethyl ether also were not teratogenic at 1000 mg/kg. The EPA also concluded that there were no remarkable treatment-related effects in this study (Anderson, L. Triethylene glycol monomethyl, monoethyl and monobutyl ethers RM1 screening document (draft), Feb. 24, 1995). The NOAEL listed under teratogenicity is the NOAEL for developmental toxicity.
Developmental toxicity / teratogenicity.002 UUID IUC5-c5b9b170-73a7-4c97-a270-8e2bf1b8ab45 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 14:29:11 EST RemarksAdministrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 90 Reliablility 1 (reliable without restriction) Rationale for reliability Robust study following GLP and standard protocol.

Data source Reference Reference type study report

Author Hoberman AM. Year 1990 Title Triethylene glycol monomethyl ether (TGME): oral developmental toxicity study in Crl:CD(SD)BR pregnant rats. Bibliograp hic source Testing laboratory Argus Research Laboratories, Inc. Report

no. StudyNumber 503-005. Owner company Company study no. Report date Materials and methods Limit test

no GLP compliance

no Test materials Test material equivalent to submission substance identity
yes Test material identity Identifier CAS number Identity 112-35-6

Identifier EC number Identity 203-962-1

Identifier Common name Identity triethylene glycol methyl ether Details on test material no details Test animals Species
rat StrainSprague-Dawley Details on test animals and environmental conditions 203 to 256 g Administration / exposure Route of administration oral: gavage Vehicle unchanged (no vehicle) Details on exposure Groups of 25 mated female rats (203 to 256 g) were given daily dosages of 4.8 ml of deionized water (control), or 0.6, 1.2, 2.4, and 4.8 ml/kg/day of triethylene glycol monomethyl ether (TGME) by gavage. These doses corresponded to 0, 625, 1250, 2500 or 5000 mg/kg/day. All doses were adjusted daily according to body weights recorded immediately prior to intubation. Analytical verification of doses or concentrations no data Duration of treatment / exposure Days 6 to 15 of gestation Frequency of treatment daily Duration of test 15 days Doses / concentrations 0, 625, 1250, 2500 or 5000 mg/kg/day Basis nominal conc. N o. of animals per sex per dose 25 females per dose Control animals yes, concurrent vehicle
yes, sham-exposed Examinations Maternal examinations Rats were observed at least twice daily during the dosage and postdosage periods for clinical signs, signs of resorption, p remature deliveries and death. Body weight and feed consumption were recorded on Day 0 of presumed gestation and from days 6 through 20 of gestation. Dams that were found dead were necropsied on day of death and subjected to the same procedures described for scheduled sacrifice. Ovaries and uterine content Rats were sacrificed on Day 20 of presumed gestation, and the thoracic and abdominal viscera were examined for gross lesions. The uterus was excised from each rat and weighed. The number and placement of implantations were recorded and sites were categorized as early or late resorptions, or live or dead fetuses. Each ovary was examined for the number of corpora lutea. Fetal examinations Fetuses were weighed, sexed, and examined for external alterations. One-half were examined for soft tissue alterations, and the remaining half were examined for skeletal alterations.Statistics Maternal and fetal incidence data were analyzed suing the variance test for homogeneity of the binomial distribution. Maternal body weight and feed consumption data, organ weight data, and litter averages for percent male fetuses, p ercent dead or resorbed conceptuses per litter, fetal body weights, fetal ossification sites, and percent fetal alterations were analyzed using Bartlett's Test of homogeneity of variances and the analysis of variance (when data were homogeneous). If the analysis of variance was significant, Dunnett's Test was used to identify the statistical significance of individual groups. If data were not homogeneous, the Kruskal-Wallis test was used when less than or equal to 75% ties were present; when more than 75% ties were present the Fisher's Exact Test was used. In cases where the Kruskal-Wallis Test was statistically significant, Dunn's Method of Multiple Comparisons was used to identify the statistical significance of individual groups.
All other Caesarean-sectioning data were evaluated using the procedures previously described for the Kruskal-Wallis Test. Results and discussions Effect levels Endpoint N OAEL Effect type maternal toxicity Effect level 1250 mg/kg bw/day (nominal) Basis for effect level / Remarks Reduced food consumption was observed at the next higher dose (2500 mg/kg bw).
Endpoint N OAEL Effect type teratogenicity

Effect level 625 mg/kg bw/day (nominal)

Basis for effect level / Remarks Groups given 1250 mg/kg/day and higher doses of TGME had significant increases in the litter and/or fetal incidences of reversible delays in fetal ossification.

Maternal toxic effects
yes Details on maternal toxic effects One nonpregnant animal in the high dose group (5000 mg/kg/day) was found dead on day 13 of p resumed gestation. This was considered by the authors to be treatment-related. Significant numbers of rats treated with the high dose exhibited decreased motor activity, excess salivation, ataxia, and impaired righting reflex. Food consumption of high dose animals were reduced over the entire dosage period. Average maternal body weight gains of rats in the high dose group were reduced on days 6-9, 6-12, 12-16, and 6-16 of gestation. Consequently, average body weights of these animals were reduced on days 9, 12, and 16. Average gravid uterine weights of high-dose animals were also reduced.
Food consumption of rats receiving 2500 mg/kg/day was reduced during days 6-16, 6-18, and 12-16. Food consumption and average maternal body weights and body weight gains in rats receiving 1250 mg/kg/day were not significantly different from controls. Therefore, 1250mg/kg/day was considered by study personnel to be the NOAEL for maternal toxicity.
There was no effect of TGME on the number of pregnant dams or number of copora lutea, implantations, live litter size or fetal sex ratios. Embryotoxic / teratogenic effects
yes Details on embryotoxic / teratogenic effects Fetal: Significant increases in embryo-fetal lethality (litter averages for total resorptions (1.6 versus 0.6 in control), late resorptions (0.3 versus 0 in controls), p ercentage of resorbed conceptuses (12.0 versus 4.4 incontrol) and dams with at least one resorption (81.8% versus 47.8 in control) occurred in the 5000 mg/kg group. Fetuses from rats treated with 2500 or 5000 mg/kg had lower body weights than controls (3.04 and 2.56 g (respectively) versus 3.32 in controls).
There was no effect of TGME on the incidences or types of gross external or internal soft tissue malformations. Groups given 1250 mg/kg/day and higher doses of TGME had significant increases in the litter and/or fetal incidences of reversible delays in fetal ossification. Fetuses from rats given 2500 or 5000 mg/kg/day also had a significant increase in the incidence of cervical ribs. The NOAEL for developmental toxicity was considered by study personnel to be 625 mg/kg/day. Remarks on results including tables and figures

The authors remarked that the skeletal variations noted were common observations in fetuses with reduced body weights. Since only reversible delays in fetal ossification were observed in the 1250 mg/kg/day group, the actual NOAEL may be close to this concentration. The NOAEL listed under teratogenicity is the NOAEL for developmental toxicity.
Developmental toxicity / teratogenicity.003 UUID IUC5-94891cda-5cf6-4094-add8-da47f26c92d4 Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 14:32:11 EST Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 19 90 Reliablility 1 (reliable without restriction) Rationale for reliability Robust study following GLP and standard methodology

Data source ReferenceReference type study report

Author Hoberman AM. Year 1990 Title Triethylene glycol monomethyl ether (TGME): oral developmental toxicity study in New Zealand White rabbits. Bibliograp hic source Testing laboratory Argus Research Laboratories, Inc. Report

no. 503-004

. Owner company Company study no. Report date Materials and methods Limit test

no Principles of method if other than guideline Study followed standard methodology GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 112-35-6

Identifier EC number Identity 203-962-1

Identifier Common name Identity Triethylene glycol methyl ether (TGME) Details on test material no details Test animals Species rabbit Strain N ew Zealand White Details on test animals and environmental conditions no data Administration / exposure Route of administration oral: gavage Details on exposure Groups of 20 artificially inseminated female rabbits were given daily dosages of 0 (samevolume of deionized water as the highest dose), 250, 500, 1000 or 1500 mg/kg/day of triethylene glycol monomethyl ether (TGME) by gavage. All doses were adjusted daily according to body weights recorded immediately prior to intubation. Analytical verification of doses or concentrations no data Details on analytical verification of doses or concentrations no data Details on mating procedure artificial insemination Duration of treatment / exposure days 6 to 18 of gestation Frequency of treatment daily Duration of test 24 days Doses / concentrations 0, 250, 500, 1000 or 1500 mg/kg/day Basis nominal conc. N o. of animals per sex per dose 20 artificially inseminated female rabbits Control animals yes, concurrent vehicle Examinations Maternal examinations Rabbits were observed daily during the course of the study for clinical signs, abortions, p remature deliveries and death. Body weights were recorded on Day 0, and Days 6 through 29 of presumed gestation. Food consumption was recorded daily. Ovaries and uterine content Rabbits were sacrificed on Day 29 of presumed gestation, and the thoracic and abdominal viscera were examined for gross lesions. The uterus was excised from each animal and weighed. The number and placement of implantations were recorded and sites were categorized as early or late resorptions, or live or dead fetuses. Each ovary was examined for the number of corpora lutea. Fetal examinations Fetuses were weighed, sexed, and examined for external and soft tissue or skeletal alterations. Statistics no data Results and discussions Effect levels Endpoint N OAEL Effect type maternal toxicity Effect level 500 mg/kg bw/day (nominal) Basis for effect level / Remarks Mortallity and maternal toxicity was observed for dose groups above 500 mg/kg bw, but effects and mortality did not occur at 500 mg/kg bw.En dpo int N OAEL

Eff
ect typ

e teratogenicity

Eff
ect lev el 1000 mg/kg bw/day (nominal)

Bas is for eff
ect lev el / Re

ma rks The authors concluded that the NOAEL for fetal toxicity was 1500 mg/kg/day because the skeletal abnormalities observed at this dose were not unique. However, in a similar study p erformed by the same laboratory in rats (see previous record), common skeletal abnormalities were considered to be adverse. On this basis, the NOAEL for developmental toxicity in rabbits should be the dose that did not produce an increase in any skeletal abnormalities (1000 mg/kg/day). The NOAEL listed under teratogenicity is the NOAEL for developmental toxicity.

Maternal toxic effects
yes Details on maternal toxic effects Maternal: Eight rabbits treated with the 1500 mg/kg/day dose died, and three aborted. A significant number of rabbits treated with this dose exhibited decreased motor activity, labored breathing, a red substance in the cage pan, dehydration, no feces, ataxia, gastric ulceration,anogenital staining, mottled gallbladders, thin-walled stomach, reddened stomach, and fluid-filled or empty small intestines, and lower average gravid uterine weight. There was one death in the 1000 mg/kg/day group. This was considered to be possibly related to treatment. One rabbit in the low dose group aborted. Study personnel did not consider this to be related to test material because it was not dose-dependent.
There was no effect of treatment on the number of pregnant rabbits, average number of corpora lutea, implantations, live fetuses, resorptions, or fetal sex ratios.
Rabbits treated with all doses except 250 mg/kg/day gained more weight during the postdosage p eriod than controls, reflecting increased food consumption during this period. Study personnel did not consider this weight gain to be an adverse effect, as it is commonly seen in developmental studies after dosing is terminated. Details on embryotoxic / teratogenic effects Fetal: There was no effect of treatment on fetal body weight, or incidences or types of gross external or internal soft tissue malformations. The fetal and/or litter incidences of angulated hyoid alae and reversible delays in ossification of the xiphoid were increased in the 1500 mg/kg/day group. Developmental toxicity / teratogenicity.004UUID IUC5-579f4ed8-027a-4ce4-ad1e-8db85368274d Dossier UUID 0

Author RodB / Boatman Toxicology Consulting LLC / Spencerport / United States of America Date 2009-02-12 14:46:18 EST Remarks

Administrative Data Purpose flag key study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1 9 9 2 Reliablility 1 (reliable without restriction) Rationale for reliability Robust study following standard procedure and following GLP. Purity of test substance was provided. Data source Reference Referen ce type Author Bates HK and de Serres FJ. Yea

r 1992

Title Developmental neurotoxicity evaluation of triethylene glycol monomethyl ether (CAS 112-35-6) administered by gavage to time-mated CD rats on gestational day 6 through p ostnatal day 21. Bibliogr aphic

source CMA Reference Ge-43.0-DEV/ N EU-RTI

Testing laborato ry Rep
ort

no. Owner compan y Compan y study

no. Rep
ort date 1992- 03-03

Materials and methods Limit test

no GLP compliance
yesTest materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 112-35-6

Identifier EC number Identity 203-962-1

Identifier Common name Identity triethylene glycol methyl ether Details on test material The analyzed chemical purity was 99.2%. Test animals Species
rat Strain Sprague-Dawley Details on test animals and environmental conditions Timed pregnant CD" (Sprague-Dawley) rats, 64 sperm plug- p ositive females per group Administration / exposure Route of administration oral: gavage Vehicle unchanged (no vehicle) Details on exposure Timed pregnant CD" (Sprague-Dawley) rats, 64 sperm plug- p ositive females per group, were gavaged with the neat test material, triethylene glycol monomethyl ether (TGME), once daily, on gestational day (GD) 6 through postnatal day (PND) 21 at doses of 0, 300, 1650 or 3000 mg/kg/day. The volume of TGME administered was adjusted based on each animal's most recent body weight. Analytical verification of doses or concentrations no data Details on analytical verification of doses or concentrations no data Details on mating procedure no details other than the females were plug- p ositive females per group Duration of treatment / exposure day 6 of gestation through postnatal Day 21 Frequency of treatment daily Duration of test 38 days Doses / concentrations 300, 1650, 3000Basis nominal conc. N o. of animals per sex per dose 64 p regnant females per dose. Control animals yes, concurrent vehicle Examinations Maternal examinations Clinical observations were made at least twice daily during the dosing period and daily otherwise. Maternal body weights were measured on GD 0, 6, 9, 12, 15, 18, 20, and on PND 0, 4, 7, 13, 17, and 21. Food consumption was measured for the intervals GD 0-6, 6-9, 9-12, 12-15, 15-18, 18-20, and PND 0-3, 3-6, 6-9, and 9-12. Maternal animals were allowed to deliver and rear their young.
On PND 22 the dams were evaluated for body weight, liver and kidney weight and the number of uterine implants (metrial glands). Fetal examinations Pups were counted, examined externally, weighed, and sexed on PND 0 and PND 4. After examination on PND 4, litter size was standardized by random culling to either a 4:4 or 5:3 sex ratio. Litters with insufficient numbers of pups were removed from the study after culling. Litters with sufficient numbers of pups remained on study, and pups wereexamined and weighed on PNDs 7, 13, 17, 21,35, 49, and 68. Male pups were examined daily starting at PND 17 for testicular descent, and females were examined daily starting on PND 30 for vaginal opening. One male and one female pup from each litter were assigned to each of three behavioral tests. Motor activity was assessed for one hour in a Figure-8 maze on PNDs 13, 17, 21, 47, and 58. Auditory startle response was assessed on PNDs 22 and 60, and learning and memory were assessed with an active avoidance paradigm run on PNDs 60-64. Three euthanizations occurred during the course of this study. The first took place after culling and involved those dams that had failed to deliver as well as the dams and pups from litters of insufficient size or sex ratio. The second took place on PND 22 and the third on PND 68.
On PND 22 and PND 68 one male and one female pup from each litter were weighed and killed. A total of 24 of these pups were perfused in situ at each euthanization (PND 22 and PND 68 i.e., 48 animals total) and were examined for histopathologic lesions of the central and p eripheral nervous system. The brains of the remaining animals at each sacrifice were removed and separated into the telencephalon, diencephalon, medulla oblongata/ p ons, and the cerebellum. These sections were all weighed separately. Statistics Data were analyzed using the FREQ, GLM, N PA R 1WAY and LIFETEST procedures in the SAS software package, in conjunction with a set of custom-designed analysis procedures. Results and discussions Effect levels En dpo int N OAEL

Eff
ect maternal toxicitytyp

e Eff
ect lev el 1650 mg/kg bw/day (nominal)

Bas is for eff
ect lev el / Re

ma rks Conclusion of summary preparer, EPA. The authors stated that “TGME administered by gavage to pregnant and lactating CD" (Sprague- Dawley) rats resulted in no overt signs of maternal toxicity”. However, they also stated that the increased kidney weights in the high dose animals occurred as a result of exposure to TGME. Based on this comment, a maternal NOAEL of 1650 was assigned by the summary preparer. This is in agreement with the maternal NOAEL derived by the EPA (Anderson, L. Triethylene glycol monomethyl, monoethyl and monobutyl ethers RM1 screening document (draft), Feb. 24, 1995).

Endpoi
nt N OAEL

Effect type teratogenicity

Effect level 300 mg/kg bw/day (nominal)

Basis for effect level / Remar ks Conclusion of summary preparer, EPA. The authors arrived at a no observable effect level ( N OEL) of “equal to or greater than 300 mg/kg/day” based on decreased postnatal weight gains at 1650 and 3000 mg/kg/day. The reviewer does not believe that a N OAEL can be assigned from this study due to the unclear significance of minor reductions in body weight gains of animals at various time points and changes in startle response at 1650 and 3000 mg/kg. A NOAEL for teratogenicity of 300 mg/kg/day has been derived by the EPA (Anderson, L. Triethylene glycol monomethyl, monoethyl and monobutyl ethers RM1 screening document (draft), Feb. 24, 1995). The NOAEL listed under teratogenicity is the NO(A)EL for developmental toxicity. Maternal toxic effects
yes Details on maternal toxic effects Of the 256 mated animals assigned to this study 33, 27, 28, and 31 litters in the control to high-dose group, respectively, had sufficient pups of both sexes to be used for the behavioral evaluations. Evaluation of data from the maternal animals revealed no dose- related patterns of clinical signs of toxicity or lethality. Maternal body weights were equivalent across all groups and for all time points. N o statistically significant effects on maternal weight gain or food consumption were noted. The length of gestation was significantly increased in the high-dose group animals compared to control although this finding was “of questionable biological significance since the difference between the groups was smaller than the 14-hour breeding time.” Necropsy of maternal animals in the high- dose group revealed significantly heavier kidneys than controls. Kidney weights increased in a dose-dependent manner.N ecropsy of maternal animals revealed that kidneys from the maternal animals exposed to 3000 mg/kg/day of TGME were significantly heavier than controls Details on embryotoxic / teratogenic effects Analysis of pup in life data revealed no significant effects for PND 0/4 p up sex ratio or for pup survival during any period. Female pups from the mid- and high-dose groups (6.7 and 6.8 +/- 0.1 g) and male pups from the high- dose group (7.0 and 7.1 +/- 0.1 g) were significantly heavier than their control cohorts on PND O (6.2 and 6.7 +/- 0.1 g for females and males, respectively). Pups from these same groups gained significantly less weight in the period from PND 4 to PND 21. Although born heavier, the male pups from the high-dose group were significantly lighter than the control pups at the end of the study on PND 68 (440.7 +/- 6.0 vs. 462.4 +/- 4.8 g). Final body weights (PND 68) of mid and high dose females and mid-dose males were not significantly different from control.
Evaluation of pup development through the determination of vaginal opening revealed no differences between groups. Male pup development, as gauged by time of testes descent, was shown to be significantly advanced in the pups from the mid- and high-dose groups. Evaluation of the behavioral data generated during the course of this study indicated no dose-related effects on motor activity or active avoidance data. Significant effects on auditory startle response p arameters were noted. In particular, the auditory startle amplitude (magnitude of the startle reflex) was increased in male and female pups in the high-dose group on PND 22. Auditory startle amplitude was also increased for male pups on PND 60 and a similar trend of smaller magnitude was observed in PND 60 females. When startle latency (time to maximum startle reflex) was examined, the pups showed no consistent effect on PND 22, but both male and female pups demonstrated a decrease in the startle latency on PND 68.

N ecropsy of weanling and adolescent pups revealed no findings that could be related to treatment. Histopathological assessment of the peripheral and central nervous systems of the p ups showed no treatment related lesions in any group. Applicant's summary and conclusion Conclusions“In conclusion, TGME administered by gavage to pregnant and lactating CD" (SpragueDawley) rats resulted in no overt signs of maternal toxicity. In addition, no discernible effects were noted in the offspring on motor activity, active avoidance, or neuropathology at exposures up to 3000 mg/kg/day. Exposure to TGME at 3000 mg/kg/day resulted inincreases in auditory startle amplitude and decreases in latency to maximum startle, but no changes in the habituation p rocess evaluated in the auditory startle test. The significance of these auditory startle observations with regard to the condition of the test animals is notclear. Exposure to TGME at levels of 1650 and 3000 mg/kg/day produced developmental toxicity evidenced by decreased p ostnatal weight gains. Therefore, the no observable effect level" ( N OEL) for this study is considered to be equal to or greater than 300 mg/kg/day.” Developmental toxicity / teratogenicity.005 UUID IUC5-cfa3ed72-3cd2-4989-9ab8-d528ddd2cd40 Dossier UUID 0 Author rgerwe2 / PCA Services, Inc. / Durham / United States of America Date 2009-02-17 21:02:50 ESTRemarks

Administrative Data Purpose flag supporting study (X) robust study summary ( ) used for classification ( ) used for MSDS Study result type experimental result Study p eriod 1993

Reliablility 2 (reliable with restrictions) Rationale for reliability Pups were not examined for malformations. Statistical analyses were not p erforme d . Otherwise the study was well conducted according to GLP and standard procedures. Data source Reference Reference type study report

Author Taupin PJY Year 1993 Title Brake Fluid DOT 4: Chernoff and Kavlock (CKA) developmental toxicity screen in the rat Bibliographi

c source Testing laboratory Shell Research Limited, Sittingbourne Research Centre Report

no. SBGR.92.2 33 Owner company Shell

Company study no. Report date 1993-02-02

Materials and methods Limit test

no Test guideline Qualifier according to Guideline other guideline: Chernoff-Kavlok teratogenicity screening test Deviations GLP compliance
yes Test materials Test material equivalent to submission substance identity

no Test material identity Identifier CAS number Identity 106008-94-0

Identifier Common name Identity Brake Fluid DOT 4 Details on test materialTest material is a mixture containing 30-50% triethylene glycol monomethyl ether borate ester (CAS No. 106008-94-0), 3-30% triethylene glycol monobutyl ether borate ester, 20-30% triethylene glycol monomethyl ether (CAS No. 112-35-6), 2-10% triethylene glycol monobutyl ether (CAS No. 143-22-6), 20-30% tetraethylene glycol monomethyl ether (CAS No. 23783-42-8), 2-10% tetraethylene glycol monobutyl ether (CAS No. 1559-34-8), and < 1% minor additives. Test animals Species
rat Strain Sprague-Dawley Details on test animals and environmental conditions no data Administration / exposure Route of administration oral: gavage Vehicle unchanged (no vehicle) Details on exposure Groups of 10 female rats were dosed by oral gavage with 25, 150 or 1000 mg/kg/day test material on days 7-17 of gestation. Additional groups of females were sham dosed (negative control) or dosed with 1000 mg/kg/day ethylene glycol diethyl ether ( p ositive control). Analytical verification of doses or concentrations no data Details on analytical verification of doses or concentrations no data Details on mating procedure no data Duration of treatment / exposure days 7-17 of gestation Frequency of treatment daily Duration of test From Day 7 of gestation to Day 5 of lactation. Doses / concentrations 25, 150, 1000 mg/kg/day Basis nominal conc. N o. of animals per sex per dose 10 female rats. Control animals other: sham dosed (negative control) or dosed with 1000 mg/kg/day ethylene glycol diethyl ether ( p ositive control). Further details on study design Groups of 10 female rats were dosed by oral gavage with 25, 150 or 1000 mg/kg/day test material on days 7-17 of gestation. Additional groups of females were sham dosed (negativecontrol) or dosed with 1000 mg/kg/day ethylene glycol diethyl ether ( p ositive control). Animals were allowed to litter naturally, and any that did not deliver by day 25 of gestation were killed. Dams and surviving pups were killed on day 5 of lactation. Examinations Maternal examinations Body weights were recorded on days 1, 7 and 21 of gestation and on day 5 of lactation (or at termination for animals that did not reproduce). Food intake was recorded over days 1 to 7 and 7 to 17 of gestation, day 17 of gestation to day 1 of lactation and days 1-5 of lactation. Ovaries and uterine content Uteri of all dams were examined for implantation sites. Fetal examinations The birth index [total number of pups born (live and dead) x 100/ number of implantation sites], live birth index (number of pups alive at day 1 of lactation/ total number of pups born x 100) and viability index (number of pups alive on day 5 of lactation/ number of pups alive on day 1 of lactation x 100) were calculated for each litter and group. Litter weights were recorded on days 1 and 5 of lactation and the uteri of all dams were examined for implantation sites. Pups were not necropsied. Statistics Statistical analyses were not performed. Results and discussions Effect levels Endpoint N OAEL Effect type maternal toxicity Effect level 1000 mg/kg bw/day Basis for effect level / Remarks 1000 mg/kg bw was highest dose tested and showed no adverse effects.

Endpoint N OAEL Effect type teratogenicity Effect level 1000 mg/kg bw/day Basis for effect level / Remarks 1000 mg/kg bw was highest dose tested and showed no adverse effects.

Maternal toxic effects no effects Details on maternal toxic effects There was no effect of Brake Fluid DOT4 on maternal body weight of food intake. Embryotoxic / teratogenic effects no effects Details on embryotoxic / teratogenic effects Mean litter weights of low dose (25 mg/kg/day) animals were slightly lower than negative controls at birth (79 +/- 24 g vs. 90 +/- 23 g in sham control) and on day 5 of lactation (109 +/- 29 g vs. 133 +/- 34 g in sham control). In contrast, mean litter weights of high dose animals were higher than negative controls at birth (97 +/- 10 g) and on day 5 of lactation (150 +/- 24 g). The authors stated that the reduction at 25 mg/kg/day could be related to slightly smaller litter sizes (the birth index was 85 +/- 15 vs. 95 +/- 7 in the sham control). Two rats in this group had a lower number of implant sites (8 and 6) than the others (ranged from 15-19), which led to adecrease in the number of pups delivered(5 in each of the animals vs. 13-18 in the others). Another low dose animal that had 16 implant sites only delivered 9 p ups. The birth index of animals treated with 150 (94 +/- 6) or 1000 mg/kg/day test material (95 +/- 6) was similar to the sham control (95 +/- 7). There was no effect of treatment on the number of dead pups (4 in control vs. 1 in each treated group). There were no treatment-related necropsy findings. There was no effect of treatment with Brake Fluid DOT 4 of the duration of gestation, the number of females littering, the mean number of implant sites, or the live birth index or viability index. Based on these data, the authors concluded that 1000 mg/kg/day Brake Fluid DOT4 did not cause fetal growth retardation or embryolethality.
By contrast, the positive control animals lost weight from days 7 to 21 of gestation. All nine p regnant animals treated with ethylene glycol diethyl ether (EGDE) resorbed their litters. Most animals treated with EGDE had enlarged livers and/or spleens. Remarks on results including tables and figures
It is not known whether the decreased mean litter weights or birth index at 25 mg/kg/day or the increased mean litter weights at 1000 mg/kg/day are significantly different from control, since statistical analyses were not performed. However, these findings do not appear to be related to treatment since they are not dose-dependent. Since the investigators concluded that 1000 mg/kg/day Brake Fluid DOT4 did not cause fetal growth retardation or embryo or fetal lethality, the NOAEL for these effects is 1000 mg/kg/day. The NOAEL listed under teratogenicity is the N OAEL for developmental toxicity.

Overall remarks, attachments Overall remarks

Reference substance: 3,6,9,12,15,18-hexaoxaicosane UUID ECB5-4fff17de-eb4d-4f3e-8517-5b27f7fa7a16 Dossier UUID 0 Author European Commision/Joint Research Centre/European Chemicals Bureau Date 2007-05-10 05:00:00 EDT Remarks Created General information Reference substance name 3,6,9,12,15,18-hexaoxaicosane EC inventory EC number 245-774-2 CAS number 23601-39-0 EC name 3,6,9,12,15,18-hexaoxaicosane Molecular formula C14H30O6 Reference substance information CAS information CAS number 23601-39-0 IUPAC name IUPAC name 3,6,9,12,15,18-hexaoxaicosaneSynonyms N ame 3,6,9,12,15,18-hexaoxaeicosane

N ame 3,6,9,12,15,18-Hexaoxaeicosane

N ame 3,6,9,12,15,18-Hexaoxaeicosane
DSL Category: Organics USEPA Category: Ethylene Glycol Ethers; N eutral Organics Molecular and structural information Molecular formula C14H30O6 Molecular weight range 294.3844 SMILES notation CCOCCOCCOCCOCCOCCOCC InChI InChI=1/C14H30O6/c1-3-15- 5-7-17-9-11-19-13-14-20-12-10 -18-8-6-16-4-2/h3-14H2,1-2H3 Structural formula

Legal entity: PCA Services, Inc. UUID IUC5-627340ec-79cf-4d47-86f0-902729c7a dc2 Dossier UUID 0 Author rgerwe / ( N o legal entity) Date 2008-11-16 11:49:37 EST Remarks General information Legal entity name PCA Services, Inc. Identifiers Other IT system identifiers IT system LEOID 8869

Contact information Contact address Address 2704 Trail Wood Drive Postal code 27705 Town Durham Region / State N orth Carolina Country United States of America Phone (919) 382-8787 Fax (919) 382-8788 E-mail r.gerwe2@verizon.net Web site www. p caserve.com Contact persons Organisation PCA Services, Inc. Title President First name Roderick Last name Gerwe Phone (919) 382-8787 Fax (919) 382-8788 E-mail r.gerwe2@verizon.net Address 2704 Trail Wood Drive Postal code 27705 Town Durham Region / State N orth Carolina Country United States of America