### COD:ING FORMS FOR SRC INDEXING


### Microfiche No. OTS0572612

86940001508

06/23/94 07/22/94 8D

CHEM MFGS ASSN



### EASTMAN KODAK CO

ETHYLENE GLYCOL MONOBUTYL ETHER: ACUTE ORAL TOXICITY STUDY IN THE GUINEA PIG WITH COVER LETTER DATED 07/21/94



### Chemical 

### category ETHYLENE GLYCOL MONOBUTYL ETHER (CASt 111-76-2)

### REV. 7/27/82**~e:'Qf'leh.** 90. 

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### Document Processing Center (TS-790) Room L-100 Office of Pollution Prevention and Toxics U.S. Environmental Protection Agency 401 MStreet, SW Washington, DC 20460 RE: TSCA Section 8(d) Health and Safety Report Rule (Notification/Reporting); 40 CFR 716.60 Dear Sir or Madam:

## ~~9110<:x::)' 

# s**o~** 

# 1b

# 8"9lfooolSo~ 0iEMICAL.MANUFACTUAERSASSOCIAllON 

### July 21, 1994 

# .,.,

-

# ..

-- .' 

# -.

-

# , .. !



### Pursuant to TSCA Section 8(d) Notification/Reporting requirements, The Chemical Manufacturers Association (CMA) 

### submits the following information on initiation and/or completion of research on ethylene glycol monobutyl ether, (EGBE), CAS Number 111-76-2. 

## CMA is submitting this information on behalf of the U.S. manufacturers of EGBE who are the research sponsors. The manufacturers/sponsors are: Eastman Chemical Company P.O. Box 431 Kingsport, 

## TN 37662 Shell Oil Company One Shell Plaza P.O. Box 4320 Houston, TX 77210 Union Carbide Chemicals and Plastics Company 39 Old Ridgebury Road Danbury, CT 06817 Dow Chemical Company 2020 Willard H. Dow Center Midland, MI 48674 Occidental Chemical Corp. 

## S Greenway Plaza Suite 2400 Houston. TX 77227-7702

The following research is reported on: 1. Development of a Physiologically-Based Pharmacokinetic Model for Hu.an Health Risk Assessment



## .... .**'~~urpose** 

### of this research is to acquire data that will Allow the construction of a reliable physiologically-based pharmacokinetic .odel for EGBE so that appropriate risk**ass.s~nt** 

### prooedures can be 

### carried out. The research is being conducted at the Toxicology Research Laboratory, The Dow Chemical Complny, Midland, MI. This research is being conducted over a multi-y.ar period and began in 1991. An 8(d) notice of initiation was submitted to EPA on March 20, 1991. A report of the initial phase of the research is submitted with this letter. This project continues.

250' M

### Street. NW.• ....

asIi1lQlD'1. DC20037 TfJI8PI'1One202-887-''00 Fax202-887-1237 

# Lc-.:= R' 

## c.. 

# "i' c; •

### Docu-ent Processing Center July 21, 1994 Page 2 

### 2. Studies of the Effects of EGBE and Butoxyacetic Acid on Normal and Abnormal Human Erythrocytes The purpose of this research is to examine the effects of EGBE and its principal metabolite, 

## BAA, on normal and abnormal human and rodent erythrocytes to further elucidate a possible mode of action for EGBE-induced hemolysis in the rodent. The research is being conducted at the Department of Medicine, Section of Hematology, Baylor College of Medicine, Houston, 

## TX. This research is being conducted over a multi-year period and began in 1990. An SCd) notice of initiation was submitted to EPA on January 17, 1990. Two publications arising from the first phase of research are submitted with this letter. Work on this project continues. 3. 

### Dermal Bioavailability Study in Fasted Volunteers The purpose of this research is to assess the dermal bioavailability of EGBE vapor by an arm-only exposure. The research is being conducted at L.A.B. Bio-Research International Inc., Senneville, Canada. The research began in April 1994 and should be completed in the fourth quarter 1994. The Panel has also recently conducted three studies that are exempt from SCd) reporting. As these studies may be of interest to EPA, we are submitting information on them as follows: 4. 

### Acute Dermal and Oral Toxicity in the Guinea Pig The purpose of these studies was to determine the oral and dermal toxicity of EGBE in male and female guinea pigs. The studies were carried out at the TOXicological Sciences Laboratory, Eastman Kodak Company. The studies began in March 1994 and were completed in June 1994. Final reports for 

### the acute dermal and acute oral toxicity, respectively, are submitted with this letter. 

### 5. Acute Vapor Inhalation Toxicity· StudY in Guinea Pigs The purpose of the study was to determine the acute inhalation toxicity in guinea pigs resulting from a single I-hr exposure to EGBE vapor. The 

### study was carried out at Bushy Run Research tenter, Export, PA. The study began in March 1994 and was co-pleted in July 1994. The final report is**su~itted** 

### with this 

## .fetter. 

# -,

-- 

### If yoa-have any questions regarding this submission, please contact me at 2021887-1293. Regards,

# ~-:!fM~ Manager Ethylene Glycol Ethers Panel Enclosures

# - 86948881588



## STIJDYlIfLE 29l109D TX-94-96 Page 

### 1 of 

### 19

ETHYLENE GLYCOLMONOBUTYLErBER ACUTE ORALTOXICITY 

### STUDYINTHE GUINEA PIG HAEL NUMBER: 

### 94-0300 KAN: 902270 CAS REGISTRY NUMBER: 111-76-1 

### FINALREPORT AUTHOR Kenneth P. Shepard, B.S. 

### PERfORMINGLABORATORY ToxicologicalSciences Laboratory 

### CorporateHealth and Environment

### Laboratories 

### Eastman KodakCompany

1100Ridgeway Avenue 

### Rochester. 

### New York 14652-6272 

### USA LABORATORYPROJECTID 

### 9403OOAO 

## STIJDY SPONSOR EthyleneGlycolEtherPanel 

### Chemical Manufacturers Association 2S01 M Street, NW Washington, DC20037 CMA

## REFERENCENUMBER

EGE-S8.o-GPIG-EASTMAN 

### STUDYCOMPLIDONDATE June

### 23, 1994

### 291109D TX-94-96 Page 

### 2 of 

### 19



### QUALITY ASSLTRANCE INSPECIJQN STATEMENT

. [21 CFRS8.3S(B)(7). 40 CPR 792.35(B)(7), and 40 CFR 160.35(B)(7)]

STUDY: 94-0300-1 STUDY DIRECTOR: SHEPARD,K.P. ACCESSION NOHBER: 902270 PAGE 1 04/20/94

STUDY TYPE: 

## };./. (AUDITOR, SURANCE UNIT)

'lO THE BEST OF MY KNOWLEDGE, THIS FINAL REPORT ACCURATELY DESCRIBES 'rIlE HE'l'BODS AND S"l'ANDARD OPERATING PROCEDURES, AND THE REPORTED RESULTS ACCURATELY REFLEcr THE RAW DATA. THIS STUDY WAS INSPECTED BY 1 OR MORE PERSONS OF THE QUALITY ASSURANCE UNIT OF HAEL, EASTMAN KODAK COMPANY ROCHESTER, N.Y. AND WRITTEN STATUS REPORTS WERE SUBMITTED ON THE FOLLOWING DATES:



# ------------------------------------------------------------------ INSPEC'l'ION DATES PHASE(S) INSPECTED STATUS REPORT DATES
03/01/94 PROTOCOL SUBMISSION TEST SYs-rEM RANDOMIZATION TEST SYs-rEM IDENTIFICATION TEST SYSTEMS WEIGHTS DOSE CALCULATIONS TEST ARTICLE MEASURE AND MIX WITH CARRIER TEST ARTICLE-cARRIER-MIXTtJRE DOSING OF TEST SYS'l'EMS
04/13/94 GROSS PATHOLOGY PATHOLOGY REPORT 04/20/94 FINAl. REPORT REVIEW DRAFT REPORT 04/13/94 04/20/94

### 291109D TX-94-96 Page 

### 3 of 19

COMPLIANCE

## WITH GOOD LABORATORY 

## PRACI1CE STANDARDS

The 

### study describedby this report 

### was conducted 

### in compliance with the following Good LaboIatoIy 

### Practice Standards: United Stares Environmental Protection Agency, 40 CFR Pan 

### 792 (TSCA) as revised August 17, 1989. United Stares Food and Drug Administration, 21 CFR Part 

### 58 as 

### revised September 4, 

### 1987. Annex 2 ofthe Organization for Economic Cooperation and Development Guidelines 

### for

### Testing of

### Chemicals C(81)30 (Final).

# ~hH ••

# ~~~ Kenneth P. Shepard, B.S. Study 

### Director 

# drtJ,<' Hll.f M nth/DaylYear

MontblDaylYear

### TABLE

## OF CONTENTS ABSTRACT 

### PERFORMINGLABORATORY SPONSOR STUDYDAl'ES STUDYDIREcrOR and 

### OIHER. KEY PERSONNEL 

### PURPOSEIOBJEC'TIVE MATERIALS AND 

### MEI'HODS TestArticleO.arac:terizatiOD and Analyses 

### TestProcedureGuideline TestSystem Isolation Bousmg and Environmental 

### Conditions Dietand Water Animal 

### Ideotification Randomization Dose Level and Dosing

### Regimen Control Substanceand 

### Vehicle Oinical 

### Observations and BodyWeight 

### Determinations 

### Necropsy RESULTS DATAANALYSIS DISCUSSION AND INTERPRETATION CONCLUSION DATASTORAGE SIGNATUREPAGE APPENDIXTABLEOF CONTENTS 

### 29ll09D TX-94-96 Page

### 4 of19

Page 

### Number' S 

### 6 6 6 

### 6 7

7 

### 8 8 8 8 9 9 

### 9 

### .9 

### 9 10 10 10 

### 17 17 17 17 18 

### 19

### 291109D TX-94-96 Page 

### 5 of 

### 19



## ABSTRACI

ETHYLENE GLYCOL MONOBUTYL 

### El'HER ACUTE ORALTOXICITY STUDY INTHE GUINEA PIG 

### BAa NUMBER: 

### 94-0300 KAN: 902270 CAS REGISTRY NUMBER:**111-7~2**


### An oral 

### toxicity study 

### was initially conducted in five male and five female 

### guineapigs administered

### a single limitdose of2000 mg/kg ofthe testarticle by gavage. Following 60% mortality for males and 100% mortality for females 

### at the limitdose, 

### a single 

### oral doseof either 1000 or

### 500 mg/kg ofthe test article 

### was administered 

### to groups offive male and five female guineapigs. Mortality 

## was 20% for both 

### sexes 

### at 1000 mglkg and 0% for both sexes 

### at SOO mg/kg. Abnonnal clinical signs included 

### slight 

### to 

### severe weakness and prostration 

### that were either transientornoted prior 

### to death. Otherabnonnal clinical signs indicate that 

### the testarticle 

## was probably irritating 

### to .the 

### stomach. These signs included sialorrhea and staining ofthe hairofthe 

### face and/orabdomen by feed 

### and saliva and were 

### initially noted approximately 48 hours 

### after

### dosing and for only 

### the two surviving males 

### at the 2000 mg/kg 

### dose 

### level. In addition, 

### gasping 

### and a 

### red nasal discharge were 

### noted for a 

### single male 

### at the 1000 mg/kg 

### dose

### levd on 

### theday following dosing. These two 

### abnormal signs 

### persisted to Day 3 

### ofthe 

### study wbeo. 

### this male 

### died. No otherabnormal clinical signs were 

### evidentduring 

### the 14-day 

### observation period. 

### All 

### guineapigs which 

### survived 

### to 

### termination ofthe study 

### g.ined weighL The primary 

### treatment-related cbanges noted 

### at necropsy confirmed 

### that the

### test 

### article

### was 

### a gastrointestinal irritant. Theseincluded 

### necrosis and hemorrhage in the gastric mucosaand the

### accumulation of

### mucoid contents in the duodenum. No tissues 

### were collected 

### for histological examination. No evidenceof

### red blood

### celltoxicity

### orhemolysis was 

### observed during 

### the study. The

### ID5C) for guineapigs 

### was calculated 

### to be 

### 1414 mglkg 

### with a 

### 95% confideDcelevel of 1020

### to 1961 rng/kg for 

### the combined sexes.

### 291109D TX-94-96 

### Page 6 of 19



## PERFORMINGLABORATORY Toxicological Sciences Laboratory Corporate Health 

### and EnvironmentLaboratories Eastman Kodak

### Company 1100Ridgeway Avenue 

### Bo320 Kodak

### Park Rochester, New York: 14652-6272 USA 

## SPONSOR Ethylene Glycol EtherPanel Chemical Manufacturers 

### Association 2501 M Street, NW Washington, DC 20037 Authorized Representative: Kathryn A. Rosica 

## STUDYDATES Study Initiation: March 1, 1994 ExperimentInitiadon: March 1, 1994 Experiment Completion: March 

### 29, 1994 Study Completion: JW1e 23, 1994 

## STUDy

## DIRECTOR. Kenneth P. 

### Shepard, B.S.


## OTHERKEYPERSONNEL
Len Sakal, 

### B.S•• StudyTechnician John W. Mosher, 

### B.S., Principal Investigator Milan 

### S. 

### VIaovic, D.V.M., Ph.D., Laboratory Animal 

### Medicine, Pathologist

### 291109D TX-94-96 Page

### 7 of 

### 19

The

### purpose ofthe 

### study was 

### to determine the oral toxicity ofthe test

### article 

### in male and 

### female guineapigs. 

## MATERIALS AND METHODS Test Article Characterization 

### Test Article 

### NamC".: Synonym: CAS RegistIy 

### Number: 

### CMA Reference 

### Number: Ethylene glycol monobutyl ether 2-Butoxyethanol**111-7~2** 

### EGE-58.o-GPIG-FASTMAN HAEL Number: Laboratory 

### ProjectNumber: Kodak 

### Accession Number: Soun:e ofthe

### Test Article: 

### 94-0300 940300AO 902270 Eastman Chemical 

### Company Kingsport, 

### TN 37622 Physical State and AppeaI3Dce: 

### Colorless liquid 

### LotNumber: 

### Lot 9792 

### Received 

### at Performing Laboratory: February 17, 1994 

### Test Article Analyses The

### testarticle

### was analyzed forpurity 

### using gas chromatography with flame ionization detection (GCIFID). Samples ofthe test 

### article

### was collectedpriorto initiation ofthe study 

### and after

### termiDation ofthe 

### in-lifephase ofthe study. Boththeinitial and 

### final samples for purity were 

### determined to 

### be99.8% ethyleneglycol monobutyl ether. Based 

### on these

## dam. the test 

### articlewas considered 

### to be stable throughoutthe 

## study. Theinitial test article sample was also 

### analyzed 

### for struetu:Ie 

### confirmation using 

### gas chromatography with 

### mass spectlometry (GCIMS). 

### The structure 

### ofthetestarticle

### was 

### consistentwith the structure of ethyleneglycol monobutyletherbased on comparison with 

### reference

## library spectra. Concentration verification ofthe dosing solutions 

### consisted ofanalyzing each ofthe three 

### concentrations**f~",** 

### 20%. and 10%) ofthe 

### test article in distilled water. 

### The solutions were 

### analyzed on the day ofdosing, or as soon as possible thereafter, using gas chromatography 

### with flame ionization detection (GCIFID) underthe same instrumentconditions as used for

### 291109D TX-94-96 

### Page 8 of 19



## MATERIALS ANDMEIHODS. COQL 

### Test

## Article Analyses. Cont. purity determination. 

### The overall mean measured concenttations 

### for the40",

# 20". and 

### 10" solutions were 

### 42.5%. 18.2". 

### and 10.1" (weight/volume), respectively. All analyses were perlormedby 

### the Chemical 

### Quality Services Division. Kodak

### Park. The analytical 

### test report 

### is presented in 

### the appendix. 

### Test

## Procedure GuicfeJinelReference 

### OECD 

### Guideline for Testing ofChemicals: 

### Guideline 401 (Annex V, 

### TestB.1); also 

### in accordance with theDepartment ofTransportation. CPRTitle49, Section 173.132, except guinea

### pigs were 

### selected 

### for the test species. 

### Test System 

### Species/Strain: Source: 

### Arrived 

### at Performing 

### Laboratory: 

### NumberofAnimals: Sex: Body

### Weight Range at 

### StudyInitiation 

### (grams): Age at 

### StudyInitiation: Isolation 

### Hanley Guinea

### PiglCrl:(HA)BRVAFIPIlJS'8 Charles RiverLaboratories, Kingston, NY, USA 

### February 16, 1994 (for 1000 and 2000 mglkg groups) March 

### 9, 1994 (for500 mglkg group) Fiveofeach sex per 

### dose 

### group Male 

### and Female Males 

### = 309

- 405 Females 

### = 310

- 375 Males 

# =5-7 weeks 

### Females 

# = 5-7 weeks

Animals were 

### isolated and 

### monitored for 

### atleast five days after

### arrival and 

### before release 

### to the

### testing facility.

All animals were 

### individually housed in 

### suspended. stainless-steel, mesh 

### cages. EnyjronrnenJal Conditions A photoperiod of 12 hoUl'S 

### lightfrom 6 a.m. 

### to 6 p.m. W2S 

### maintained. Room tempe:ratuIe 

## was maintained at

## 69-72 'F. Relative humidity

## was maintained at

## 57-59".

### 291109D**TX~94-96** 

### Page

### 9 of 

### 19


## Mt\1lJUA1$ 

## ANDMETHODS. Cont,

. J2je:t iDd Water**Agwa~** 

## Prolab- Animal 

### Diet (RMH 

### 3000) certified 

### pellets and 

### water (Monroe Co\Dlty 

### (NY) 

### Water 

### .t\utbority) were available

## ad. libitum. No known contaminants which would 

### interfere 

### with the outeOllle ofthis study were 

### expected 

### to bepresent 

### in feed or 

### water from these 

# soura:s. Analyses offeed and results ofquarterly analyses of

### water are maintained on file 

## within the

### testing laboratory. 

# AP.inmI Identification 

## All aniJnals were identified by cage numbers and uniquely-numbered, metal ear tags.
Cage 

### NUiIlbers: Cage

### Numbc:rs: Cage 

### NUI11bers: 

### Males 161-165 176-180 201-205 

### Females 166-170 (2000 mglkg dose group) 186-190 (1000 mglkg dose group) 206-210 (500 mg/kg dose group)



### A 

### clinical examination 

## was performed on 

### each animal 

### to 

### ensure that only healthy 

### animals were utilized. The 

### procedure for including

### animals in 

### this 

### study 

## was to randomly select and assign 

### animals from the same shipment to 

### each 

### doselevel. 

### Randomization was 

### done by 

### computer

### genera.ted lists

### using the Automated Animal 

### Toxicology System. After 

### assignment of

### animals to 

### the 

### study, the

### body weights were 

### determined 

### to ensure 

### that individual

### body weights did not 

### exceed 20% ofthe mean weight for each sex.



### Doses of2000, 1000, or500 mg 

### test articlelkg body weightwere 

### administered 

### to the 

### animals•

.t\ single dose ofthe teSt 

### article

## was administered by gavage 

### to animals that 

### had been 

### fasted overnight. 

### C9ntro1 S,ybstance 

### No

## control substance was 

### used.

### 291109D TX-94-96 

### Page 

### 10 of 

### 19



## MATERIAlS AND METHODS. Cont, Vehicle The 

### test article

## was dissolved 

### in distilled 

### water. Variability 

### in the volume oftest article and vehicle 

### administered was 

### minimized by adjusting the concentration to ensure 

### a constant volume 

### at all dose levels. Clinical Observations Animals 

### were observed 

### at least three 

### times on the day ofdosing and at 

### least once each day 

### thereafter for the duration ofthe experiment (atotal of 14 calendar days). Observations included, but 

### were not limited to, changes 

### in the 

### skin; fur, feces; urine; eyes; mucous membranes; respiratory, ciIculatory, autonomic, and 

### central nervous systems; somatomotor activity; and behaviorpattern. Body WeightPetenninations Body 

### weights were collected on 

### Days 0 (prior to treatment), 

### 7, and 14.

Animals that

### died during the study 

### were necropsied 

### as soon 

### as possible. Surviving 

### animals 

## were necropsied 

### at the completion ofthe 14-day observation 

### period.


## RFSPLTS Mortality Mortality 

## was 60% for males and 100% for females 

### at the limitdose (2000 mglkg). Forthe lower doses, mortality 

### was 20% for both sexes at 1000 mglkg and 0% for 

### both sexes 

### at 500 mglkg.

### RESTTLTS. Cont,

MORTALITY TABLE 291109D TX-94-96 

### Page 11 

### of 19



### 2000
1000 

### 500 

## 5,5 5,5 5,5 3,5 1,1 

### 0,0 Day 

### 0 to 

### Day 

### 1 Day 1 and 

### Day 3



## DoseVolumes TABLES OF DOSE VOLUMES 

### (Dose Group

- 2000 mg/kg)

161 

### 162 

## 163 164 

## 165 388 309 335 387 

### 386 1.94 1.55 

### 1.68 1.94 1.93 

## 166 167 168 169 170 

## 358 357 333 365 

## 358 1.79 

### 1.79 1.67 1.78 1.79

### 291109D 

## TX-94-96 Page 

## 12 of

## 19

RFSlJLTS. Coot. 

## Dose Volumes. Cont, TABLFS OF DOSEVOLUMES. Cont. (Dose 

### Group

- 1000 mglkg)

# '~."'=" 

# '
! .•.'RECEIVED

..·.·.:.

## v

.:O.:

# (:.·.:·.·~T.·.· ..··. ", 

## N"QMBER :.**:~)::** UUwJ 

## 176 397 1.99 186 

## 375 1.88 

# rn 178 179 

## 180 405 

## 399 359 392 

## 2.03 2.00 

### 1.80 

## 1.96 187 

### 188 

## 189 

## 190 350 331 343 368 1.75 1.66 1.72 

### 1.84
(Dose Group

- 500 mg/kg)



## 201 202 

## 203 204 

### 205 

### 334 

## 326 326 

### 326 322 

## 1.67 1.63 

### 1.63 1.63 1.61 206 

# 2m 208 209 

## 210 310 322 

## 319 336 

## 320 1.55 1.61 

# too 1.68 

### 1.60

### RFlillLTS. Coot. Clinjcal Observations 

### TABLE OF CLINICAL OBSERVATIONS 

### 29ll09D TX-94-96 Page 

### 13 of 

### 19

2000 

### SevereWeakness and Prostration Day 0 

### SIS Males (Transient orPrior 

### to Death) 

### SIS Females 2000 

### Death Day 0 

### to Day 1 

### 3/S Males 

### SIS Females 2000 

### Slight

### to Moderate Weakness Day 1 

### to Day 2 

### 212 Males
2000 

### Sialorrhea Day 2 

### 212 Males
2000 

### Staining 

### (Feed and Saliva) ofthe Hair Day 2 

### to Day S 

### 212Males ofthe Face and/or Abdomen 2000 

### Appeared Clinically 

### Normal Day 6 

### to Day 14 

### 212 Males
1000 

### Moderate 

### to SevereWeakness Day 0 

### SIS Males (Transient orPrior

### to Death) 

### SIS Females 1000 Prostration 

### Day 0 

### 4/S Males (Transient orPrior

### to Death) 

### 3/5 Females 1000 Death 

### Day 1 

### 115 Females
1000 

### Appeared Clinically 

### Normal Day 0 

### (p.m.) 

### 4/5 Males 

### to Day 14 

### 4/4 Females 1000 

### Moderate-SevereWeakness,Gasping,and Day 1 

### to Day 3 

### 115 Males Red 

### Nasal Discharge (Prior 

### to Death) 1000 Death 

### Day 3 

### 115 Males

### 291109D 

### TX-94-96 Page 14 of 19



## RWJLTS. Cont. Clinical Observations. 

## Cont.
TABLE OF CLINICAL OBSERVATIONS. Cont.

SOO
SOO SlightWeakness (Transient) Appeared Clinically Normal Day 

### 0 Day 

### 0 (p.m.)



### to Day 14 

### SIS Males 

### 515 Females



### SIS Males 

### SIS Females

Atthe 2000 mg/kg dose level, abnormal clinical signs included slight

### to severe weakness and prostration 

### thatwere eithertIansient (severe weakness and prostration were noted only on the day ofdosing, moderate weakness 

## was noted only on Day 

### 1, and slight weakness 

### was noted only on Day 

### 2) 

### or noted prior 

### to death. Three 

### ofthe five males and all females died either on the day ofdosing orthe day following dosing. Abnormal clinical signs for the two remaining males included sialorrhea and staining ofthe 

### hair ofthe face and/or abdomen with feed and 

### saliva. These signs, were noted approximately 48 hours 

### after dosing. Slight

### to moderate weakness 

### was 

### also noted for the two surviving males 

### at this 

### dose level. By Day 6 ofthe study, theremaining two males 

### appeared clinically normal. Forthe 1000 mg/kg dose level, moderate 

### to severe weakness and prostration were noted only on the day ofadministration ofthe test material 

### and 

### were eithertransientor noted prior 

### to death. One offive females died on the day following dosing. 

### In the afternoon on the day of dosing, four 

### offive males and 

### all remaining females 

### appeared clinically normal. Abnormal clinical signs for the remaining 

### male included modeIate

### to severe weakness, gasping, and 

### a red nasal discharge. 

### This male died on Day 3 ofthe study. Abnormal clinical signs noted for the SOO mglkg dose group 

### were limited 

### to slightweakness for 

### all animals 

### on the day ofdosing. By the afternoon examinations on the day ofdosing, 

### all animals 

### at

### this dose level 

### appeared clinically normal.

## 291l09D TX-94-96 Page 

## 15 of 

## 19

RESULTS. Coot.



## All anjmals 

### that survived to 

### termination ofthe 

## studygained weighL 

### TABLE OF INPMDUALBODY

## WEIGHTS
- MALES

2000 2000 2000 2000 2000 1000 

## 1000 1000 1000 1000 

## 500 500 500 500 500 161 388 441 162 309 

## DiedDay 1 163 335 DiedDay 0 164 387 DiedDay 1 165 386 430 176 397 DiedDav 3 177 40S 

## 486 178 399 493 179 359 427 180 392 476 201 334 428 202 326 417 203 

## 326 386 204 

## 326 394 205 322 397 498

512
548 555 469 512 

## 498 486 

## 436 466 

## 430

### 291109D TX-94-96 Page 

### 16of 

### 19



## RESULTS. Cont. 

## Boc!y Wei&hts. 

### Cont, TABLE OF INDIVIDUALBODY

## WEIGHTS

- FEMALES



### 2000 166 358 Died Dav 

### 1 2000 167 357 Died Day

### 0 2000 168 333 Died Day 

### 1 2000 169 365 Died Day 

### 0 2000 170 358 Died 

### Day 0 1000 186 375 469 50' 1000 187 350 416 457 1000 188 331 1000 189 343 1000 190 368 500 206 310 500 207 322 500 208 319 500 209 336 500 210 320 Died Day 

### 1 406 

### 443 427 456 366 405 375 420 406 

### 443 424 454 391 447

### 291109D TX-94-96 Page 17 of 19



## RESULTS. Cont, 

### NecromY and Histgpathology Emdinp Theprimary treatment-related chaDges noted 

### at necropsy included minorto moderate 

### diffuse necrosis and mjnjmal to minorhemorrhage in the gastric mucosa; and 

### minimal to minor accumulation ofmucoid contents in the duodenum. No 

### tissues were collected for histological examjnation. A 

### record ofthe individual 

### animal necropsy findings 

### is presented in 

### computergenerated tables which 

### are included in the appended pathology report.


## DATA ANALYSIS TheLD

### so in male and female 

### guineapigs: 1414 mglkg (95% C.I. 

# = 1020 to 1961 mg/kg) No dose/mortality curve

## was constructed since graphs become statistically useful only with the 

### use oflarge numbers ofanimals and dose groups.

DISCUSSION

## AND INTERPRETATION The test. 

### article

## was a gastrointestinal irritant

### as evidencedby abnormal clinical 

### signs of 

### sialoabea and staining ofthe face and abdomen with feed and saliva 

### and treatment-related chaDges ofnecrosis 

### and hemorrhage in the gastric mucosa and the accumulation 

### ofmucoid contents in the duodenum 

### that

### were noted 

### at necropsy. All 

### otherabnormal clinical 

### signs were eithertransient (noted only on the day ofdosing) 

### ornotedprior to death. No evidence 

### ofred blood cell toxicity or hemolysis 

### was observed 

### during the study.

CONCLUSION TheIDsofor the combined sexes ofguineapigs

## was 1414 mglkg with a 95% confidence level of 1020

### to 1961 

### mg/kg.

DATA 

## STORAGE All 

### testresults presented in this 

### report

### are supportedby raw·datawhich 

### are maintained in the archives ofthe 

### Corporate Health and EnvironmentLaboratories. 

### Eastman Kodak: Company.

### SIGNATUREPAGE

Kenneth 

### P. Shepard, B.S. Smdy

### Director



### .M.D., Ph.D. th 

### and EnvironmentLaboratories 29l109D 

### TX-94-96 Page 18 of 19



# '-:::\'--& \c;C1

# 'f

__ MontlllDaylY ear



# L**ZZ,IC,~'i**

MontlllDay/Year

### TABLE 

### OF CONTENTS FOR 

### THE APPENDIX

ANALYTICALTESTREPORT PATHOLOGYREPORT 

### 291109D TX-94-96 

### Page 19 of 19



## PAGE NUMBER

1 

### 19

### 291109D 

### TX-94-96 APPENDIX Page 1 of32 ANALYTICAL TEST REPORT
PUlUTY, STRUCTURE CONP:IlUmT:I:ON AND CONCENTRATION DE'1'E1UIDm.TJ:ON OF 

### Ethyl.ene Gl.ycol. !lODobutyl. Ether

KAN: 902270 HAEL 

### No. 94-0300



### Nancy K. 

### Porter

TESTING FACILITY


### Environmental Analytical Services Chemicals Quality Services Division Eastman Kodak 

### Company

1100 

### Ridgeway Avenue B-320 Kodak Park 

### Rochester, New York 14652-6276

SPONSOR 

### Toxicological. Sciences Section Corporate Health and Environment Laboratories Eastman Kodak 

### Company

1100 

### Ridgeway Avenue B-320 Kodak Park 

### Rochester, New York 14652-6272 COMPLETION 

### DATE: 

# 4q494 AMENDMENT 

### DATE: 

# v.jifJ,l

### 291109D TX-94-96 

### APPENDIX Page 2 

### of32

ANALYTXCl\I, QUr.I.rn ASSOIUUICE I:NSPECT'ION S'rJ'.'1'EHEN'1 (CFR 58.35(B) (7) 792.35(B)(7) 160.35(B)(7»**~:** 94-o300-Z STUDY DI:RECroR: STAUDENKJ'.YER.Jt..**~OL** DDIECTOJl: IOUI: 902270 CQS JOB 1ItJHBER: S'l'UDy TYPE: PUIUTY. S'rROcr.OONFDUi. AND CONC. DE'rERIUNATI:ON

# ~~CE·tJNrr)

7BE E'OLLOWI:NG PBJ>.SES OF 'J:HI:S sraDY WERE I:RSPECrED BY ORE OR MORE PERSONS OF 7BE QOALI:'rY ASStJIUUfCE UHrr ON 'DIE DA:rES LISrED BELOW. WRI:TrEN STATOS REPORTS 'lEIlE SOBKl:'f'TED 1:0 "mE STUDY DDlEcrOR AND APPROPRXA'ft: M»tAGEHENT. I:NSPEcr REQUEST PImSE(S) STA'rOS REPORr

DA7ES NtIKBER DlSPEClED DATES 03/14/94 PROTOCOL SOBKI:SSI:ON 03/14/94**PROTOCOL~** 04/06/94 179342 TEST REPORT I:NSPECTl:ON 04/06/94 179347 179343 179344 179346 PtJRI:Tr. STRUCTURE CONFI:RHATI:OR AND CONC. DETERHI:NATI:ON 04/07/94 179342 179347 179343 179344 179346 TEST REPORT I:NSPEl::'l"l:ON 04/07/94

04/18/94 179342 179343 179344 179346 179347 REPORT AMENDMENT

Page 2 of J.8 04/18/6!J4



### KAN: 902270

### 291l09D TX-94-96 APPENDIX Page 3 of 32

To the best 01: the sigDer's JciIow1edge and be1ief. the study described by this report vas conducted in COIIIPli.ance 'lith the rollowinq Good Laboratory Practice standards: United states Food aDd DrUg Administration, 21 CFR Part 58 as revised september 4. 1987. united. states EmriromDental. Protection Agency, 40 CFR Part 792 ('.rSCA) as revised AugUst 17, 1989_ Annex 2 of the OX'ganization for ECOnomic COOperation and Development Guidelines for Testing of Cbeai.cal.s (C(81)30(FinaJ.) ) as required by council Directive 87/18fF:E.C of December, 1986.

Kathy staudezmayer study Director

Page 3 of 18

### <t/I~f1'i 

## T' Date

JO>,N: 902270

### 291109D 

### .•'-94-96 APPENDIX Page 

### 4 of 

### 32

TABLE OF CONTENTS 

# ." ABSTRACT • • _ _ _ • • _ SPONSOR"S STUDY • • • • • • _ • _ SPONSOR REPRESENTATIVE STUDY INITIATION DATE. ANALYTICAL START DATE TEST SUBSTANCE • _ •

_ STUDY DIRECTOR • _ • • ANALYTICAL PERSONNEL STORAGE CONDITIONS HATERJ:ALS AND METHODS • PORIT'l DETERM:t:NAT:t:ON STRUCTURE CONFIRMATION

_ _ _ _ _ CONCENTRAXION DETERMINATION

_ CALCULATIONS •

_ EXAMPLE CALCULATION.

__ REStlLTS PURITY • _ • • • - • • STRUCTURE CONF:t:RMATION _ _ _ • CONCENTRATION DETERMINATION • DISCUSSION • • • • _ • _ • _ • DATA STORAGE AND RECORD RETENTION SIGNATURE PAGE • _ • • • • _ • • • Page 5 6 6 6 6 6 6 6 6 6 6 7 7 8 9 9

_ .10

• 10

• 12

• 12 • • _ 13 FIGURES: 1 EXAMPLE CHROMATOGRAM FROM PURITY DETERMINATION • • 14 2 EXAMPLE CHROMATOGRAM FROM CONCENTRATION DETERMINATION • • • • • • • • • • • • _ • • 15 3 EXAMPLE TOTAL ION CHROMATOGRAM FROM STRUCTURE CONFIRMATION • _ • _ • • _ _ _ _ • • • _ _ • _ • • 16 4 EXAMPLE MASS SPECTRUM FROM STRUCTURE CONFIRMATION 17 REPORT AMENDMENTS • • _ _ • _ • _ _ _ • • _ • _ • • • • 18

Page 4 of 18 KAN: 902270

### 291109D 

### TX-94-96 APPENDIX Page 

### 5 of

### 32

The purity phase of the analYtical support for this study consisted of an initial and final purity assay of the test substance. The purity was determined to be 99.8% at the beginning and 99.8% at the end of the study. A mass spectra1 analysis was also done on the initial sample to confirm the structure of the test substance. The concentration verification phase consisted of analyzing each batch of the test substance mixtures at concentration levels of 40%, 20% and 10% test substance in distilled water. The overall. mean measured concentrations for the 40%, 20%, and 10% test mixtures were 42.5%, 18.2% and 10.1% (weight/vol.ume) respectively. The mean measured concentration for the reanalysis of the 40% dose was 44.5% (weight/volume).

Page 5 of 18 

### KAN: 902270

### 291109D TX-94-96 APPENDIX Page 6of32

SPONSOR. REPRESENTATXVE Kenneth Shepard STUDY**~:IAT:ION** DATE: 2/23/94 ANALYTZCAL**S~** DATE: 2/2S/94

. Name:

HAEL No.: KAN: sample Ref. No.: S'rODy D:IREC'rOR Ethylene glycol monobutyl ether 94-0300 902270 Lot 9792
Kathy Staudenmayer, Chemist l\NALYTI:CAL PERSONNEL Nancy K. Porter, B.S. STORAGE**COND~:IONS** The samples were stored at room temperature in a locked cabinet.**~IUALS** lWD HETBODS The following procedures were used to obtain the data presented 

### in this report.
PURITY DETERMINATION 

### A test solution 

### was prepared by dissolving approxilllately 2.0 g of the test substance into a 100 mL volumetric flask and diluting with methanol. The test solution was analyzed using gas chromatography with flame ionization detection (GC/FID) and the following method:

Instrument: Column: carrier: OVen: :Injection: Znj. Temp.: Detector Temp.: Hewlett Packard 5890 J+W DBWAX. 30m X 0.2Smm i.d., 0.2Sum film thickness Belium at 10psi initial bead pressure 80·C (no hold time) to 17S·C (no final hold time) at S·C/min 1 ul split with split flow at 60cc/min 27S·C 27S·C Page 6 of 18 

### KAN: 902270

### 291109D TX-94-96 APPENDIX Page 7 of32

STRUCTURE CONFIRMATION A test solution was prepared by dissolving approximately 0.2 g of the test substance ·i.'nto a 10 mL volumetric flask and diluting with methanol. The test solution was analyzed using gas chromatography with mass spectrometry (GC/MS) and the following method:

:Instrument: COlumn: carrier: Oven: Injection: Inj. Temp.: Interface Temp.: Source Temp.: Hode: Hewlett Packard S970 quadrupole MS J+W DBWAX, 30m x O.25mm Ld., G.1Sum film thickness Helium at 10psi initial head pressure 80°C (no hold time) to 175°C (no final hold time) at s·oc/min 1 ul splitless injection 27S0C 27SoC 250°C electron ionization (EI)
CONCENTRATION DETERMINATION Three samples of the test substance in distilled water were submitted for analysis on three separate days. The test substance mixtures were analyzed using gas chromatography with flame ionization detection (GC/FID) using the same instrument conditions as the purity phase of this study. A dose preparation of 40% (weight/volume) of the test substance in distilled water was received and analyzed on 3/1/94. An "al.iquot of the 40% dose preparation was diluted with distilled water and analyzed. A five point calibration curve (ranging from 4000 mg/L to 20,000 mg/L) was prepared using the pure test substance diluted in distilled water, and was analyzed along with the dose sample. A dose preparation of 20% (weight/volume) of the test substance in distilled. water was received and analyzed on 3/3/94. The results were highly variable from injection to injection of the same dilution; therefore, the data were considered unreliable (:these data are not reported) and the method of analysis was modified to inclUde the addition of 1- m.ethyl-2-propanol as an internal standard. The 20% preparation was reanalyzed on 3/4/94. The 40% preparation was also reanalyZed to determine the stability of the test sUbstance in distilled water. However, due to a technical error, the 20% and 40% preparations were reanalyzed on 3/5/94 when it was discovered that the standards were not analyZed on 3/4/94. All the values from the 3/4/94 and 3/5/94 analyses are reported. Page 7 of 18 KAN: 902270

### 291109D TX-94-96 APPENDIX 

### Page 8 

### of32

A third dose preparation of 10% (weight/vol.ume) ·of the test substance in ctistiJ.l.ed water 

### was received and ana1yzed on 3/1.5/94. The intez:nal. standard (1-methoxy-2-propanol.) 

### was used 

### with this anal.ysis**al.so~** The following dilutions were used:

.

SAMPLE :IO ALJ:QUar (mt..) ALIQUOT (mL) FINAL DOSE :INTERNAL 

### VOLUME STANDARD (mL) 40% Dose 1.0 NA 25 20% Dose 0.6 0.15 10 40% Dose Repeat 0.3 0.15 10 10% Dose 1.0 0.15 10

CALCULATIONS



## * 100% 

## * 1CL1 1000(mL) 

## * 1(gl 1000(mg) Linear regression (used for initial. .(0% samp1e): y=lIIX+b y 

## = area m 

## = slope 

### x 

## = conc. (mg/L) b 

## = y-intercept OF 

## = volume sol (mL1 Al.iquot taken(mL)

, sample 

## = conc. from linear reg. curve (mg/L) 

## * OF

lUtE" (used for remaining samp1es) Definitions: :IS 

## = internal standard RRF 

## = rel.ative response factor determined from 

### a ca1ibration standard RF 

# = average of the RRF factors determined for the individual. calibration levels 

### DF 

# = dilution factor

Page 8 of 18 KAN: 902270

### 29ii09D TX-94-96 APPENDIX 

### Page 9 

### of32

RRF 

## = area std. 

## * amount IS (mqlL) amount Std. (mq/L) 

## * area IS

OF = volume sol (mL) 

## * 1.(gl 

## '* 1. (Ll 

## '* 100 A1iquot taken(mL) 1000(mg) 1000(mL)
Amount spl. (wt/vol %) = area spI. 

## '* amount IS 

## '* OF area :IS 

## '* RF

EXNWLE CALCULATION RRF for injection 

### U (3/15/94) 4144 (1IlCJfL) std. RRF 

# = 234389 '* 1.5000(mg/Ll 

# = 1.3687 4144(mq/L) '* 619853 Average RRF for 3 injections of 4144 (1II9'/L) standard 

## = 1.4086 

### RF 

# = Average 

### RRF for 5 calibration standards 

# = 1.39696 OF for 10% dose sample: OF 

## = 10(mLl 

## * l(g) 

## * 1CLl '* 100 1 (mL) 1000(mg) 1000

### (mL) 0.001 (gl CLl (mg) (mL)
10% spl. inj 

### U (wt/vol %) 

## = 605074 '* 15000('mg/Ll '* O.OO1Cgl (Ll 631381'* 1.39696 (mq)(mL)



## = 10.3 

### (g/mL) 

## = 10.3%

RESULTS PURITY sample Request for Date Mean 

### std. N: 

### IO Analysis No. Analyzed Dev. Initial 179342 2/25/94 99.8% 0.015 3
Final 179347 3/25/94 99.8% 0.012 3

Page 9 of 18 KAN: 902270

### 291109D TX-94-96 

### APPENDIX Page 

### 10 of

### 32

STRUCTURE CONFIRMATION The structure of the test substance was consistent with the structure of ethylene glycol monobutyl ether based on comparison witli reference libr.u:y 

### spectra.

CONCENTRATION DETERHrNATION

40% '.rest Hi%ture Date Ana1yzed: 3/1/94 Request for Ana1ysis No.: 179343 Concentration of the Test SUbstance 

### in Distilled Water (weight/volume%) 40% Test Mixture

mean 

## = n (Injection 

# '2 not used) Injection 

### tJ. Injection 

# '3
42.5% 2 42.6% 42.4%

20% '.rest Hixture Dates Ana1yzed: 3/4/94, 3/5/94 Request for Analysis No.: 179344 concentration of the '.rest Substance in Distilled Water (weight/volume%) 20% Test Mixture

'4

- '6 injected 3/5/94) 18.8% 19.7% 20.9% 17.0% 16.7% 16.0% Injection

# '1 Injection

# '2 Injection

# '3 Injection

# '4 Injection 

# '5 Injection 

# '6
18.2% 6 1.92 10.5% mean n 

### Sx CV 

### ('1

- '3 injected 3/4/94;
Page 10 of 18 KAN: 902270

### 291109D TX-94-96 APPENDIX Page 11 of32

40%**~est** Hixture Repeat Dates Anal.yzed: 3/4/94, 3/5/94 Request for Analysis No.: 1.79344 Concentration of the Test SUbstance in Distil1ed Water (weight/volume%) 40' Test Mixture

mean n 

### SX CV = 

## = :Injection

# 'I :Injection 

### 12 :Injection 

### 13 :Injection

# '4 :Injection '5 Xnjection 16 44.5' 6 2.12 4.76% 46.6% 47.2% 44.7% 41.8% 44.1% 42.7%

(tl.

- '3 injected 3/4/94: '4

- 

# '6 injected 3/5/94)

10% Test Hixture Date Analyzed.: 3/15/94 

### Request for Analysis No.: 179346 Concentration of the Test Substance in Distilled Water (weight/volUJ1le%) 10% Test Mixture



### mean n SX CV 

## = = = = J:njection '1 :Injection 

### 12 :Injection 

### 13
10.1.% 3 0.51 5.05%

Page 1.1 of 18 10.3% 9.53% 10.5%



### RAN: 902270

### 291109D TX-94-96 APPENDIX 

### Page 12 of32

DI:SClJSSI:ON The purity of the test substance 

### was measured using' gas chromatography with flame ionization detection. 'Xhe initial. purity of the test substance 

### was**99.8~** and the final. purity was 99.8:t at the end of the study. The structure confi.xmation of the test substance was perfo:r:med 

### using gas chromatography with 

### mass spectrometry. The structure of the test substance 

### was consistent with the structure of ethyl.ene gl.ycol. monobutyl. ether based on comparison with reference l.ibrary spectra. An exampl.e spectrum is shown in figure 4, along with a reference l.ibrary spectrum of 2-butoxy ethanol (ethyl.ene glycol. monobutyl. ether). The concentration verification of the test substance mixtures 

### in distil.led water were determined foll.owing dilution with distil.l.ed water. The mean concentrations obtained for the 10,20, and**40~** preparations were 10.1, 18.2 and 42.5, respectivel.y. Al.though an oversight 

### in the 3/4 analysis of the**20~** preparation was discovered 

### in which the standards were not injected, the data from the 3/4/94 analyses could not be discounted because the**40~** preparation which was reanal.yzed at the same time 

### was within 10% of the val.ue from the 3/1/94 anal.ysis. DAn STORAGE AND RECORD RETENT:IOH Al.l original. raw data wUl. be transferred to the Health and Environment Laboratories archives of the Eastman Kodak Co., Building 320, for storage.
.

Page 12 of 18 KAN: 902270

### 291109D TX-94-96 

### APPENDIX 

### Page 13 

### of32
signature Page

# ADLYST._:"'-~J2~···**~~,;g.......k~~~u..~.=-.· 4~-'~2** **_-<:>a_4~_** N<lraCirj. Porter**D~**

Page J.3 of 1.8 KAN: 902270

### 291109D TX-94-96 APPENDIX Page 14 of32
FIGURE 1 EDHPLB CHR01m'.rOGRlU( PROH PURrrY**D~I:ON** SAHPLB OF SUBSTANCE J:N HB'rB]WOL

llut.,cIwoe.



# . 1000 900 eao 700 ;::

# -


# -

. 400 300 200 100

8.0 

# . 

# . 4.0 6.0 1.2.0 

# . . 14.0 16.0 

# .



# -


# - eao 700


# - sao



# .

# - 300 200 100

8.0 2.0 4.0 6.0 

## "0 10.0 '11_
...--....,

Page 14 of 1S U.Q 14.0 111.0

!<AN: 902270

### 291109D 

### TX-94-96 APPENDIX Page 15 

### of32



### FIGURE 2 EDHPLB**cmto~ ~OK**  COBCENntAttON**DE'r~:tON** 40% ':rES'r SUBSDNCB HLUuQ Dl:L1J'.rJ:ON 

### wrm D:tSTXLLED

. tm:rElt. (DlCLVDES S'DNDMm)

"",..Ietrwo-

l

..O 1••0

....0 "l.O

...0 S20
280
240
:zoo 

## :- 160 

# "i 120 

### 110'"**~.O**

:DN: 902270

### 291109D TX-94-96 

### APPENDIX Page 

### 16 of

### 32

FIGURE 3

BDHPLE ".rO'.rAL :tON**cmt.~** PROH s-ntUCTQRB CONE':IR!m.TJ:ON IDHPLB Ol!' 'nIB SUBSTANCE :tN**~OL**

Fil. >E8ftU

Page 16 of 18 

## is .'

DN: 902270

### 29ll09D TX-94-96· APPENDIX Page 17 

### of32



### fIGURE 4

EXAHPLE HAaS SPEc.rR1JH I'ROH**S~UC'rlJRE** CONP':IRHA'rXON
Fi 1. )E&n£2 904-0300 SPL. 1U1.. 9pl< Ab 21159. SPLLT. 30n Cl9UAX. 0.15Ut1 FILn Scan U-7 SUB 5.86 _in. 57 

# , 100

'110

REFERENCE X.rspARY IlABS SPEC'rRUH OP'

ETHu.ENE**GL~COL** HONOBUTYL ftHER

Fil. )91609 BpI< Ab 99')9_ Scan 19751 0.00 .in.

19 

# , 57 

# ,

100 104 

### ,./

Page 1.7 of 1.8 DN: 902270

### 291109D TX-94-96 

### APPENDIX Page 18 of32

Report Amendments Title: Purity. Structure Confirmation and Concentration Determination of Ethylene Glycol Monobutyl Ether KAN: 902270 The following changes were made to the report: Location: Page 7 Change: Concentration Determination Paragraph 2 Reason: The preparation and analysis descriptions of the 20% dose and the reanalysis of the 40% dose on 3/4/94 and 3/5/94**w~e** changed to clarify the analyses. Location: Page**~2** Change: The discussion was changed Reason: The discussion was changed to clarify the concentration determination analyses.

study Kathy Director: 

# K 

# t-.,_....-.......---- Staudenmaye%l

Page 18 of 18 !CAN: 902270

### 291109D TX-94-96 APPENDIX 

### Page 19 

### of32

PATHOLOGY REPORT Compound: Ethylene glycol monobutyl ether Male and female guineapigs given 2000. 1000, or500 mglkgofthe test mate:riaJ by gavage, as partofan acuteoral toxicity study. 

### were necropsied. Necropsy lesions are listed 

### in computer-generated tables. Thecause ofdeath for guineapigs, which died afterexposure to the test mate:rial, 

### was not determined. However, necrosis and hemOIrhage 

### in the glandular gastric mucosa. may have contributed to the deaths. GROSS PATHOLOGY Male Guinea Pigs

- 

### 2000 mglkg dose grouJ): Treatment-related changes 

### in two animals, which died on Day 

### I, and a singleanimal, which died on theday ofdosing, included minor to moderatediffuse necrosis (313) and minorhemorrhage 

### (313) in the gastric mucosaand minoraccumulation ofmucoid contents 

### in the duodenum (313). The carcasses oftwo animals showed minorautolysis. No treatment-related changes were observed 

### in the remaining two 

### animals that survived the 14-day obselV2.ti.on period. Male GuineaPigs

- 1000 mg/kg dose 

### groW: Treatment-related changes in a single animal which died on Day 

### 3 included moderate diffuse necrosis ofthe gastric mucosa, and minor red discolOIation ofthe facial 

### hair. No treatment-related changes were observed in the remaining four 

### animals which survived the 14-day observation period. 

### Male Guinea

### Pigs

- 500 mglkg dose grouJ!: No treatment-related changes were observed. All guinea

### pigs survived the 14-day observation period.

. Female Guinea Pigs

- 

## 2000 roglkg dW.e gI'OlJ1!: Treatment-related changes included minorto 

### modetate diffuse

### necrosis (5/5) and minorhemoabage (515) 

### in the gastric mucosa, and minor 

### accumulaliOD ofmucoid 

### contents in the duodenum. (415). Three

### animals died on theday of dosing and 

### the remaining two 

### animals died on Day 

### 1. Carcasses oftwo 

### animals showed minorautolysis. FemaleGuinea Pigs

- 1000 mglkg dose group: Treatment-related changes 

### in a singleznimal that died on Day I included minordiffusenecrosis and minima] bemoIIbage in the gastric i:''JCOS2., and 

### minimal accumulaDon ofmucoidcontents 

### in the duodenum. No treatment

### rdated ch3nges 

### were observed in theremaining four animals, which survived the 14-day 

### C?bservation period.

### 291109D TX-94-96 APPENDIX Page 

### 20 of

### 32

Female Guinea Pigs

- 

### 500 mglkg dose gtOU1!: No tIeatment-related changes were observed. All guineapigs survived the 14-dayobservationperiod. All otherlesions listed in the

### attachC:d tables 

### were not considered treatment-related. In the absence ofsignificantgross organ lesions, otherthan the obvious signs of**gastroin~** iIritation, no tissue

### was collected for microscopic examination. Comments: The test material 

### was a gastrointestinal

### irritantas evidenced by necrosis and hemonbage in the gastric mucosaand accumulation ofmucoid contents 

### in theduodenum. The cause for incomplete collapseofthe lungs upon thoracotomy and lung hemoIIbagethat were observed 

### in GuineaPigs 176 (1000 mg/kg) and 188 (1000 mglkg) 

### was notdetermined.

Milan 

### S. Vlaovic, 

### D.V.M., Ph.D.

MSV:dap 

### 04/12194EXPERIMENT I 9483e9Ae 

### 291109D TX-94-96 APPENDIX Page21 

### of32

SlMlARY GROSS PA1l1OLOCY INCIDENCE TABLE COIotPOUNO , 9+-e3ee SOFTllARE VERS I 3.8 ACCESSION NlU3ER 982270 

### see.oo9 '009.009 2ee8.ee8 IoIG/I<G IoIG/I<G 1oIG/l<G



### .. 

## .. .. TRACHEA 5 5 5 LUNGS 5 5 5

COLI.N'S£ INCOtoFLETE ON l'HORACOTa.rt' 8 

# , 8 HDICRI'lHf.GE 8 

# , 8 nmaJS 5 5 5 HEART 5 5 5

• ESOPHAGUS 5 5 5

STCUAOt 5 5 5 IoIJCOSA NECROSIS. DIFFUSE 8 

# , 3 HOIJRRHAGE 8 8 3 llUClDOUol 5 5 5

INTESTINAL CONTENTS INCREASED e e 3 JEJl.INUM 5 5 5. Il..ELU 5 5 5 C£Cl.U 5 5 5 COLON 5. 5 5 RECTUot 5 5 5 LIVER 5 5 5 KIONEYS 5 5 5**~INAR'r** BI,.q)l)ER 5 5 5 PITUITARY GlAND 5 5 5 ADRENAlS 5 5 5**p~.** NOS 5 5 5 THYROID GlANDS 5 5 5 PARATHYROID GLANDS S S S SPLEEN S S 5 MESENTERIC L"BFH NODES S 5 5 BONE MARROW S S S BRAIN 5 S S EYES S S 5 SALIVARY GLANDS S S S ADIPOSE TISSUE S S S I«IoIBERS REPRESENT7f!ER OF TISSUES EXAMINED. OR IN 1HE CASE OF A8NClRMAL FINDINGS. THE tu.lBER OF TI**Wl~ ~TY**  - REVIEWED BY:

# fkL.W/rP~**DATE:~ BY~~** **\1~Wv** DATE:tJl,j.fqlj 

## (J /CROUP 

### 291l09D TX-94-96 APPENDIX 

### Page 22 of32

CROSS PATHOLOGY INCIDENCE TABLE COIFCJUtoD , 94-0386 SOFlWARE VERS' 3.0 ACCESSION ......eER 902278 5e8.ee8 1ee8.ee8 2ee8.ee8 lotC/KC lotC/KC lotC/KC

.. M M SKIN. NOS 5 5 5 HAIR 5 5 5

HAIR OF' FACE OISCOl..CAATION.RED 

### e e JroCC£SSOln' SEX ORGANS (WALE) 5 5 5 EPIDIO'tUIDES 5 5 5 TESTES 5 5 5 BODY AS A WHOLE. NOS 

### e 8 2

AUTOl. YSIS 

### e 8 2 ER OF TISSUES EXAMINED. IN THE CASE OF ABNORMA.L FINDINGS. WIlM EACH ASNORNALITY REVIEWED

## B'f:.~!t!l:...::;t.q.L.1i2.l.~DATE: 3::Y)'i"FEPTED

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INDIVIDUAL ANI

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DAYS 01 TEST TRAOtEA L.l,N;S TtmIJS HEART ESOPHACUS STOloW:H OUODENIAI JEJUNtIoI ILDM CECLU COLON REC1Uol UVER KIDNEYS URINARY BLADDER PITUITARY GLAND AIlR£NALS PANCftEAS. NOS THYROID GI.NOS PARATHYROID GLANDS SPLEEN MESENTERIC L'lV'H NOOES BONE IolARROlI BRAIN EYES SALIVARY GLANDS ADIPOSE TISSUE SKIN. NOS 201 282 2e3 2M 285 14 14 14 14 14 X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X**~R** X X X X x ACCESSORl SEX ORGANS (NALE) X X X X x EPIDID'lUIDES 

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INDIVIDUAL ANIMAL CROSS PATHOI..OGY INCIDENCE TABLE EXPERIMENT , 948388A9 COI'OUND 9+-e3ee SOFTWARE VERS 3.9 ACCESSION toe 982Z78 1998.998 Y:/l<G GROlP
- lot ANIMAL , 176 177 178 179 188

DAYS ON TEST 3 14 14 14 14 lRACH£A

. X X X X X I.J..IoIGS X X X X

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INlIVIOUAL ANllIAl. GROSS**PA~** IHCIDDCE TABLE

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ANIMAL I

DAYS ON TEST TlWH:A I..lH:S TMYIIJS HEART E:SOPtWlUS S'1'CIMQi YJCClSA

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INTESTINAl. CONTDlTS

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- .. 161 162 163**1~** 165

14 8 14 X X X X X X X X X X X X X X X X X X X X X X X X X X X 323 222 X X 222 X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X· 

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SUAlARY GROSS PATHOLOGY' INCIDENCE TA8I..E COFOlN) , 94-938fI SOFTWARE VERS' 3.8 ACCESSIQI N.I8ER 982278 

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### 291109.D TX-94-96 

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### 32 INDIVIDUAl. ANIMAL GROSS PATHOLOGY INCIDENCE TABLE

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### APPENDIX 

### Page 32 of32

GROSS PATHOLO(;'( CClI&I£NT REPORT COWPOUND , 94--03ee SOFTWARE VERS' ;S.B ACCESSION MMlER 982278 DAY DOSE LEVEL AHIWAL-'



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