Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont l 0657 Study Title Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits Laboratory Project ID: DuPont 10657 . r TEST GUIDELINES: U. S. EPA Health Effects Test Guidelines OPPTS 870.3700 Prenatal Developmental Toxicity Study U. S. EPA Federal Register ( August 5, 1999). " Dibasic Esters; Final Enforceable Consent Agreement and Testing Consent Order." Vol. 64, No. 150, pp. 42692 42695.

AUTHOR: Susan M. Munley, M. A.

STUDY COMPLETED ON: April 15,2003 SPONSOR: SOCMA Dibasic Esters Group 1850 M Street, N. W., Suite 700 Washington, D. C. 20036 5810 PERFORMING LABORATORY: E. I. du Pont de Nemours and Company Haskell Laboratory for Health and Environmental Sciences Elkton Road, P. O. Box 50 Newark, Delaware 19714 0050 WORK REQUEST NUMBER: 13495 SERVICE CODE NUMBER: 733 Page 1 of 207 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT This study was conducted in compliance with U. S. EPA TSCA ( 40 CFR part 792) Good Laboratory Practice Standards, which are consistent with the OECD Principles of Good Laboratory Practice ( as revised in 1997) published in ENV/ MC/ CHEM( 98) 17 except for the item documented below. The item listed does not impact the validity of the study.

The test substance was characterized by the sponsor prior to the initiation of the study. Although the characterization was not performed under Good Laboratory Practice Standards, the accuracy of the data is considered sufficient for the purposes of the study.

Study Director; m. alecApI .

5/$ xdZm3 san M. Munley, M#. Dale Research Scientist E. I. du Pont de Ncmoursand Company 2 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 QUALITY ASSURANCE STATEMENT Haskell Sample Number( s):

25136 Dates of Inspections:

Protocol: May 20,2002; June 17,24,2002 Conduct: July 3,17,2002 Records, Reports: January 15 17,20 24,27,2003 Dates Findings Reported to:

Study Director: May 28,2002; June 17,2002; January 23,27,2003 Management: February 6,2003; April 14,2003 Reported by: j5 APR ao03 Date Staff Quality Assurance Auditor Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 CERTIFICATION We, the undersigned, declare that this report provides an accurate evaluation of data obtained from this study.

InhalationEvaluatbnsby: / s 45 J . & u3 Linda A Malley, W. D. Date Senior R h Toxicologist Issuedby Study Director: 13= 4 Y aa23 SusanM. Muley, M/ AI Date 4 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10457 TABLE OF CONTENTS Page GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT ......................................... 2 QUALJTY ASSURANCE STATEMENT...................................................................................... 3 CERTIFICATION ........................................................................................................................... 4 STUDY INFORMATION............................................................................................................... 7 STUDY PERSONNEL.................................................................................................................... 8 SUMMARY .................................................................................................................................... 9 OBJECTIVE.................................................................................................................................. 10 MATERIALS AND METHODS .................................................................................................. 10 A. Test Guidelines................................................................................................................... 10 B. Test Substance and Vehicle............................................................................................... 10 C. Test Species....................................................................................................................... 10 D. Animal Husbandry............................................................................................................. 11 E. Quarantine and Pretest Period ........................................................................................... 12 F. Study Design ..................................................................................................................... 12 G. Selection of Dose Levels ................................................................................................... 12 H. Randomization .................................................................................................................. 12 I. Inhalation Exposure System .............................................................................................. 13 J. Characterization of Chamber Atmosphere ........................................................................ 14 K. Animal Euthanasia ............................................................................................................ 15 L. Parameters to be Studied ................................................................................................... 15 M. Control of Bias .................................................................................................................. 17 N. Statistical Analyses............................................................................................................... 18 RESULTS AND DISCUSSION.................................................................................................... 19 Inhalation Exposures ..................................................................................................................... 19 A. Chamber Concentrations ofthe Test Substance................................................................ 19 B. Chamber. Environmental Conditions ................................................................................. 20 C. Clinical Observations During Exposure ............................................................................ 21 Developmental Evaluations........................................................................................................... 22 A. Maternal Findings.............................................................................................................. 22 B. Fetal Findings .................................................................................................................... 23 CONCLUSIONS ........................................................................................................................... 24 RECORDS AND SAMPLE STORAGE....................................................................................... 24 REFERENCES.............................................................................................................................. 25 TABLES ........................................................................................................................................ 27 1 2 3 4 5 6 7 8 9 10 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 FIGURES ...................................................................................................................................... 48 APPENDICES............................................................................................................................... 52 LIST OF TABLES Page TABLE CHAMBER CONCENTRATIONS OF DMG ............................................................................................ 29 TABLE PARTICLE SIZE DISTRIBUTION OF DMG ........................................................................................... 31 TABLE CHAMBER ENVIRONMENTAL CONDITIONS .................................................................................... 32 TABLE MEAN MATERNAL BODY WEIGHTS ................................................................................................... 34 TABLE MEAN MATERNAL BODY WEIGHT CHANGES ................................................................................. 38 TABLE MEAN MATERNAL FOOD CONSUMPTION ........................................................................................ 41 TABLE CLINICAL OBSERVATIONS................................................................................................................... 43 TABLE REPRODUCTIVE OUTCOME.................................................................................................................. 44 TABLE INCIDENCE OF FETAL MALFORMATIONS ........................................................................................ 45 TABLE INCIDENCE OF FETAL VARIATIONS................................................................................................. 46 LIST OF APPENDICES APPENDIX A CERTIFICATE OF ANALYSIS ......................................................................................................... 53 APPENDIX B PROTOCOL ........................................................................................................................................ 55 APPENDIX C DAILY CHAMBER CONCENTRATIONS ....................................................................................... 72 APPENDIX D DAILY CHAMBER ENVIRONMENTAL CONDITIONS ............................................................... 76 APPENDIX E INDIVIDUAL BODY WEIGHTS....................................................................................................... 81 APPENDIX F INDIVIDUAL BODY WEIGHT CHANGES ................................................................................... 108 APPENDIX G INDIVIDUAL FOOD CONSUMPTION.......................................................................................... 125 APPENDIX H INDIVIDUAL. CLINICAL OBSERVATIONS................................................................................. 137 APPENDIX I GROSS POSTMORTEM FINDINGS ................................................................................................ 155 APPENDIX J INDIVIDUAL REPRODUCTIVE DATA ......................................................................................... 162 APPENDIX K INDIVIDUAL FETAL WEIGHTS AND ALTERATIONS ............................................................. 169 6 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 STUDY INFORMATION 9th Collective Nomenclature: Pentanedioic acid, dimethyl ester Synonyms/ Codes: 0 DBE 5 DMG H931363 A ( Lot NO.) H 24300 Haskell Number: 24300 CAS Registry Number: 1119 40 0 Composition: 99.61% Dimethyl glutarate ( DMG DBES) by GC Known Impurities: 0.085% Dimethyl adipate ( DMA DBEG) by GC 0.163% Dimethyl succinate ( DMS DBE4) by GC 2.8 ppm HCN Physical Characteristics: Colorless liquid Stability: The test substance was stable under the conditions of the study.

Sponsor: SOCMA Dibasic Esters Group 1850 M Street, N. W., Suite 700 Washington, D. C. 20036 5810 Study InitiatedCompleted: June 18,2002/ ( see report cover page)

7 Dimethvl Glutarate ( DMG): Inhalation DeveloDmental Toxicity Study in Rabbits DuPont 10657 STUDY PERSONNEL Study Director: Susan M. Munley, M. A. Inhalation Consultant: Linda A. Malley, Ph. D. Management: Eve Mylchreest, Ph. D. Robert M. Parker, Ph. D., D. A. B. T Supervisor: Deborah L. Tyler Primary Technician: William P. Boyer Supervisor: Arthur J. O Neill, B. S. Inhalation Technician: John A. Nogaj, B. S.

Toxicology Report Preparation: Mary K. LaRoe Management: Nancy S. Selzer, M. S.

Laboratory Veterinarian: Thomas W. Mayer, D. V. M., A. C. L. A. M. William Singleton, D. V. M., A. C. L. A. M.

8 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 SUMMARY Dimethyl glutarate ( DMG) was administered by inhalation to groups of 22 time mated Hra:( NZW) SPF rabbits. The inhalation exposures were whole body exposures and animals were exposed for approximately 6 hours each day on days 7 through 28 of gestation. Target chamber concentrations were 0, 30, 100,300, or 1000 mg/ m3. During the in life period, maternal body weight, food consumption, and clinical observation data were collected daily. Animals were euthanized on day 29 of gestation; dams were subjected to a gross external and internal postmortem examination. Gravid uteri were removed, weighed, and dissected and the uterine contents were described. Each live fetus was weighed, sexed, and examined for external, visceral, and skeletal alterations.

At 1000mg/ m3, there was compound related mortality; one animal was found dead on gestation day 13 and one animal was sacrificed in extremis on gestation day 22. Among survivors, there were compound related reductions in maternal body weight gains and food consumption and there were compound related clinical observations ( ocular discharge and wet fur). At 300 mg/ m3, evidence of compound related maternal toxicity was limited to reduced maternal body weight gains and increased clinical observations ( ocular discharge).

Under the conditions of the current study, there was no evidence of compound related maternal toxicity at 30 or 100 mg/ m3 and there was no evidence of developmental toxicity at any level tested. Thus, the no observed effectlevel ( NOEL) afor maternal toxicity was considered 100 mg/ m3 and the NOEL for developmental toxicity was considered 1000mg/ m3.

The NOEL for this study is defined as the highest dose at which toxicologically important effects attributable to the test substance were not detected. Thus, for this study, the NOEL is equivalent to the NOEL as defined by the United States EnvironmentalProtection Agency ( 1985) and to the no observed adverse effectlevel ( NOAEL) as defined by the European Union ( 1994).

9 Dimethvl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 OBJECTIVE The objective of this study was to evaluate the developmental toxicity of the test substance when administered by inhalation to pregnant rabbits or from around the time of implantation to near the end of gestation.

MATERIALS AND METHODS A. Test Guidelines The study design complies with following test guidelines:

United States Environmental Protection Agency ( EPA), Office of Prevention, Pesticides, and Toxic Substances ( OPPTS) Health Effects Test Guidelines, OPPTS 870.3700 Prenatal Developmental Toxicity Study ( 1998).'"

EPA Consent Agreement and Testing Consent Order.' 2'

B. Test Substance and Vehicle The sponsor supplied the test substance and an analytical standard of known purity. The test substance was assigned Haskell Laboratory Number 24300.

C. Test Species The Hra:( NZW) SPF rabbit was selected for this study to provide data in a nonrodent species and because it is a preferred species for developmental toxicity testing. The Hra:( NZW) SPF strain was chosen because extensive background information is available from the literature, the supplier, and previous studies with other compounds at Haskell Laboratory.

A total of 110 nulliparous, time mated female rabbits were received from COVANCE, Denver, Pennsylvania. Sixty six female rabbits were received on June 19, 2002 and 44female rabbits were received on June 21,2002. Body weights on the day of mating defined as day 0 of gestation ( G) were supplied by the vendor. The rabbits for this study were approximately 6 months old and were at either day 1,2, or 3G upon arrival.

10 Dimethvl Glutarate ( DMG): Inhalation DeveloDmental Toxicitv Studv in Rabbits DuPont 10657 D. Animal Husbandry 1. Housing Animal rooms were maintained at an acceptable temperature of 17 23 ° C ( targeted at 20 ° C) and a targeted relative humidity of 50% rf~ 10%. Animal rooms were artificially illuminated ( fluorescent light) on a 12 hour lighvdark cycle ( approximately 0600 1800 hours). Animals were housed individually in suspended, wire mesh, stainless steel cages. Nesting material was not provided because the does were euthanized prior to parturition.

To address logistical considerations, the rabbits on this study were housed in 4 animals rooms near the exposure chambers. There was a significant aerosol component in the high level chamber; therefore, to prevent unintentional exposure of control or lower level animals to the residual aerosol, the control group rabbits were housed separately in one room. The rabbits exposed to 1000mg/ m3were housed separately within a hood so that the higher air flow in the hood promoted evaporation of aerosol deposits on the fur. The remaining 3 groups of rabbits were housed in 2 other rooms.

2. Feed and Water On the day of arrival and daily thereafter each rabbit received approximately 150 grams per day of PMINutrition International, Inc. Certified High Fiber Rabbit LabDiet@ 5325. Food was not available during inhalation exposures. Water from United Water Delaware was available ad libitum.

3. Identification Each animal was assigned a unique number and identified with a microchip implant by the supplier prior to shipping. Upon receipt, each animal was assigned a unique Haskell animal number. Both the Haskell animal number and the number provided by the supplier were recorded on each cage card. A master list of unique Haskell animal numbers and corresponding unique supplier provided animal numbers was maintained with the study records.

4. Health Monitoring Program As specified in the Haskell Laboratory animal health and environmental monitoring program, the following procedures are performed periodically to ensure that contaminant levels are below those that would be expected to impact the scientific integrity of the study:

Water samples are analyzed for total bacterial counts and the presence of coliforms, lead, and other contaminants.

Feed samples are analyzed for total bacterial, spore, and fungal counts.

Samples from freshly washed cages and cage racks are analyzed to ensure adequate sanitation by the cagewashers.

11 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 Certified animal feed is used, guaranteed by the manufacturer to meet specified nutritional requirements and not to exceed stated maximum concentrations of key contaminants, including specified heavy metals, aflatoxin, chlorinated hydrocarbons, and organophosphates. The presence of these contaminants below the maximum concentration stated by the manufacturer would not be expected to impact the integrity of the study.

The animal health and environmental monitoring program is administered by the attending laboratory animal veterinarian. Evaluation of these data did not indicate any conditions that affected the validity of the study.

E. Quarantine and Pretest Period Rabbits were quarantined according to procedures outlined in Haskell Laboratory SOP LAOO3 P and then released for the study upon approval of the laboratory animal veterinarian s designee.

F. Study Design The study design is as follows:

Group I II III N V Target Concentrationa ( mg/ m3)

Ob 30 100 300 1000 Mated Females 22 22 22 22 22 a DMG was administered by inhalation, 6 hours per day, on days 7 286. b Conditioned air.

G. Selection of Dose Levels The exposure levels and route of exposure for the current study were selected by the Sponsor.

H. Randomization Does were ranked on the basis of day 0 gestation body weights and assigned to control and experimental groups by random sampling from the ranked list. The distribution resulted in mean body weights for all groups that were not statistically different ( p> 0.05).

12 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 I. Inhalation Exposure System ( Figure 1)

1. Atmosphere Generation Chamber atmospheres were generated by aerosolization of the test substance in air with a Spraying Systems Nebulizer. The test substance was metered into the nebulizer with a Cole Palmer Mastefflex@ Console Drive pump. Filtered, high pressure air, metered into the nebulizer by a Brooks model 585li Mass Flow Controller, aerosolized the liquid test substance. The resulting aerosol and/ or vapor mixture was mixed with filtered, high pressure air that carried the mixture to the exposure chambers. The pumps and mass flow controllers were controlled and monitored by the Camile Inhalation Toxicology Automated Data System ( CITADS). The concentration of the test substance in each test chamber was adjusted by varying the amount of liquid test substance delivered to the nebulizer.

Test atmospheres were exhausted through a water filled scrubber prior to discharge into the exhaust stack.

2. Chamber Construction and Design All exposure chambers were constructed of stainless steel and glass ( NYU style) with a nominal internal volume of 9 1113. A tangential feed at the chamber inlet promoted uniform chamber distribution of the test atmosphere.

3. Exposure Duration and Mode During exposure, rabbits were individually restrained in wire mesh cages and exposed, whole body, inside the exposure chamber. Exposures were conducted during approximately the same time period each day to minimize diurnal physiological variations. Control group rabbits were treated exactly as test rabbits, with the following exceptions: the wire exposure cages for the control group rabbits were slightly larger than those used for the rabbits in the treatment groups and the control group rabbits' chamber atmosphere did not contain the test substance. The chamber volume was chosen so that the total body volume of the test animals did not exceed 5% of the chamber volume.

Rabbits were exposed approximately 6 hours per day during days 7 286. The starting time of each exposure was defined as the time when the generation system was turned on. The ending time of each exposure was defined as the time when the generation system was turned off. Rabbits were exposed to the test substance during both the time it took to reach the target concentration, and the time it took for the test substance to be purged from the chamber. After each exposure, the rabbits were returned to their home cages.

The animals were received in 5 lots based on their day of gestation upon arrival. Therefore, the initiation of exposures was staggered over 5 days such that each lot started exposures on day 7G.

13 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 J. Characterization of Chamber Atmosphere 1. Test Substance Sampling and Analysis For all test exposure chambers, the vapor component of the atmospheric concentration of DMG was determined by gas chromatography. For the test exposure chambers, known volumes of chamber atmosphere were drawn, at approximately 90 minute intervals, from the breathing zone of the animals through glass impingers containing acetone as the collection medium. The control chamber was similarly sampled once daily for measurement of atmospheric concentration. Aliquots of impinger solution were injected on a Restek@ fused silica glass ( inside diameter 0.53 mm) with RTX 502.2 coating column in a Hewlett Packard model 6890 Series Gas Chromatograph equipped with a flame ionization detector. The atmospheric concentration of the test substance was determined from a standard curve derived from liquid standards. Standards were prepared weekly by the quantitative dilution of DMG liquid in known volumes of acetone.

For the 300 and 1000 mg/ m3exposure chambers, the aerosol component of the atmospheric concentration of DMG was determined by gravimetric analysis. Known volumes of chamber atmosphere were drawn, at approximately 30 minute intervals, from the breathing zone of the animals through a 25 mm filter cassette that contained a pre weighed Gelman glass fiber ( Type A/ E) filter. The filters were weighed on a Cahn model C <EMAIL_ADDRESS>The filter weights were automatically transferred to CITADS, which calculated the chamber concentrations based on the difference in pre and post sampling filter weights divided by the volume of chamber atmosphere sampled. Gravimetric sample start and stop times for each sample were also controlled and recorded by CITADS. Prior to study start, gravimetric samples collected from the 30 and 100 mg/ m3chambers indicated that no aerosol was present for these 2 concentrations.

A sample to determine particle size distribution ( mass median aerodynamic diameter and percent particles less than 1,3, and 10 pm diameter) was taken once per week from the 1000 mg/ m3 exposure chamber with a Sierra@ Series 210 Cyclone Preseparatodcascade Impactor and Sierra@ Series 110 Constant Flow Air Sam~ ler.'~)

2. Environmental Monitoring Chamber airflow was set at the beginning of each exposure to achieve at least 12 air changes per hour and was monitored continually with a calibrated Brooks model 5851i Mass Flow Controller. Chamber temperature was targeted at 17 23 ° C and was measured with an Omega Thermocouple Thermometer. Chamber relative humidity was targeted at 50 & 10% and was measured with Jumo wet bulb/ dry bulbresistance temperature detectors. Airflow, temperature, and relative humidity were monitored continually with CITADS and recorded at approximately 15 minute intervals during each exposure. Chamber oxygen concentration was targeted to be at least 19%. Chamber oxygen concentration was measured with a Biosystems model 31OOR Oxygen Analyzer and was recorded twice during each exposure.

14 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont I 0657 K. Animal Euthanasia 1. Adults Does were euthanized by the intravenous injection of sodium pentobarbital. The identity and lot number of the euthanasia solution was recorded in the study records.

2. Fetuses Fetuses were euthanized by intraperitoneal injection of sodium pentobarbital after external examination was complete, prior to performing visceral examinations.

L. Parameters to be Studied 1. In life Observations of Females a. Body Weight Body weights were recorded in the morning on the day after arrival through day 29G.

b. Food Consumption Food consumption was measured daily on days 4 296.

c. Clinical Signs Clinical signs were recorded each morning on days 4 296 and each afternoon following exposures on days 7 286. Observations, at approximately hourly intervals, were made during the exposures to assess, to the extent possible, the overall state of the animals. In addition, the response of the animals to a sound stimulus while in the chambers was recorded before vapor generation began, after approximately 3 hours of exposure, and prior to removal of the animals from the chambers.

2. Postmortem Observations of Females Dying Prior to Scheduled Euthanasia A gross external and visceral examination was performed within 24 hours after the doe was found dead or sacrificed in extremis. Pregnancy status was determined and the uterine contents were described. Dead rabbits were refrigerated until necropsied.

15 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 3. Postmortem Observations of Does Aborting or Delivering Early a. Dam Observations Dams that aborted ( day 27G or earlier) or delivered early ( day 28 or 29G) were euthanized within 24 hours of detection and a gross external and visceral examination was performed.

b. Fetal Observations Fetuses remaining in the uterus or aborteddelivered early were examined to the extent possible. Data from these litters were maintained with the raw data but were excluded from all relevant fetal data calculations.

4. Postmortem Observations of Does Surviving to Scheduled Euthanasia a. External Appearance Each doe was examined immediately after euthanasia on day 29G.

b. Viscera Viscera were examined grossly immediately after euthanasia.

C. Uterine Weight The intact and empty uterus of each doe having at least one viable fetus was weighed to permit calculation of maternal body weight adjusted to exclude the products of conception.

d. Corpora Lutea The count for each ovary of darns with viable fetuses was recorded.

e. Implantations For each female with visible implants, the type ( live and dead fetuses, and resorptions) and their relative positions were recorded. The uterus of each apparently " nonpregnant" female was stained with ammonium sulfide to detect very early res~ rptions.'~'

5. Fetuses of Does Surviving to Scheduled Euthanasia a. Number, Location, and Condition These parameters were recorded for each fetus.

b. Fetal Weight The body weight for each fetus was recorded.

16 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 C. External Alterations The alterations detected for each live fetus was recorded.

d. Soft Tissue Alterations For each live fetus, fetal sex and any visceral alterations detected were re~ orded.'~) A transverse section, deep enough to permit examination of the brain, was made between the parietal and frontal bones. On the day of sacrifice, the eyelids of each fetus were removed to examine the eyes for alterations.

e. Skeletal Alterations After fixation in alcohol, the alizarin stained skeletons were examined and alterations detected were recorded for each live fetus.

M. Control of Bias In addition to random assignment to groups, all does were coded before scheduled euthanasia and remained coded during the collection of postmortem and fetal data.

17 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 N. Statistical Analyses Descriptive statistics including mean, standard deviation, and standard error of the mean were used to summarize exposure concentration and environmental data.

For the parameters listed below, descriptive statistics were performed and sequential trend tests were applied to the data as tabulated below.@) If a significant dose response trend was detected, data from the top dose group were excluded and the test repeated until no significant trend was evident. For litter parameters, the proportion of affected fetuses per litter or the litter mean was used as the experimental unit for statistical eval~ ation.'~) The level of significance selected was p e 0.05.

Parameter Maternal weight Maternal weight changes Maternal food consumption Live fetuses Dead fetuses Resorptions Nidations Corpora lutea Incidence of fetal alterations Incidence of pregnancy Clinical observations Maternal mortality Females with total resorptions Abortiondearly deliveries Fetal weight Sex ratio Trend Test Linear contrast of means@)

Jonckheere's test'"

Cochran Armitage test'"

Linear contrast of least square means' 10)

Where the data were tied and the standard large sample version of Jonckheere's test was not applicable, exact p values for Jonckheere's test were calculated using permutation methodology.'' li 18 Dimethvl Glutarate ( DMG): Inhalation DeveloDmental Toxicity Study in Rabbits DuPont 10657 RESULTS AND DISCUSSION Inhalation Exposures A. Chamber Concentrations of the Test Substance ( Table 1, Appendix A, Figures 2 3)

1. 30mg/ m3 The mean vapor concentrations over the 22 day exposure period ranged from 30 31 mg/ m3for lots A E, and the overall mean concentration for all 5 lots over the 26 day sequence of exposures was 30 zt 0.58 mg/ m3. Daily mean concentrations generally ranged from 93% 123% of the target concentration for the 30 mg/ m3 group ( with the exception of the first exposure day in which the mean was 19 mg/ m3). Although the mean daily chamber concentrations occasionally exceeded 90% 110% of the targeted concentrations, the mean concentrations for the exposure period were consistent ( Figures 2 3), and were acceptable for evaluating the toxicity at the targeted concentrations.

Preliminary exposures conducted prior to study start demonstrated that an aerosol component was not present for this concentration. The calculated overall nominal concentration was 43 mg/ m3.

2. 100mg/ m3 The mean vapor concentrations over the 22 day exposure period ranged from 99 100mg/ m3for lots A E, and the overall mean concentration for all 5 lots over the 26 day sequence of exposures was 100 & 0.74 mg/ m3. Daily mean concentrations ranged from 89% 110% of the target concentration for the 100mg/ m3group. Although the mean daily chamber concentrations were occasionally exceeded 90% 110% of the targeted concentrations, the mean concentrations for the exposure period were consistent ( Figures 2 3), and were acceptable for evaluating the toxicity at the targeted concentrations.

Preliminary exposures conducted prior to study start demonstrated that an aerosol component was not present for this concentration. The calculated overall nominal concentration was 129mg/ m3.

3. 300mg/ m3 The mean vapor concentration over the 22 day exposure period was 300 mg/ m3 for lots A E, and the overall mean vapor concentration for all 5 lots over the 26 day exposure period was 300 . e 2.7 mg/ m3. The mean aerosol concentrations ranged from 1. O 1.2mg/ m3 for lots A E, and the overall mean aerosol concentration for all 5 lots over the 26 day exposure period was 1.1 rt 0.11 mg/ m3. Based on the vapor concentration and the aerosol concentration ( and rounding 19 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 to 2 significant figures), the mean total calculated concentrations were 300 mg/ m3for each lot and for the overall mean for all 5 lots over the 26 day sequence of exposures. The concentrations ranged from 90% 110% of the target concentration for the 300 mg/ m3 group were consistent for the exposure period ( Figures 2 3), and were acceptable for evaluating the toxicity at the targeted concentrations.

Since the amount of aerosol in the 300 mg/ m3chamber was low, particle size of the aerosol droplets was not determined.

The calculated overall nominal concentration was 590 mg/ m3.

4. 1000 mg/ m3 The mean vapor concentration over the 22 day exposure period ranged from 520 530 mg/ m3for lots A E, and the overall mean vapor concentration for all 5 lots over the 26 day exposure period was 520  t 6.5 mg/ m3. The mean aerosol concentrations ranged from 470 480 mg/ m3 for lots A E, and the overall mean aerosol concentration for all 5 lots over the 26 day exposure period were 480 f. 7.96 mg/ m3. The mean daily vapor concentrations ranged from 450 590 mg/ m3, and the mean daily aerosol concentrations ranged from 410 580 mg/ m3for all 5' lots. Based on the vapor concentration and the aerosol concentration ( and rounding to 2 significant figures), the mean total calculated concentrations were 1000mg/ m3for each lot and for the overall mean for all 5 lots over the 26 day sequence of exposures. The concentrations were consistent for the exposure period ( Figures 2 3), and were acceptable for evaluating the toxicity at the targeted concentrations.

The mass median aerodynamic diameter ( MMAD) ranged from 8.0 9.0 pm, and the geometric standard deviation ( GSD) ranged from 2.1 to 2.4 for the 1000mg/ m3group. In the 1000 mg/ m3 group, 0.2% 0.55% of the particles were less than 1pm, 8% 11% of the particles were less than 3 pm, and 54% 62% of the particles were less than 10 pm. Although the particle size was larger than the reported respirable range for rabbits,(' 2) the animals did receive a sufficient concentration of the test substance to produce mortality in 2 rabbits.

The calculated overall no'minal concentration was 3160 mg/ m3.

Since the aerosol concentration was the highest in the 1000 mg/ m3 chamber, distribution of the aerosol component was determined prior to the initiation of exposures in the 1000mg/ m3 chamber only. Thirteen aerosol concentration measurements were collected from 9 separate sampling locations, and the concentrations ranged from 611 716 mg/ m3. The Wilk Shapiro test of normality was used to analyze these data, and the chamber concentrations were normally distributed with no significant differences detected for any sampling site.

B. Chamber Environmental Conditions ( Table 2, Appendix B)

The overall mean chamber temperatures in the 4exposure chambers during the total of 26 exposures for all 5 lots were 2 1 22 ° C. The daily mean chamber temperature values ranged 20 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 from 19 24 ° C. Although the chamber temperature slightly exceeded the targeted range of 1723OC the slightly higher temperature did not adversely affect the health of the animals, based on their clinical appearance.

The overall mean relative humidity values in the 4 exposure chambers during the total of 26 exposures for all 5 lots was 51% 56%. The daily mean relative humidity values in the 4 chambers ranged from 45% 64%. Although the relative humidity exceeded the targeted range of 40% 60%, the slightly higher relative humidity did not adversely affect the health of the animals, based on their clinical appearance.

The overall mean chamber airflow in the 4 exposure chambers during the total of 26 exposures for all 5 lots exposure was 1800 1900Urnin. The daily mean airflow values in the 4 chambers ranged from 1700 2100L/ min. The airflow in the chamber was adequate to achieve at least 12 air changes per hour.

The chamber oxygen content was 21% in all 4 chambers throughout the 26 day exposure sequence.

C. Clinical Observations During Exposure For each exposure concentration, the response of the animals to an alerting stimulus administered prior to exposure, during exposure, and after the conclusion of the exposure period was normal. In addition, although some animals in the 1000mg/ m3 chamber had wet fur from deposition of the aerosol on the fur during exposure, there were no clinical signs of toxicity observed during exposure.

21 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 Developmental Evaluations A. Maternal Findings 1. Mortality and Reproductive Outcome ( Table 8, Appendix J)

There was no compound related mortality at exposure levels 5 300 mg/ m3. At 1000 mg/ m3, one female was found dead on day 13G and another female was sacrificed in extremis on day 22G.

There were no compound related effects on indicators of reproductive outcome. One control group rabbit aborted on day 19G and one 100 mg/ m3group rabbit delivered early prior to euthanasia on day 29G. In addition, one 1000 mg/ m3 litter consisted entirely of late resorptions. The findings for this one litter were not considered to be compound related because no other litters were similarly affected and additionally, there was no increase in resorptions for litters also containing live fetuses. At 1000mg/ m3, there was a significant decrease in the mean number of nidation sites per doe. This was not considered related to the exposure because implantation is considered to have occurred prior to the start of exposures on day 7G. Furthermore, this decrease is consistent with a lower mean corpora lutea count in this group.

2. Body Weights and Weight Changes ( Tables 4 and 5, Appendices E and F)

There were no compound related effects on maternal body weight parameters at exposure levels I 100 mg/ m3. There were significant reductions in overall weight change ( days 7 296) at 300 and 1000mg/ m3; these significant effects were evident at the onset of exposures ( days 7 9G) and generally persisted throughout gestation.

3. Food Consumption ( Table 6, Appendix G)

There were no compound related effects on maternal food consumption at exposure levels 5 300 mg/ m3. At 1000mg/ m3, mean food consumption was significantly reduced when averaged over the exposure period ( days 7 29G); the reduction was significant and pronounced at the onset of exposures ( days 7 9G) and persisted throughout exposures to some extent as well.

4. Clinical Observations ( Table 7, Appendix H)

There were no compound related increased clinical observations at exposure levels 2 100 mg/ m3. At 300 and 1000 mg/ m3, compound related clinical observations included clear ocular discharge; at 1000mg/ m3, all animals had wet fur.

22 Dimethyl Glutarate ( DMG): Inhalation DevelopmentalToxicity Study in Rabbits DuPont 10657 5. Postmortem Findings ( Appendix I)

There were no compound related gross postmortem findings at any level tested.

B. Fetal Findings 1. Mortality and Sex Ratio ( Table 8, Appendix J)

There were no compound related effects on embryofetal viability or on fetal sex ratio at any level tested. The mean number of live fetuses per litter appeared to be slightly reduced at 1000 mg/ m3, however, this apparent reduction was not considered compound related and is believed to have resulted from previously discussed reductions in mean numbers of corpora lutea and nidations at this level that were not considered compound related.

2. Body Weight ( Table 8, Appendices J and K)

There was no compound related effect on fetal body weight at any level tested.

3. Malformations ( Table 9, Appendix K)

There were no compound relatedfetal malformations at any level tested.

4. Variations ( Table 10, Appendix K)

There were no compound related fetal variations at any level tested.

There was a significant increase in retarded sternebral ossification at 1000mg/ m3. This increase, however, was not considered to be compound related; rather, the statistical significance appears to be the result of an unusually low control group value relative to relevant historical control group data. Current study incidences for this finding are 9 fetuses ( 4 litters), 15( 5), 15( 4), 12( 5), and 28( 8) for the 0,30,100,300, and 1000mg/ m3 groups respectively. In comparison, for three recently completed studies ( DuPont 7405, DuPont 3932, and DuPont 1162) control group incidences for this finding were 16 fetuses ( 9 litters), 29( 8), and 38( 1 l), respectively. Furthermore, there are no other data supportive of a compound related fetal effect at this level.

23 Dimethvl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 CONCLUSIONS Under the conditions of the current study, there was no evidence of compound related maternal toxicity at 30 or 100mg/ m3 and there was no evidence of developmental toxicity at any level tested. Thus, the no observed effect level ( NOEL) afor maternal toxicity was considered 100 mg/ m3 and the NOEL for developmental toxicity was considered 1000 mg/ m3.

RECORDS AND SAMPLE STORAGE All data and records for analytical characterizations conducted by the sponsor will be retained by the sponsor. Laboratory specific or site specific raw data, such as personnel files and equipment records will be retained by the facility where the work was done.

A sample of the test substance will be collected for archive purposes and retained at Haskell Laboratory, Newark, Delaware. Specimens ( if applicable), raw data, and the final report will be retained at Haskell Laboratory, Newark, Delaware, or at Iron Mountain Records Management, Wilmington, Delaware.

a The NOEL for this study is defined as the highest dose at which toxicologically important effects attributable to the test substance were not detected. Thus, for this study, the NOEL is equivalent to the NOEL as defined by the United States Environmental Protection Agency( 13) and to the no observed adverse effect level ( NOAEL) as defined by the European Union.(' 4)

24 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 1.

2.

3.

4.

5.

6.

7.

8.

9. REFERENCES United States ( U. S.) Environmental Protection Agency ( EPA), Office of Prevention, Pesticides and Toxic Substances ( OPPTS) ( 1998). OPPTS 870.3700 Prenatal Developmental Toxicity Study. Health Efsects Test Guidelines.

United States ( U. S.) Environmental Protection Agency ( EPA) Federal Register ( August 5, 1999).   Dibasic Esters; Final Enforceable Consent Agreement and Testing Consent Order.  Vol. 64, No. 150, pp. 42692 42695.

Calculation described in Sierra Instruments, Inc., Bulletin 7 79 219IM, Instruction Manual: Series 210 Ambient Cascade Impactors and Cyclone Preseparators.

Salewski, E. ( 1964). Farbemethode zum makroskopischen Nachweis von Implantationstellen am Uterus der Ratte. Archiv. Path. Exp. Pharmakol. 247: 367.

Staples, R. E. ( 1974). Detection of visceral alterations in mammalian fetuses. Teratology 9( 3): A37 A38.

Selwyn, M. R. ( 1995). The use of trend tests to determine a no observable effect level in animal safety studies. J. Am. Col. Toxicol, 14( 2): 158 168.

Haseman, J. K. and Hogan, M. D. ( 1975). Selection of the experimental unit in teratology studies. Teratology 12: 165 171.

Snedecor, G. W. and Cochran, W. G. ( 1967). Statistical Methods, 6th ed. The Iowa State University Press, Iowa, pp. 246 248,349 352.

Jonckheere, A. R. ( 1954). A distribution free K sample test against ordered alternatives. Biometrika 41: 133 145.

10. Dempster, A. P., Selwyn, M. R., Patel, C. M., and Roth, A. J. ( 1984). Statistical and computational aspects of mixed model analysis. J. Roy. Statist. SOC., C ( Appl. Statist.) 33( 2): 203 214.

11. Patefield, W. ( 1982). Exact tests for trends in ordered contingency tables. Appl. Statist. 31~ 32 43.

12. Raabe, O. G., Al Bayati, M. A., Teague, S. V., and Rasolt, A. ( 1988). Regional deposition of inhaled monodisperse coarse and fine aerosol particles in small laboratory animals. Inhaled Particles VI ( J. Dodgson, R. I. McCallum, M. R. Bailey, and D. R. Fisher, Eds.), pp 53 63. Pergamon Press, Oxford.

13. Hazard Evaluation Division, Standard Evaluation Procedure, Toxicity Potential: Guidance for Analysis and Evaluation of Subchronic and Chronic Exposure Studies. Paynter, O. E. et 25 Dimethvl Glutarate ( DMG): Inhalation Develo~ mentalToxicitv Study in Rabbits DuPont 10657 al. United States Environmental Protection Agency, Office of Pesticide Programs, Washington, D. C., 20460. EPA 540/ 9 85 020, June 1985.

14. Risk Assessment of Notified New Substances Technical Guidance Document ( XI/ 283/ 94 EN), Chapter I, Sections 2.24 and 2.25.

26 : I i Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 TABLES 27 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 Tables Explanatory Notes Notes Chamber Concentrations of DMG Particle Size Distribution of DMG Chamber Environmental Conditions Values are reported to 2 significant figures. Means and standard errors of the mean were calculated prior to rounding values.

Abbreviations Chamber Concentrations of DMG Chamber Environmental Conditions S. E. M.  standard error of the mean mg/ m3  milligrams per cubic meter n  number of samples 28 i 000000 000000 ZSSZZZ r3 E n B v)

z 0, 2 E u i5 IIIII u I3 a E 6 vllx u ~ oooooc oooooc mmmmmmc 12 I V 0 s cdP oa Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 TABLE 2 PARTICLE SIZE DISTRIBUTIGN OF DMG

w XA I * * nrhlur  i 1   a DESIGN MASS MEDIAN GEOMETRIC % PARTICLES CONCENTRATION EXPOSURE AERODYNAMIC STANDARD BY MASS ( ms/ m3> 1000 3 8. O 2.1 0.25 11 62 10 8.8 2.4 0.55 11 58 17 9.0 2.1 0.2 8 54 24 9. o 2.4 0.35 9 56 NUMBER DIAMETER ( vm) DEVIATION < 1 pm c3 pm c10 pm 31 oooooc oooooc oooooc c\ Ilc\ lc3~ CJc\ IIIIII IIIIII oooooc oooooc oooooc oooooc zz! 2zsz oooooc oooooc oooooc oooooc oooooc oooooc 0000000000cc dd141 22frT; 2frT;? mmmmosu IIIIII oooooc Inwmmmv nmmoot lc\ lc?: 5ooooc 3 0 2 M 2 M M 00000 00 oc 00000 0080c ~~ 0000 44 3.

ommmmm F; Immmmc\ ~ IIIII IIIII 0000 33 I ....

I1 I n x)

r W m E rlri. r*

* o 0 0 0 0 0 0 0 0 0 m rl m rl H H H H H 4 m m l

OW clm . N* o* cn * Nd N . mcc NO * LCIaJ E;,?;: wm* mm"

COW dloy mm 0 0 0 0 0 0 0 m d m 0 d H H H H 3 H ml 00 m H H H 0 0 rl H H H 0 0 m 0 0 0 rl 3 Y r If U a a, E U . vi cE W  d e k V ( de m k 0 a' id a, a a d W a rlrl a, . md e2 m a, k x d d id u 0 u a, k g G d k id a,

a a, v1 c) m m l k B ? .

rl2 d c d . e > a $. a urnm kfi > 00 13 n  d 0 .3 60 X id . ri 03 dV ( d  c)

2; DIU a,

Es ha, 03 a$ Q) > 8 E 0 .3 * ( d 3 8 mmwY ..

E e 0 0 0 3 0 m 0 0 * 3 rl m rl 1 a 3 h .. c, H H H E" H H 3H b m rl I m ti m rl I n d rl WG * I 0 6% 8 G VE ... mooru mru 0 O m 0 0 rl H H H 0 0 0 0 0m d ? I 3 3 0 0 0 m 0 0 rl m H H H H > H H r a IC a, \ c V . r( E W c  d k eE u Id m i k 0 a' ( d 2 a d W a' a, . Q k 0 m a, k h rl rl Id u cn 0 u ; cn * d a, k I a, 3 2 d k ( d a,

a a, k < a,+  43 d . i a, C a I 0 0 0 0 i 0 0 0 0 0 i m d m 4 c 4 , , t H H H HH H c b L i I 0 0 0 0 m 0 0 0 rl m 0 rl H H H H 3 H m N r a N I r cv P N m m cv I m N m N I rl cv rl cv I m rl ' C u 6' 0 V E p: a 0 m H H 0 0 d H H H 0 0 m 3 I I cv .. II II I1 II * 0 IIrfO ooNmorf~ ooooooNo 3 ON II H mol II II II II I1 II II II II II HO 1100 00Nrf0000rl0000rf0 I H ON II H rlN II II II II II II I1 II II II II 0rf H ON II H mN II II II II II II II II I II II 0rl N I1 I H ON I1 I1 II II I1 .. .. .. I1 m 0 0 V a  u rn a, E u H a, 2 07 ( d 8 u E 4 E orlo * mwNN00 * cow wm* 0 ......... ONP m 0 cn~ oooo~ m m .... rl ooco 0 Nd00000rl co* r1orlo ma* mmm m NN N ......... cnmr m 5: m ocnoooo cn** .... rl 0 ***

HO Nrl0rl0000 cn* mrlCvo NON c mt m HO NN N ......... rrlm m HA ocnoooo om* .... rl CQcncoO mmm HO N0000000 UJUJdOrlO * cum cncnm UJ ~ m NN N ......... ocnm m ocnoooo cnm* .... d ocno 0 * me HO NNrlOOOOrl rmmomo ovw NN N ......... ocnoooo a** rl m QaJ .... a Z% &\ atn E v 8 l i 3 u CE  r E c n u P z 8 ........ > 00000000 a zzz~ zzzz U I < I!

Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits TABLE 9 INCIDENCE OF FETALMALFORMATIONS Group:

Concentration ( mg/ m3):

EXTERNAL No. examineda Head Micromaxilla Palate Cleft Snout Naris atresia No. affected VISCERAL No. examined Heart and/ or Greater Vessels Misshapen Septal Defect No. affected HEAD No. examined No. affected SKELETAL No. examined Rib Fused Skull Micromaxilla Vertebra Hemi No. affected DuPont 10657 TOTAL NUMBER AFFECTED .. .. .. O( 0) 2( 2) a No. examined and affected, including the number affected with the listed malformations, are expressed as Fetuses [ Litters] or Fetuses ( Litters). b For ease of reading, zeros have been replaced with dashes for the listed malformations. c In Group IV, 2 fetuses from the same litter were inadvertently disarticulated.

Note: Statistical analyses ( Jonckheere's trend test) were conducted on only the individual endpoints. The overall total and totals by exam are presented for information only. No significant trends were detected.

45 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 TABLE 10 INCIDENCE OF FETALVARIATIONS Group : I I1 I11 IV V Concentration ( mg/ m3): 0 30 100 300 1000 DEVELOPMENTAL VARIATIONS EXTERNAL No. examineda No. affected VISCERAL No. examined No. affected HEAD No. examined No. affected SKELETAL No. examined 190 [ 211 189 [ 20] 184 [ 20] 195 [ 21] 133 [ 181 0 [ OI 0 [ OI 0 [ OI 0 EO1 0 [ OI 190 [ 21] 189 [ 20] 184 [ 20] 195 [ 21] 133 [ 181 0 [ OI 0 [ OI 0 [ OI 0 [ OI 0 101 190 [ 21] 189 [ 20] 184 [ 201 195 [ 21] 133 1181 0 [ OI 0 101 0 to1 0 [ OI 0 LO1 190 [ 21] 189 1201 184 [ 20] 193 [ 2l] b 133 1181 Rib Supernumerary 137 ( 21 122( 20) 122 96 ( 17) Sternebra Fused  c 1( 1)  2( 2)

No. affected 137 ( 21 122( 20) 122 19) 122( 21 97 [ 181 TOTAL WITH DEVELOPMENTAL VARIATIONS 137 ( 21 122( 20) 122 19) 122( 21 971181 46 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 TABLE 10 ( Continued)

INCIDENCE OF FETALVAUTIONS Group: I I1 I11 IV V Concentration ( mg/ m3): 0 30 100 300 1000 VARIATIONS DUE TO RETARDED DEVELOPMENT EXTERNAL No. examineda No. affected VISCERAL No. examined Kidney Small Papilla  Size 2 Papilla  Size 3 No. affected HEAD No. examined No. affected SKELETAL No. examined 190[ 211 189E201 184[ 20] 195[ 21] 1331181 0 [ OI 0 [ Ol 0 [ OI 0 [ OI 0 [ OI 190[ 21] 189[ 20] 184[ 20] 195[ 21] 133[ 18]

190[ 211 189[ 201 184[ 20] 1951211 133 [ 18]

0 LO1 0 LO1 0 [ OI 0 [ OI 0 [ OI Pelvis Retarded Ossification Skull Retarded Ossification Sternebra Retarded Ossification Vertebra Retarded Ossification No. affected TOTAL WITH VARIATIONS DUE TO RETARDED DEVELOPMENT 23( 13) 18( 8) 24 ( 9) 17( 9) 36 ( 9)

TOTAL, WITH VARIATIONS 142( 21) 131( 20) 134( 19) 127( 21) 106[ 18] a No. examined and affected, including the number affected with the listed variations are expressed as Fetuses [ Litters] or Fetuses ( Litters). b In Group IV, 2 fetuses from the same litter were inadvertently disarticulated. c For ease of reading, zeros have been replaced with dashes for the listed variations.

* Significant trend ( Jonckheere's test), p .= 0.05.

Note: Statistical analyses ( Jonckheere's trend test) were conducted on only the individual endpoints. The overall total and totals by exam are presented for information only.

47 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 FIGURES P 0 II vi c1 3 10 t 0 0 W 0 0 v, 0* 0 0 m Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 APPENDICES 52 ,

Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 APPENDIX A Certificate of Analysis 53 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 of A Dale : Pye :

< DU POND E. I. DU PONT # E NEWOURi & CO. < IN WLMINGTON. DELAWARE is~ eea . ' DU PW CO .,: 409 E WALLISVILLE RD HI PORT INDUSTRIES HIGHLANDS TX 77562 Sample Number 990027264 Sampllng Tim. 8/ 37/ 99 01: 43: 34 Lot Numbsr H931363 A Batch Number : NIA Type of Sample : OBI? S 13E Cust Order Number : INTRA ~

I ~~

IT_ ests_ Performad D 101  KARL FISCHER D 303  APHA COLOR D 104  APPEARANCE D lt8J  TURBIDITY D 6029BE AClD NUMBER D 603  DBE BY GC D 603  DBE 8Y GC 4603  DBE BY QC D 603 DEE BY QC B 603QBE BY GC D 610. HCN BY ION SE naytics e cw sptrtment DBE 5 PO Number : BGSM0876SEl2 Date Shipped : 09/ 12/ 99 Tsnk Truck : 8032 Element LowUmittiiahUn WATER 0.025 % 0.1 APHA COLOR 7 Pt co .15 APPEARANCE PASS PASS TURBIDITY 1 ppm 5 AClD NUMBW 0.05 mg KOWg 0.5 DMG DE5 99.6' 1 % 98.5 ~

DMA DBEI 0.085 % 0.2 TOTAL ESTER 99.858 36 99.5 MEOH ',' 0% 0.3 OMS DBE4 0.163 % 1 HCN 2.8 ppm 15 Dimethvl Glutarate ( DMG I: Inhalation DeveloDmental Toxicitv Studv in Rabbits DuPont 10657 APPENDIX B Protocol 55 Dimethvl Glutarate ( DMG): Inhalation Develo~ mentalToxicity Study in Rabbits DuPont 10657 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Studyin Rabbits DuPont 10657 Dimethyl Glutarate ( DMG): InhalationDevelopmentd ToxicityStudy in Rabbits Work Request Number 13495 Service Code Number 733 Protocol Haskell Animal Welfare CommitteeNo. DGRT SOGP 1 56 1 2 3 4 5 6 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 Dimethyl Glutaratc ( DMG): Inhalation Developmentrml Toxicity Study in Rabbits DuPOnt 10657 TABLE OF CONTENTS & g OBJECTlVE.............................................................................................................................. 3 REGULATORY COMPLIANCE............................................................................................. 3 SPONSOR AND TEST FACILITY ......................................................................................... 3 MATERIALS AND METHODS.............................................................................................. 3 A. Test Substance........................................................................................................................... 3 B. Animals...................................................................................................................................... 3 1. Species ( Strain)................................................................................................................... 3 2. Reason for Selection........................................................................................................... 4 3. Source ....................................................................................... .................... 4 4. Description.......................................................................................................................... 4 5. Identification....................................................................................................................... 4 c. Husbandry.............................................................................................. ;................... i.....;;........ 4 . Caging..........................................................................................................,............... 4 . Food .................................................................................................................................... 4 . Water.................................................................................. z..;. ......:................... .. iin. l. i............ 5 . EnvironmentalConditions ................................................................................................... .. 5 . Animal Health Monitoring.................................................................................................. 5 . Quarantine........................................................................................................................... 5 D. ExperimentalDesign................................................................................................................. 6 E. Selection of Exposure Levels .................................................................................................... 6 F. Randomi~ tion........................................................................................................................... 6 G. Cheration. Administration. and Analysisof Test Atmospheres .............................................. 6 .. 1. Atmosphere'Generation...................................................................................................... 6 2. ChamberConditions............................................................................................................ 7 3. Administration ....................................................................................... ............................. 7 4. Analyses of the Test Atmosphere ....................................................................................... 7 5. Frequency ofMeasures....................................................................................................... 8 H. Safety Precautions and Disposal of Waste Material.................................................................. 8 I. Animal Euthanasia..................................................................................................................... 9 1. Adults.................................................................................................................................. 9 2. Fetuses..................... ........................................................................................... 9 J . Parametersto be Studied ........................................................................................................... 9 1. In Life Observationsof Does.............................................................................................. 9 2. PostmortemObservations of Does Dying Prior to Scheduled Euthanasia............. ............ 9 3. Observations ofDoes that Abort or Deliver Early .............................................................. 9 4. PrstmortemObservations of Does Surviving to Scheduled Euthanasia........................... 10 5. FetusesofDoesSurviving to Scheduled Euthanasia........................................................ 10 K. Statistics................................................................................................................................... 12 L. Control of Bias......................................................................................................................... 12 M. Records Maintenance...... .............................................................................................. 13 CRITICAL DATES................................................................................................................... 13 REPERENCES......................................................................................................................... 14 2 57 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPoM 10657 OBJECTIVE The objective ofthis study is to evaluate the developmental toxicity of the test substance when administered by inhalation to pregnant rabbits or from around the time of implantation to the end of gestation.

REGULATORY COMPLIANCE Thestudy will be conducted in compliance with the United States ( US) Environmental Protection Agency ( EPA) ToxicSubstances Control Act ( TSCA) Good Laboratory Practice Standards'" which areconsistent with Organisation for Economic Cooperation and Development ( OECD) Principles of Good Laboratory Practice ( as revised in 1997) published in ENV/ MC! CHEM( 98) 17.' 2' The test substance will be characterized by the sponsorprior to the initiation of this study. Although the characterization will not be performed under Goad Laboratory Practice Standards, the accuracy of the data will be considered sufficientfor the purposes of this study.

This study design complies with theU. S. EPA Office of Ptevention. Pesticides, and Toxic Substances ( OPPTS)'~' and the Consent Agreement and Testing Consent Order.' 4' Areas of noncompliance will be documented in the final report.

SPONSOR AND TEST FACILlTY This study is sponsored by SOCMA Dibasic Esters Group ( 1850 M Street, N. W., Suite 700, Washington, D. C. 20036!% lo), The study will be conducted at DuPont Haskell Laboratory for Health and Environmental Sciences, E. I. du Pontde Nemours and Company, Newark, Delaware.

MATERIALS AND METHODS A. Test Substance The test substancewill be identified in this protocol and in the study records as Dimethyl Glutarate ( DMG) or by the Haskell Sample Number 24300. The Certificate of Analysis ( COA) will be maintained with the study records.

B. Animals 1. Species ( Strain) Hra:( NZW) SPFrabbits 58 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 Dimethyl Glumate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 2. Reason for Selection The rabbit was selectedto provide data in a nonrodent species. The New Zealand white strain was selected because background data are available from the literature, the supplier, and previous studies at Haskell Laboratory.

3. Source COVANCE, Denver, Pennsylvania.

4. Dcscription Nulliparous, time mated females will be received onJune 19 ( 66 females) and June 21 ( 44 females), 2002. Body weights on the day the rabbits are mated, day 0 of gestation ( day OG) will be supplied by the vendor. The rabbits for this study will be requested to be at either 1,2, or 3 days ofgestation upon receipt, and approximately 6 6.5 months old.

5. Identification Each animal is assigned a unique number and identified with a microchip implant by the supplier prior to shipping. Upon receipt, each animal wifl be assigned a unique Haskeli animal number. Both the Haskell animal number and the number provided by thesupplier will be recorded on each cage card. A masterlist ofunique Haskell animal numbersand correspondingunique supplier providedanimal numbers will be maintainedwith the study records.

C. Husbandry 1. Caging Housedindividually in suspended, wire mesh, stainless steel cages. Nesting material will not be provided because the does will be sacrificed before part& ti'in?.

To address logistical considerations, the rabbits on this study will be housed in 4 animals rooms near the exposure chambers. It is expected that there will be a significant aerosol component in the high level chamk, therefom there may be residual test substance on the fur of the high level rabbits followingthe whole body exposures. Thus, the control group rabbits will be housed separately in one mom to prevent any potential exposureto test substance. The ribbits exposed to 1000mdm3will be housed separately within a hood so that khe higher air flow in the hood will promote evaporation ofaerosol deposits on the fur. The remaining 3 groups of rabbits will be housed in 2 other rooms.

2. Food On the day ofarrival and daily thereafter each rabbit will receive approximately 150grams per day of Purim@ Certified Rabbit Chow"# 5325; food will not be available during inhalationexposures.

4 59 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 3. Water Water from United Water Delaware( VWD) will be available ad libitum, except during inhalation exposures.

4. Environmental Conditions Fluorescent illumination will be provided for 12 hours daily ( 0600 1801) hours) and a record of temperature and humidity will be maintained throughout the study. Room temperature will be targeted between 19 and 2l0C, and relative humidity betwccn #% and 60%. Environmental conditions for each room will be monitored and documented daily, Any deviations will be addressed and acknowledged by the study director.

5. Animal Health Monitoring As specified in the DuPont Haskell Laboratory animal health and environmental monitoring program, the following procedures areperformed periodically to ensure that contamjnant levels arebelow those that would be expected to impact the scientific integrity of the study:

Water samplesare analyzed for total bacterial counts, and the presencc of colifoms, lead, and other contaminants.

Feedsamples are analyzed for total bacterial, spore andfungal counts.

Samples from freshly washed cages and cage racksare analyzed to ensure adequate sanitation by the cagewashers.

Certified animal feed is used, guaranteedby the manufacturerto meet specified nutdional requirements and not to exceed stated maximumConcentrationsof key contaminants, including specifiedheavy metals, aflatoxin, chlorinated hydrocarbons, and organophosphates. The presence of these contaminants below the maximum concentrationstated by the manufacturer would not be expected to impact the integrity of the study.

The animal health and environmental monitoring program is administered by theattending laboratory animal veterinarian. Data are maintained separatelyfrom study WCO& and may be included in the final repon at the discretjon of the study director.

6. Quarantine The rabbits will be quarantined accordingto procedures outlined in Haskcll Laboratory SOP LAOO3 P and released fromquarantine following approval from the laboratory animal veterinarian or a designee.

60 " I Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 Dimethyl Glutarate ( DMG): Inhalation DevelopmentalToxicity Study in Rabbits DuPont 10657 D. Experimental Design The experimental design is shownbelow:

Target Concentrationa Mated GFOUD ~ rn~/ rn~ l Females I Ob 22 II 30 22 JIT loo 22 IV 300 22 V 1000 22 a DMGwill be administered by inhalation, 6 hours per day, on days 7 286. b Conditioned air.

E. Selection of Exposure Levels The exposure levels and route of exposure for the current study were selected by the Sponsor.

F. Randomization AI1 animals will be ranked on the basis of day 0 gestation body weights and assigned to control and experimental groups by random sampling from the ranked list. The distribution should result in mean body weights for all groups that are not stdtisticdly different (~~ 4.05). Does that lose excessive weight or appear ill prior to the start ofdosing will be removedfromthe study.

G. Generation, Administration, and Analysis of Test Atmospheres 1. Atmosphere Generation In general, each group of rabbits will be exposed 6hours per day during gestation days 7 28G. The starting time of each exposune will be defined as the time when the generation system is turned on. The ending time of each exposure will be defined as thetime whenthe generation system is turned off. Rabbits will be exposed to the test substance during both the time it takes for the chamber to reach concentration, and the time it takes for the test substance to he purged from the chamber. After each exposure, rabbits will be returned to their home cages.

Attempts will be made to generate respirable atmosphem ofthe test substance that approximate the physical fonn of the test substance expected to be encountered in human exposure situations. Test atmospheres will be generatedby metering the test substance into a Spraying System nebulizer with an infusion pump or a fluid meteringpump. Filtered, high pressure air introduced into the nebulizer will atomize the liquid test substance. The resulting aerosol and vapor mixture will be mixedwith conditioned, filtered air leading to the inhalation chambers+ The concentration of the test substancein each test chamberwill be adjusted by varying the amount of the liquid test substance delivered to the nebuIizer. Testatmospheres will be generated 61 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 Dimethyl Glutarate ( DMG): Inhdation DevelopmentalToxicity Study in Rabbits DuPont iO657 dynamicallyusing airflowsneeded to achieve at least 12 air changes per hour in the exposure chamber. Uniform distribution of the test substance in the exposure chamber will be verified prior to the study start.

All componentsof the vapor generation system will be fabricated from stainless steel, glass, Neoprene@ or <EMAIL_ADDRESS>The actual generation equipment and conditions will be documented in the study records and described in the final report.

The exposure chambers ( 9m') to be used for this study will be constructed of stainless steel and glass. Exposure chambers will be cubical with square pyramidalchamber inlets and outlets (" Ustyle); a tangential feed at the chamber inlet promotes mixing and uniform chamber distribution of aerosol andor vapor.

2. Chamber Conditions Anemometersprobes located in the chamber inlet will monitor total chamber airflow. Chamber temperatureswill be measured by thermistor or themocouple probes; relative humidity will be determined by weddry bulb type resistance temperature detectors; and chamber oxygen concentrations will be monitored by electrochemical sensors. Ideally, chamberconditions will be set so that temperaturewill be 17 23 ° C; relative humidity will be 4096 60%, with minimum oxygen content of 19%. However, temperature and humidity variations outside of these ranges are commonly encountered due to the generation procedures used and the characteristics of the test substance itself. Efforts will be made to minimizetemperature and humidity variations during this study. Potentially adverse effects rcsulting fromvariations in temperature, relative humidity, or oxygen content will be addressed in the final repon.

3. Administration Rabbits will be exposed whole body to the test substance. Rabbits will be placed in stainless steel cages inside the exposurechamber. Exposures will be conducted during approximately the same timeperiodeach day to minimize diurnal physiological variations. Control rabbits will be treated exactly as test rabbits, with the following exceptions: the wire exposwe cages for the control rabbits wili be slightly larger than those used for the rabbits in the treatment groups exposed to test substance and the control rabbits' chamber atmosphere will not contain the test substance.

4. Analyses of the Test Atmosphere The concentration of the test substance in the 300 and loo0mgh3chambers will be determined by gas chromatographyand gravimetric analysis for the vapor and aerosol components, respectively. Sampleswill be taken from the 0,30, and 100 mg/ tn3 chambers forvapor components only, since he mean daily aerosol concentration at 300mg/ m3 in the pilot study ranged from 1.990 6.731 mg/ m3, and therefore the aerosolconcentration in the 30 and 100 mg/ m3 chambersis expected to be negligible or nondetectable. Knownvolumes of chamber atmospherewill be drawn from the breathing zoneof the rabbits though a samplingtrain consisting of a 25mm filter cassette. A separate sample for analysis of vapor concentration will be drawn through an impjnger. Aliyuots of impinger solutions will be injected into a gas 7 62 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 Dimethyl Glutarate ( DMG): Inhalation DevelopmentalToxicity Study inRabbits DuP~ ttt 10657 chromatograph equipped with a flameionization detector. Liquid standards ( usually 3 standards of different concentrations spanningthe range of test substance concentrations) will be prepared at least once per week by the quantitative dilution of the test substance in known amountsof acetone. The derived chamber concentrations will be stored in a computerized database for future data collation and reporting; hard copies of collected data will be printed daily. The filter cassette will contain a preweighed fiber filter to capture the aerosol portion of the sampled atmosphere. The impinger will contain acetone to capture the vapor portion, Filters will be weighed on a Cahn Automatic Electrobalance. The aerosol concentration from each sample will be determined fromthe pre and post sampling filter weight divided by the volume of air sampled.

Foreach exposure, the mean aerosol concentration will be added to the mean vapor concentration to calculate the total chamber concentration of the test substance.

Samples to determine particle size distribution ( massmcdian aerodynamic diameter and percent particles less than 1.3, and 10 pm diameter) will be taken from the high concentration chamber once per week with a Sierra@ Series210 Cyclone Preseparator/ CascadeImpact andlor Sierra@ Series 110Constant Flow Air Sampler ( Calculationdescribed in Sierra Instruments, Inc., Bulletin 7 79 219IM, Instruction Manual: Series 210 Ambient Cascade Impactors and Cyclone Preseparators). Since the aerosol concentration in the pilot study waslow at the 300 mg/ m3 concentration and is expected to be negligible or nondetectable at lower concentrations, particle size will not be determined at concentrations of 300mg/ m3 and below.

The generalprinciples of monitoring chamber atmospheresare documented in the Inhalation Toxicology SOP S. Details of the analytical method( s) used will be documented in the study records, and described in the final report.

5. Frequency of Measures The atmospheric concentration of the test substance in the breathing zonesof the rabbits will be determined approximately5 times daily forthe 30,100.300, and loo0 m@ m3chambers, and once daily for the controlchamber. Moreor less frequent samplesmay be takenat the discretion ofthestudy director. The chamberairflow, temperature, and humidity will be monitmed continuously and recorded at least every 30 minutes during exposure. Oxygen concentrations will be monitored and recorded at least twice per exposure per chamber. The actual frequency of measures will be recorded in the study records.

H. Safety Precautions and Disposal of Waste Material Good industrial hygiene practices will be followed during the conduct of this study and appropriate personal protective equipment ( PPE) will be used by study personnel. Handling of test substance, chamber waste and animal carcasses will follow procedures outlined in standard opcrating procedures and in the Stine Haskell Safety and Occupational Health Manual. The test substance will be released to the atmosphere by permit fromthe State of Delaware.

8 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits Wont 10657 1. Animal Euthanasia 1. Adults Does will be euthanized by the intravenous injection of an appropriate euthanizing agent. The identity and lot number of the agent will be recorded in the study records.

2. Fetuses Fetuses will be injected withsodium pentobarbital prior to performing visceral examinations.

J. Parameters to be Studjed 1. In Life observations of Does a. Body Weight Body weights will be recorded in the morning on the day after arrival through day 29G.

b. Food Consumption Food consumed will be measured daily on days 4 29G.

c. Clinical Signs Clinical signswill be recorded each morning on days 4 29G and each afternoon following exposures on days 7 28G. Clinical signs observed at othertimes will be recordedby exception. Observations, at approximatelyhourly intervals, will be madeduring the exposures to assess, to the extent possible, the overall state of the animals. In addition, the responseof the animals to a sound stimulus while in the chamberswill be recorded beforevapor generation begins, after approximately three hours of exposure, andprior to removal ofthe animalsfromthe chambers.

2. Postmortem ObservationsofDoesDying Priorto ScheduledEuthanasia A gross external and visceral examination will be performed within 24 hours after the doe is found dead. Pregnancy status will be determined and the uterine contents will be described. Lesions noted will be retained only if further examination is necessary ( at the discretion of the study director or a designee). Dead rabbits will be refrigerated until necmpsied.

3. Observations of Does that AbortorDeliver Early a. Dam Observations Damsthatabort or deliver early will be euthanized within 24 hours of detection and a gross external and internal examination will be performed. Lesions noted will be tetained only if further examination is necessary ( at the discretion of the study directoror a designee).

64 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 Dimethyl Glutarate( DMG): Inhalation Developmental Toxicity Study inRabbits DuPont 10657 b. Fetal Observations Fetuses remaining in the uterus or aborteddelivered early will be examined to the extent possible. Data from these litters will be maintained with the raw data but will be excluded from all relevant fetal data calculations.

4. Postmortem Observations of Does Surviving to Scheduled Euthanasia a. ExternalAppearance Each doe will be examinedimmediately after euthanasia on day 290.

b. Viscera Viscera will be examined grosslyimmediately after euthanasia. Lesions noted will be retained only if further examination is necessary.

c. Uterine Weight The intact and empty uterus of each doe having at least one viable fetus will be weighed to permit calculation of maternal body weight adjusted to exclude the products of conception.

d. Corpora Lutea The count for each ovary of dams with viable fetuses will be recorded.

e. Implantations For each female with visible implants, the type( live and dead fetuses, and resorptions) and their relative positions will be recorded. The uterus of each apparent1 " nonpregnant" female will be stained with ammonium sulfide to detect very early resorptions. K 5. Fetuses of Does Survivingto Scheduled Euthanasia a. Number, Location, and Condition These parameters will be recorded for each fetus.

b. Fetal Weight The body weight foreach fetus will be recorded.

c. ExternalAlterations The alterations detected for each live fetus will be recorded.

10 65 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 Dimethyl Glutarafe ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 d. Soft Tissue Alterations For each live fetus, fetal sex and any visceral alterations detected will be recorded.@) A transverse section, deep enough to pennit examination of the brain, will be made between the parietal and Frontal bones. On the day of sacrifice, the eyelids of each fetus will be removed10 examine the eyes for alterations.

e. Skeletal Alterations After fixation in alcohol, the alizarin stained skeletons will be examined and alterations detected will be recorded foreach ljve fetus.

f. Dead Fetuses Dead fetuses will be examined externally, viscerally, and skeletally to the extent possible. Data fromthese fetuses will be excluded from all calculations performed for live fetuses.

g. Retention of Tissues Fetal organs or tissues will be retained if deemed necessary forobtaining a definitive diagnosis of a visceral exam finding. Bilateral organs will be retained when only one is affected. Sufficient tissues fromcontrol fetuses will be fixedto provide comparison with suspect tissues, if needed; if not needed, tissues will be discarded.

11 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 Dimethyl Glutarate( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 K. Statistics Sequential trend tests will be applied to the data for each parameter as tabulated below."' If a significant dose response trend is detected, data from the top dose groupwill be excluded and the test repeated until no significant trend is evident. Fur litter parameters, the proportion of affected fetuses per litter or the litter mean will be used as the experimental unit for statistical evaluation.' 8' The level of significance selected will be p < 0.05. Additional statistical testswill be used, and otherparameters analyzed, if deemed necessary.

Parameter Maternal weight Maternal weight changes Maternal food consumption Live fetuses Dead fetuses Resorptions Implantations Corpora lutea Incidence of fetal alterations Incidence of pregnancy Clinical observations Maternal mortality Females with total resorptions Abortiondearly deliveries Fetalweight Sex ratio Trend Test Linear contrast of means[')

Jonckheere's test'")

Cochran Annitage test'')

Linear contrastof least square means('')

Where the data aretied and the standard large sample version of Jonckhere's test is not applicable, exact p values for Jonckheere's test will be calculated using permutation methodology."')

L. Control of Bias In addition to the random assignment to groups, all does will be coded before autopsy and will remain coded during the collection of postmortem and fetal data. Dimethyl Glutarate ( DMG): Inhalation DeveloDmental Toxicity Study in Rabbits DuPont 10657 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study inRabbits DuPont 10657 M. Records Maintenance All data and records for analytical characterizationsconductedby the sponsor will be archived by the sponsor. Laboratory specificor site specific raw data, such as personnel files and equipment records will be retainedby the facility where the work was done.

A sample of the test substance will be collected for archive purposesand retained at DuPont Haskell Laboratory, Newark, Delaware. Specimcns, raw data, and the find report will be retained at DuPont Haskell Laboratory, Newark, Delaware or at Iron Mountain Records Management, Wilmington, Delaware.

CRITICAL DATES Experimental staft date ( first day of exposure): June 23,2002 Completion( last fetal evaluation): September2002 ( approximate) Find report April 16,2003 68 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 Dimethyl Olutarate ( DMO): Inhalation Developmental Toxicity Study in Rabbits DUPOIU 10657 REFERENCES 1. United States ( U. S.) Environmental Protection Agency ( EPA), Toxic Substances Control Act ( TSCA) 40 CFR Part792. 2. Organization for Economic Cooperation and Development ( OECD), Principles of Good LaboratoryPractice ( as revised in 1997) published in ENV/ MCICHEM( 98) 17. 3. United States ( U. S.) Environmental Protection Agency ( EPA). Office of Prevention, Pesticides and Toxic Substances ( OPPTS)( 1998). OPPTS870.3700 Prenatal Developmental Toxicity Study. Health Effects Test Guidelines.

4. United States ( U. S.) Environmental Protection Agency ( EPA) Federal Register ( August 5, 1999).   Dibasic Esters; Final EnforceableConsent Agreement and Testing Consent Order.  Vol. 64, No. 150, pp. 42692 42695. 5. Salewski, E. ( 1964).   Farbemethode zum rnakroskopischen Nachweis von Implantationsstellenam Uterus der Ratte,  Archiv. Path. Exp. Pharmakol., M367.

6. Staples, R. E.( 1974).   Detection of Visceral Alterations in Mammalian Fetuses,.  Terdology, 9( 3): A37 A38. 7. Selwyn, M. R.( 1995).   TheUse of Trend Tests to Determine a No Observable EffectLevel in Animal Safety Studies.  Journal of the American College ofToxicology 14( 2): 158 168.

8. Haseman, J. K. and Hogan, M. D. ( 1975).   Selectionof $ e Experimental Unit in Teratology Studies,  TerutoZogy,$ 2( 2): 165 171.

9. Snedecor, G. W. and Cochran, W. 0. ( 1967). StatisticalMefhods, 6thed., The Iowa State University Press, Iowa, pp. 246 248; 349 352.

10. Jonckheere, A. R. ( 1954).   A Distribution Free K sample Test Against Ordered Alternatives,  Biomefnka. 41: 133 145.

11. Dempster, A. P., Selwyn, M. R., Patel, C. M., andRoth, AJ. ( 1984).   Statistical and Computational Aspects of Mixed Model Analysis,  The Journal of the Royal Statistical Society, Series C ( Applied Statistics), 33( 2): 203 214.

12. Patefield, W. ( 1982).   Ex; actTests for Trends in Ordered ContingencyTables,  Applied Stazistics 31: 32 43.

69 Dimethvl Glutarate CDMG): Inhalation DeveloDmentd Toxicitv Study in Rabbits DuPont 10657 Dimethyl Glutarate ( DMG): Inhalation DevelopmentalToxicity Study in Rabbits DuPont 10657 Dimethyl Glutarate CDMG): Inhalation DeveloDmental Toxicitv Study in Rabbits  5 Service Code Number 733 Protocol 15 70 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 Dimethyl Glutarate ( DMG): Inhalatinn Devtlopmental Toxicity Study in Rabbits Duponl 10657 Dimethvl Glutarate ( DMGL Inhalation Develoumental Toxicity Studyin Rabbits Work Reouest Number 13495 Service Code Number 733 Protocol

S A Dibasic Eltm Group 71 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 APPENDIX C Daily Chamber Concentrations 72 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 DAILY CHAMBER CONCE~ RATZONS_ j, l I mu L ,"_ i EXPLANATORY NOTES ABBREVIATIONS:

S. D.  standard deviation mg/ m3  milligrams per cubic meter n  numberofsamples FOOTNOTES:

a Standard deviation could not be calculated from this sample size. b Due to equipment malfunction, the exposure for the 100mg/ m3chamber was shortened to approximately 5 hours.

NOTES:

Values are reported to 2 significant figures. Means and standard deviations were calculated prior to rounding values. Aerosol concentration was only measured for the 300 and 1000mg/ m3 chambers.

73 000 omoooooooooooo 00000ddoddodrloorld~ orldddid o% 2go: m dd d d d d rl rl d d d d d d d d d 11 00 0 0 00 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 & g mmmmmmmmmmmmmmmmmmmmsmnmlm 00000000000000000000000000 I Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 APPENDIX D Daily Chamber Environmental Conditions Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 DAILY CHAMBER ENVEONNIENTAL CON? maONS . _ LI EXPLANATORY NOTES ABBREVIATIONS:

n  number of observations FOOTNOTES:

a Due to equipment malfunction, the exposure for the 100mg/ rn3chamber was shortened to approximately 5 hours.

NOTES:

Values are reported to 2 significant figures. Means and standard deviations were calculated prior to rounding values,

77 . E a ......................... ~ 000000000000000d000000000 I ddddddddddddddddmddddddddd NNNNNNNNNNNNNNNNNNNNNNNNNN o~~ mrrddmrnodrrrrnm~ mmmd~ odd mwwwmmmwmmwwmmmmmwmmmwwwww l~ 1111,1111111111111111111 H ' 1 dddddldddfddddddWddddddddd NNNNNNNNNNNNNNNNNNNNNNNNNN  4 4 4 4 44444 444 4 44 44 d"  777777777777~ 777m7777~ 77~~ 1' 1 NNNNNNNNNNNNNNNNNNNNNNNNNN 000000000000 000000 000000000000 000000 mdmmmmmmmmmo mmmmmm NNNnn,, dNdddddddddN0dddddd __ Illggggl I, IIIIIIII 1g1 IIIII 000~~~~ 000000000000~ 000000 000 000000000000 000000 mmm aoaammamammm mamaam ddd drndddddddddd rlddddd ~ drmr~ ma~ rnmddw~ o~ rmo~ moao~ ~ ddddddmAdNNNdNNNdNNNNNNmN i: m 00000000000000000000000000 00000000000000000000000000 ommmmmmadmammmmmmmmmmammmm NdddddddNddddddddddddddddd 7~ 777~ 7777777777m7777777~~ NNNNNNNNNNNNNNNNNNNNNNNNNN 000 0000000000000000000 000 0000000000000000000 oommmmmmmmmmmmmmmmm 000~"~ 0000000000000000000 000 0000000000000000000 000 mmrrarrrcoammammmmaa NNN ddrldddddddddddddddd Y 00000000000000000000000000 00000000000000000000000000 a ~ ooooooommammammmmmmmmmmmmE NNNNNNNNdddddddddddddddddd 777777e~~ 777~ 777m777077777 NNNNNNNNNNNNNNNNNNNNWNNNNN 0000000000000000 000000000 0000000000000000 000000000 ~ ddooommdmooooom mmommoomo NNNNNNddNdNNNNNdOddNddNNdN 0000000000000000~ 000000000 0000000000000000 000000000 dmmmmaarommmmmmm commmmmmrm NdddddddNddddddd ddddddddd

' 77777777777e7777w777777777 NNNNNNNNNNNNNNNNNNNNNNNNNN 0000000000000000000 0000000000000000000 mom~ mmmmmmmmmaaoodo Nddd,, dNdNdddddddddddNNNN lIllgggll,,, lllllllIIIIIII 0000~~~ 0000000000000000000 0000 0000000000000000000 mmmm mmmmrmararramrrammm 000000~ 0000000000000000000 000000 0000000000000000000 maamroo rmrrmammarawpmrr~ mr dddddd ddddddddddddddddddd 9 i Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 APPENDIX E Individual Body Weights 81  Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 Individual Body Weights Explanatory Notes Footnotes a Weight calculated using the final body weight minus the weight of the products of conception.

Abbreviations = Nodata AB = Aborted NP = Notpregnant ED = Earlydelivery R = Litter totally resorbed SE = Sacrificed in extremis FD = Founddead 82 ,

Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits INDIVIDUAL ADULT BODY WEIGHTS GROUP I: 0 mg/ m3 ANIMAL DAYS OF GESTATION NUMBER DAY 0 DAY 4 DAY 5 DAY 6 DAY 7 DAY 8 35570 3008.0 3215.7 3063.6 3109.9 3047.8 3097.4 35572 4199.0 4334.6 4286.1 4231.5 4274.2 4317.0 35576 3533.0 3642.4 3476.3 3605.3 3693.6 3702.4 35578 3303.0 3548.7 3389.9 3337.6 3359.2 3359.7 35579 3135.0 3385.0 3365.6 3252.3 3269.3 3283.3 35597 3384.0 3480.6 3436.8 3457.1 3481.6 3459.5 35599 2932.0 3069.3 2996.4 2963,8 2788.5 2699.2 35601 3464.0 3575.0 3487.9 3643.4 3517.9 3584.0 35604 3754.0 3812.6 3783.0 3791 5 3752.8 3782.8 35616 3480.0 3424.5 3429.0 3474.3 3428.9 3499.7 35621 3202.0 3210,8 3177.2 3186.2 3203.6 3199.7 35628 3705.0 3647.7 3651.1 3868.4 3674.4 3706.8 35632 3982.0 3834.3 3854.0 3806.8 3827.1 3832.2 35639 3505.0 3570.9 3538.6 3529.8 3565.4 3542.0 35644 3598.0 3666.6 3612.6 3626.7 3626.3 3607.7 35646 3026.0 3075.1 3057.7 3101.0 3099.1 3050.7 35656 4179.0 4107.3 4100.2 4075.3 4080.1 4137.3 35658 3871.0 3791.2 3783.1 3815.0 3804.0 3822.5 35659 3487.0 3481.8 3463.0 3473.9 3506.5 3502.5 35666 3648.0 3682.1 3671.2 3672.3 3673.1 3696.7 35675 3391.0 3336.9 3354.9 3351.3 3368.4 3442.2 35677 3198.0 3326.4 3351.7 3333.7 3361.0 3371.5 DuPont 10657 DAY 9 ~ ~ ANIMAL STATUS 3071,2 4236.8 3754.0 3354.9 AB 3324.7 3482.6 3037.9 3596.8 3799.1 3490.1 3183.0 3697.5 3813.2 3569.1 3609.2 3046.5 4129.9 3811.6 3564.0 3699.9 3415.8 3372.2 Dimethvl Glutarate ( DMG): Inhalation DeveloDmental Toxicitv Studv in Rabbits DuPont 10657 INDIVIDUAL ADULT BODY WEIGHTS GROUP I: 0 mg/ m3 ANIMAL DAYS OF GESTATION NUMBER DAY 10 DAY 11 DAY 12 DAY 13 DAY 14 DAY 15 DAY 16 ANIMAL STATUS 35570 3113.0 3116.6 3158.0 3186.9 3239.7 3254.7 3243.4 35572 4279.2 4245.3 4309.5 4332.2 4372.0 4361.6 4393.1 35576 3695.1 3692.1 3774.8 3765.4 3841.1 3897.5 4027.8 35578 3348.8 3310.8 3325.6 3339.8 3318.8 3349.5 3356.3 AB 35579 3335.9 3322.3 3357.4 3405 . O 3451.6 3490.4 3531.5 35597 3443.5 3468.9 3469.8 3467.6 3520.4 3535.0 3537.7 35599 2958.8 3024.3 3021.7 3050.5 3092.9 3111.5 3103.3 35601 3605.2 3659.0 3668.2 3709.3 3746.9 3753.1 3775.4 35604 3809.3 3836.3 3880.3 3922.6 3954.4 4044.9 4060.3 35616 3482.7 3498.9 3524.5 3596, O 3635.7 3689.4 3698.2 35621 3205.6 3235.3 3214.0 3211.7 3259.8 3101.1 3334.8 35628 3737.2 3738.6 3769.5 3803.1 3852.2 3890.6 3859.2 35632 3890, l 3870.8 3875.6 3880.5 3910.4 3937.9 3959.3 35639 3546.5 3542.1 3556.1 3587.6 3637.2 3663.2 3665.1 35644 3630.3 3632.7 3638.8 3662.4 3757.6 3796.4 3793.5 35646 3026.0 3027.9 2970.9 2998.8 3064.9 3158.7 3179.2 35656 4161.6 4175.2 4135.5 4180.8 4240.7 4221.9 4214.1 35658 3795.6 3811.0 3854.5 3872.1 3927.6 3911.1 3950.5 35659 3583.2 3588.1 3605.4 3629.0 3688.0 3689.5 3727.2 35666 3730.7 3706.0 3766.8 3738.0 3804.4 3818.7 3855.1 35675 3410.1 3392,3 3469.9 3542.3 3598.9 3628.4 3613.6 35677 3390.4 3396.4 3292.6 3418.5 3437.3 3481.9 3500.3 84    Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 INDIVIDUAL ADULT BODY WEIGHTS GROUP I: 0 mg/ m3 ANIMAL DAYS OF GESTATION NUMBER DAY 17 DAY 18 DAY 19 DAY 20 DAY 21 DAY 22 ANIMAL STATUS 35570 3248.2 3238.8 3256.5 3244.3 3237.2 3253.8 35572 4414.1 4394.4 4428.4 4414.9 4442.1 4415.5 35576 4046.3 4056.5 3980.9 3972.3 4017.3 3969.8 35578 3369.7 3359.1 3267.9 AB 35579 3539.0 3543.0 3547.1 3595.1 3579.0 3622.4 35597 3572.0 3519.9 3544.9 3581.7 3569.1 3593.8 35599 3135.9 3130.9 3128.0 3160.2 3215.0 3255.0 35601 3744.1 3769.7 3775.3 3822.6 3823.5 3879.2 35604 4104.5 4075.6 4127.8 4113.9 4138.7 4132.9 35616 3730.1 3709.7 3732.6 3727.7 3753.6 3794.0 35621 3330.9 3324.5 3350.4 3328.6 3349.3 3345.3 35628 3845.1 3890.9 3931.5 3894.4 3944.0 3937.5 35632 3923.7 3979.9 3954.1 3952.8 3980.6 3908.7 35639 3658.0 3673.9 3665.9 3668.0 3694.9 3693.5 35644 3814.0 3736.3 3768.1 3770.4 3727.3 ' 3767.5 35646 3172.2 3157.9 3157.2 3174.0 3166.4 3180.2 35656 4270.9 4255.0 4272.2 4261.7 4258.5 4259.6 35658 3928.2 3942.2 3953.3 3967.0 3969.1 4017.2 35659 3731.1 3741.0 3788.9 3784.8 3858.6 3809.3 35666 3853.6 3903.1 3915.8 3858.7 3878.6 3911.8 35675 3597.3 3613.3 3601.7 3590.8 3576.7 3615.9 35677 3429.2 3457.7 3475.3 3460.9 3460.1 3477.7 85

  Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits INDIVIDUAL ADULT BODY WEIGHTS GROUP I: 0 mg/ m3 ANIMAL DAYS OF GESTATION NUMBER DAY 23 DAY 24 DAY 25 DAY 26 DAY 27 DAY 28 35570 3288.8 3332.7 3343.8 3367.9 3362.5 3374.4 35572 4436.3 4462.2 4476.4 4490.5 4479.3 4465.8 35576 3954.3 3976.0 4002.5 4032.4 4070.3 4071.7 35578 35579 3656.3 3687.1 3703.3 3730.9 3744.5 3722.2 35597 3629.1 3680.6 3697.8 3727.5 3755.6 3729.1 35599 3243.2 3244.1 3338.1 3375.0 3387.9 3435.8 35601 3788.9 3822.3 3860.6 3825.7 3949.1 3988.2 35604 4103.4 4142.6 4174.4 4217.0 4220.9 4273.4 35616 3782.4 3812.4 3812.2 3844.9 3801.7 3823.0 35621 3364.0 3388.3 3392.7 3391.2 3428.8 3448.0 35628 3951.4 4003.4 4001.1 4043.7 4013.7 4081.7 35632 3901.0 3960.6 3934.4 3940.3 3937.8 3959.2 35639 3753.8 3797.9 3812.1 3848.7 3882.8 3935.6 35644 3812.5 3815.9 3814.9 3840.8 3857.7 3882.2 35646 3248.8 3296.2 3294.7 3330.9 3386.5 3435.6 35656 4312.4 4324.3 4305.7 4322.2 4323.5 4307.3 35658 4006, l 4048.9 4058.2 4097.3 4088.2 4149.0 35659 3838.9 3921.2 3946.0 3905.0 3849.3 3906.0 35666 3968.0 3998.4 4032.9 3998.2 4054.6 4002.0 35675 3602.8 3645.5 3646.8 3703.1 3747.1 3769.7 35677 3528.7 3538.9 3532.9 3559.7 3567.6 3583.7 DuPont 10657 DAY 29 ANIMAL STATUS 3426.9 4442.1 4167.3 AB 3766.4 3747.2 3401.5 3976.9 4249.5 3867.4 3973.9 3959.3 3903.5 3413.9 4320.4 4180.1 3958.0 4044.3 3841.4 3639.4  Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 INDIVIDUAL ADULT BODY WEIGHTS GROUP I: 0 mg/ m3 ANIMAL NUMBER DAY 29a 35570 3101.1 35572 4111.5 35576 3644.6 35578 35579 3337.9 35597 3294.4 35599 2988.9 35601 3510.5 35604 3700.2 35616 3402.4 35621 3544.9 35628 3099.0 35632 3616.1 35639 3455.5 35644 3493.0 35646 2882.4 35656 3923.4 35658 3699.6 35659 3446.4 35666 3591.4 35675 3304.8 35677 3144.9 DAYS OF GESTATION ANIMAL STATUS AB 87 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits INDIVIDUAL ADULT BODY WEIGHTS GROUP 11: 30 mg/ m3 ANIMAL DAYS OF GESTATION NUMBER DAY 0 DAY 4 DAY 5 DAY 6 DAY 7 DAY 8 35573 3176.0 3322.3 3279.2 3252.3 3213.8 3218.9 35574 3774.0 3704.8 3684.2 3650.5 3633.9 3615.1 35584 2995.0 3025.4 3044.5 2996.9 3021.5 3004.6 35585 3236.0 3290.6 3194.8 3188.7 3156.2 3234.6 35588 4104 0 3971.2 3918.2 3874.6 3892.9 3844.3 35593 3430.0 3461.0 3378.8 3398.4 3399.3 3430.9 35595 3264.0 3396.5 3356.3 3386.4 3406.8 3419.6 35600 3754.0 3647.1 3646.6 3706.4 3692.5 3679.1 35603 3335.0 3303.0 3254.1 3315.2 3278.6 3293.2 35606 2863.0 2960.7 2895.5 2896.0 2921.5 2926.4 35614 3830.0 3691.7 3695.2 3685.7 3677.5 3757.8 35617 3111.0 3184.4 3136.5 3095.4 3110.2 3183.1 35630 3232.0 3282.9 3238.7 3223.5 3242.4 3241.6 35633 3588.0 3494.2 3537.5 3548.1 3547.6 3627.4 35642 3416.0 3414.9 3363.0 3383.0 3506.0 3405.7 35647 3559.0 3719.9 3748.8 3783.4 3743f 9 3721.3 35649 4071.0 4122.4 4019.7 3899.6 4025.4 4002.7 35654 3548.0 3572.8 3568.5 3587.3 3603.5 3598, O 35667 3613.0 3543.2 3542.7 3573.7 3574.8 3603.8 35669 3167.0 3149.9 3155.2 3192.1 3247.2 3232.3 35670 3429.0 3434.0 3465.0 3467.2 3497.3 3472.3 35674 3866.0 3833.1 3899.5 3767.1 3803.5 3840.3 DuPont 10657 DAY 9 ANIMAL STATUS 3188.4 3628.4 2989.4 3205.2 3845.7 3469.0 3416.8 3691.8 3347.0 NP 2957.6 3715.6 3124.5 3232.5 3583.3 3419.3 3712.4 4044.9 3571.3 NP 3599.0 3246.3 3479.8 3826.3 88 Dimethyl Glutarate ( DMG): Inhalation DevelopmentalToxicity Study in Rabbits DuPont 10657 INDIVIDUAL ADULT BODY WEIGHTS GROUP 11: 30 mg/ m3 ANIMAL DAYS OF GESTATION NUMBER DAY 10 DAY 11 DAY 12 DAY 13 DAY 14 DAY 15 DAY 16 ANIMAL STATUS 35573 3189.6 3228.5 3279.5 3286.7 3323.2 3379.3 3438.9 35574 3622.2 3661.3 3671.2 3688.3 3716.5 3755.2 3785.4 35584 3009.2 2995.4 3028.1 3066.8 3072.4 3129.4 3165.6 35585 3223.1 3212.7 3215.0 3254.3 3277.7 3326.3 3383.2 35588 3857.1 3841.9 3867.7 3923.3 3942.9 3956.1 4006.6 35593 3446.1 3462.6 3480.2 3475.9 3516.2 3547.1 3526.7 35595 3419.2 3438.3 3437.4 3460.9 3512.2 3554.7 3576.8 35600 3705.3 3684.9 3685.2 3686.6 3732.6 3786.1 3825.8 35603 3349.7 3387.5 3359.1 3386.4 3365.9 3378.8 3440.5 NP 35606 2939.5 2963.4 2980.9 2997.3 3043.6 3084.5 3086.3 35614 3737.8 3742.1 3782.0 3848.9 3919.9 4017.1 4067.9 35617 3063.1 3165.7 3139.3 3192.1 3218.3 3256.3 3263.8 35630 3245.9 3250.7 3272.4 3290.8 3349.2 3376.3 3383.3 35633 3585.2 3582.8 3566.1 3588.5 3650.5 3712.3 3715.6 35642 3415.6 3396.1 3443.2 3468.7 3540.5 3585.7 3534.9 35647 3737.6 3775.1 3882.4 3927.6 4013.9 4086.7 4130.8 35649 4016.3 3985.7 3986,3 4051.4 4076.6 4111.7 4105.7 35654 3549.2 3581.7 3534.6 3551.8 3577.6 3607.3 3588.0 NP 35667 3585.7 3596.0 3625.5 3643.6 3655.9 3665.6 3680.7 35669 3229.8 3241.1 3278.4 3306.3 3347.7 3358.9 3394.4 35670 3483.3 3484.9 3523.9 3580.9 3587.1 3606.8 3624.9 35674 3843.8 3856.0 3894.1 3952.8 4038.1 4062.2 4082.8 89 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 INDIVIDUAL ADULT BODY WEIGHTS GROUP 11: 30 mg/ m3 ANIMAL DAYS OF GESTATION NUMBER DAY 17 DAY 18 DAY 19 DAY 20 DAY 21 DAY 22 ANIMAL STATUS 35573 3481.2 3486.4 3495.7 3500.8 3517.8 3445.9 35574 3795.4 3821.3 3823.6 3829.4 3845.7 3849.3 35584 3146.6 3170.6 3155.6 3155.9 3202.2 3235.9 35585 3374.7 3381.0 3382.5 3384.1 3433.9 3437.6 35588 4032.9 4015.5 4004.8 4029.6 4025.0 4055.5 35593 3544.7 3557.2 3576.7 3591.0 3605.0 3639.8 35595 3549.9 3564.7 3541.7 3553.1 3543.3 3611.9 35600 3867.9 3887.3 3868.1 3876.1 3861.8 3891.1 35603 3442.7 3405.4 3471.2 3429.2 3430.0 3431.9 NP 35606 3087.5 3099.0 3128.8 3146.9 3159.2 3175.7 35614 4061.0 4110.6 4078.4 4048.8 4051.5 4080.8 35617 3196.7 3235.8 3203.9 3191.5 3285.1 3255.1 35630 3401.6 3433.3 3410.6 3445.6 3472.3 3491.0 35633 3672.8 3690.5 3669.2 3676.4 3703.3 3722.7 35642 3571.0 3539.3 3536.8 3530.7 3531.2 3485.5 35647 4170.4 4168.2 4120.4 4066.2 4062.3 4073,9 35649 4166.3 4193.2 4177.9 4164.2 4182.2 4179.2 35654 3517.1 3493.8 3492.0 3496.2 3472.7 3471.1 NP 35667 3704.3 3709.3 3726.0 3715.4 3746.4 3777.5 35669 3410.6 3412.4 3431.5 3444.6 3447.4 3469.3 35670 3590.8 3606.3 3620.0 3642.3 3652.3 3688.1 35674 4018.4 4077.6 4005.5 3957.2 4019.0 4013.3 90 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits INDIVIDUAL ADULT BODY WEIGHTS GROUP 11: 30 mg/ m3 ANIMAL DAYS OF GESTATION NUMBER DAY 23 DAY 24 DAY 25 DAY 26 DAY 27 DAY 28 35573 3545.6 3586.3 3608.5 3633.4 3645.7 3622.5 35574 3916.7 3907.5 3922.3 3944.1 3992.1 3993.4 35584 3260.6 3268.3 3287.0 3277.8 3257.9 3310.5 35585 3467.7 3542.2 3313.2 3209.3 3555.9 3548.7 35588 4114.6 4164.6 4205.1 4215.2 4285.0 4294.9 35593 3704.6 3714.9 3739.0 3788.6 3776.3 3778.9 35595 3623.9 3668.0 3669.8 3704.0 3708.9 3727.1 35600 3904.2 3893.8 3956.1 4018.7 4041.1 4008.7 35603 3439.5 3439.1 3474.2 3475.4 3479.5 3473.7 35606 3195.0 3214.2 3244.9 3276.2 3237.5 3279.0 35614 4114.6 4139.0 4139.1 4147.9 4133.2 4147.6 35617 3320.9 3377.4 3360.1 3362.5 3413.4 3397.7 35630 3509.6 3541.0 3590.6 3602.4 3610.6 3614.3 35633 3757.9 3777.0 3798.3 3822.9 3836.9 3838.1 35642 3564.3 3531.9 3561.7 3600.3 3610.4 3604.9 35647 4133.7 4181.7 4212.4 4258.6 4245.1 4283.7 35649 4214.6 4242.7 4264.7 4293.6 4285.7 4301.6 35654 3520.9 3494.1 3515.3 3495.3 3510.8 3479.5 35667 3773.4 3795.4 3807.7 3808.0 3844.3 3877.8 35669 3485.5 3519.6 3545.0 3590.7 3610.6 3644~. 7 35670 3726.6 3760.1 3791.7 3832.8 3862.5 3874.3 35674 4029.8 4063.4 4102.4 4112.8 4145.3 4162.8 DuPont 10657 DAY 29 ANIMAL STATUS 3655.1 4016.3 3310.3 3596.5 4314.1 3786.5 3772.0 4049.5 3505.2 NP 3323.5 4122.7 3415.0 3709.2 3859.9 3672.1 4343.5 4316.6 3541.7 NP 3915.4 3644.6 3926.2 4185.8 91

 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 INDIVIDUAL ADULT BODY WEIGHTS GROUP 11: 30 mg/ m3 ANIMAL DAYS OF GESTATION NUMBER DAY 29a ANIMAL STATUS 35573 3216.6 35574 3452.3 35584 2959.8 35585 3176.6 35588 3764.9 35593 3308.1 35595 3231.8 35600 3484.9 35603 NP 35606 2832.3 35614 3602.7 35617 3088.8 35630 3269.6 35633 3506.2 35642 3283.4 35647 3799.3 35649 3765.7 35654 NP 35667 3501.6 35669 3259.3 35670 3433.7 35674 3717.8 92 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits INDIVIDUAL ADULT BODY WEIGHTS GROUP 111: 100 mg/ m3 ANIMAL DAYS OF GESTATION NUMBER DAY 0 DAY 4 DAY 5 DAY 6 DAY 7 DAY 8 35580 3021.0 3216.2 3132.1 3185.9 3202.3 3127.6 35582 2871.0 2798.2 2830.4 2774.8 2825.0 2836.5 35587 3665.0 3537.3 3455.7 3399.5 3349.5 3266.4 35589 3898.0 3825.8 3786.4 3804.8 3751.1 3818.1 35594 3058.0 3172.4 3102.2 3159.2 3188.3 3173.8 35596 3813.0 3909.9 3866.2 3858.1 3918.7 3876.2 35609 3529.0 3652.7 3608.5 3617.5 3598.7 3598.7 35610 3415.0 3554.9 3412.0 3447.5 3417.9 3412.4 35611 3315.0 3344.3 3369.5 3375.4 3406.7 3462.8 35615 3165.0 3541.6 3561.4 3550.5 3558, l 3565.5 35622 4238.0 4184.7 4144.3 4162.3 4181.2 4238.3 35624 3486.0 3307.6 3428.5 3452.0 3509.6 3530.2 35627 3262.0 3251.7 3255.8 3295.6 3300.3 3334.0 35634 3695.0 3110.2 3200.0 3189.3 3203 3 3174.1 35641 3634.0 3579.3 3603.9 3579.7 3608.5 3604.0 35643 3164.0 3223.6 3229,7 3206.2 3224.2 3296.7 35645 3480.0 3385.9 3253.5 3330.4 3405.7 3447.5 35652 4084.0 4104.9 4085.7 4087.9 4065.7 4100.9 35657 3261.0 3060.7 3173.9 3073.7 3129.3 3124.7 35660 3416.0 3357.3 3336.3 3344.2 3328.6 3362.2 35661 3620.0 3556.6 3540.5 3546.2 3567.3 3566.3 35662 3771.0 3726.5 3749.9 3734.8 3716.5 3779.0 DuPont 10657 DAY 9 ANIMAL STATUS 3181.6 2874.6 3305.0 3788.5 3209.0 3904.6 ED 3579.3 3433.9 3459.4 3570.4 4204.5  3463.7 3307.8 3175.3 3590.3 3211.1 3413.9 4079.4 3108.1 NP 3384.2 3564.8 3709.0 93 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits INDIVIDUAL ADULT BODY WEIGHTS GROUP 111: 100 mg/ m3 ANIMAL DAYS OF GESTATION NUMBER DAY 10 DAY 11 DAY 12 DAY 13 DAY 14 DAY 15 35580 3222.8 3220.6 3200.8 3262.5 3352.0 3386.5 35582 2895.2 2907.2 2966.6 3002.5 2998.6 3015.6 35587 3235.9 3216.1 3194.0 3206.8 3171.0 3173.9 35589 3783.1 3807.2 3832.6 3893.7 3923.8 3991.0 35594 3229.5 3265.4 3205.6 3235.9 3297.1 3305.8 35596 3933.1 3962.1 4016.4 4098.6 4155.0 4088.3 35609 3576.1 3601.2 3622.8 3650.9 3622.0 3674.4 35610 3462.6 3443.7 3472.0 3481.8 3530.1 3569.1 35611 3437.3 3464.6 3482.6 3501.0 3528.4 3600.2 35615 3606.5 3591.3 3589.4 3648.6 3676.7 3723.4 35622 4248.0 4178.2 4237.5 4210.2 4280.1 4325.9 35624 3512 3 3473.3 3484.6 3544.8 3585.2 3610.9 35627 3328.9 3325.5 3330.3 3382.9 3434.8 3459.8 35634 3212.4 3209.8 3215.1 3264.6 3334,8 3294.8 35641 3593.3 3596.7 3623.1 3647.4 3695.4 ' 3725.9 35643 3189.2 3178.4 3230.1 3288.4 3316.5 3336.0 35645 3428.7 3390.3 3452.9 3468.0 3488.5 3516.5 35652 4072.0 4067.7 4067.2 4143.0 4162.4 4171.0 35657 3076.1 3112.7 3088.8 3128.2 3130.5 3106.5 35660 3360.8 3343.1 3368.5 3378.8 3393 * 7 3414.6 35661 3589.7 3638.3 3676.9 3717.2 3776.8 3823.7 35662 3730.6 3758.9 3806.3 3845.1 3885.2 3910.0 DuPont 10657 DAY 16 ANIMAL STATUS 3414.3 3076.2 3180.1 4000.0 3331.7 4114.2 ED 3662.0 3583.4 3474.9 3730.6 4379.2 3621.8 3444.9 3342.6 3705.6 3304.5 3568.1 4161.6 3098.7 NP 3423.5 3847.3 3938.9 94 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 INDIVIDUAL ADULT BODY WEIGHTS GROUP 111: 100 mg/ m3 ANIMAL DAYS OF GESTATION NUMBER DAY 17 DAY 18 DAY 19 DAY 20 DAY 21 DAY 22 ANIMAL STATUS 35580 3380.6 3464.8 3476.1 3492.8 3448.5 3468.9 35582 3099.7 3126.4 3037.4 3090.4 3100.9 3152.6 35587 3207.8 3251.3 3280.1 3309.1 3322.9 3340.9 35589 4012.3 3999.8 3994.3 4033.1 4063.1 4078.9 35594 3301.3 3343.2 3300.8 3340.8 3341.8 3352.6 35596 4141.5 4171.2 4221.9 4355.6 4244.9 4316.1 ED 35609 3685.9 3660.5 3682.5 3695.8 3706.5 3727.4 35610 3574.4 3584.6 3600.8 3599.2 3639.2 3670.5 35611 3640.8 3604.5 3625.1 3621.4 3645.1 3692.9 35615 3697.6 3683.5 3682.9 3711.5 3715.2 3727.1 35622 4345.0 4318.3 4374.6 4323.0 4342.0 4237.% 35624 3640.4 3615.3 3606.2 3623.6 3634.3 3636.5 35627 3454.6 3444.2 3445.4 3468.8 3492.9 3491.3 35634 3269.7 3319.6 3338.5 3352.4 3467.3 3454.2 35641 3699.7 3692.1 3705.8 3561.1 3756.1 3745.7 35643 3273.1 3296.3 3300.1 3309.7 3332.6 3378.5 35645 3526.8 3582.2 3600.5 3612.1 3657.6 3656.3 35652 4169.2 4152.8 4172.6 4195.3 4199.8 4230.6 35657 3138.9 3077.2 3203.3 3126.4 3081.1 3146.2 NP 35660 3439.2 3435.8 3439.9 3425.8 3433.6 3431.2 35661 3853.5 3864.1 3888.0 3939.0 3937.4 3949.1 35662 3967.3 4001.9 4012.7 4027.8 4017.7 4040.4 95 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits INDIVIDUAL ADULT BODY WEIGHTS GROUP 111: 100 mg/ m3 ANIMAL DAYS OF GESTATION NUMBER DAY 23 DAY 24 DAY 25 DAY 26 DAY 27 DAY 28 35580 3492.1 3556.8 3530.6 3558.4 3573.9 3606.4 35582 3154.9 3200.6 3250.2 3296.7 3296.9 3285.6 35587 3368.3 3367.8 3438.3 3453.0 3476.6 3471 6 35589 4098.2 4130.0 4135.7 4192.0 4214.6 4149.6 35594 3361.4 3421.0 3430.5 3458.4 3457.6 3494.7 35596 4267.4 4324.1 4333.7 4036.8 4344.4 4372.9 35609 3762.7 3785.2 3816.0 3829.9 3752.0 3891.0 35610 3684.6 3730.1 3735.5 3779.9 3847.4 3853.3 35611 3719.9 3731.6 3756.1 3768.2 3730.1 3690.9 35615 3712.4 3753.5 3798.7 3825.3 3772.6 3815.3 35622 4406.9 4370.1 4384.6 4386.6 4371.6 4379.7 35624 3670.5 3689.6 3718.5 3721.6 3728.5 3743.3 35627 3549.1 3546.3 3597.0 3608.5 3582.7 3637.9 35634 3516.1 3505.3 3544.6 3522.7 3572.4 3535.3 35641 3735.0 3785.0 3844.5 3729.5 3823.4 ' 3817.3 35643 3429.9 3459.7 3478.4 3498.6 3519.6 3523.2 35645 3674.2 3706.8 3747.4 3743.3 3746.9 3762.6 35652 4250.3 4258.4 4261.5 4249.2 4306.1 4316.9 35657 3126.5 3101.8 3127.0 3216.7 3186.2 3196.3 35660 3451.9 3439.9 3444.0 3474.5 3485.7 3500.6 35661 3976.2 4001.0 3972.8 4039.2 4024.5 4051.2 35662 4035.5 4088.3 4083.6 4127.1 4147.9 4157.7 DuPont 10657 DAY 29 ANIMAL STATUS 3565.4 3284.1 3491.2 4162.6 3490.8 4087.6 ED 3921.2 3891.7 3710.8 3810.8 4468.8 3785.8 3660.6 3613.7 3819.7 3541.4 3853.7 4350.5 3212.3 NP 3511.4 4048.7 4171.4 96

 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 INDIVIDUAL ADULT BODY WEIGHTS GROUP 111: 100 mg/ m3 ANIMAL DAYS OF GESTATION NUMBER DAY 29a 35580 3101.0 35582 2852.6 35587 3051.0 35589 3663.3 35594 3158.8 35596 35609 3466.3 35610 3527.7 35611 3298.4 35615 3340.9 35622 4152.0 35624 3339.7 35627 3217.1 35634 3129.0 35641 3345.9 35643 2992.5 35645 3402.3 35652 3871.3 35657 35660 3326.2 35661 3646.8 35662 3676.9 ANIMAL STATUS ED NP 97 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits INDIVIDUAL ADULT BODY WEIGHTS GROUP IV: 300 mg/ m3 ANIMAL DAYS OF GESTATION NUMBER DAY 0 DAY 4 DAY 5 DAY 6 DAY 7 DAY 8 35571 3835.0 3798.0 3801.6 3780.3 3828.7 3855.8 35577 3239.0 3283.5 3273.5 3302.8 3320.9 3314.5 35583 2897.0 2926.3 2893.8 2900.5 2928 .2 2979.4 35586 3573.0 3747.0 3702.1 3619.7 3669.7 3673.9 35591 3112.0 3131.2 3109.8 3150.0 3236.9 3185.1 35592 3658.0 3761.5 3659.7 3648.9 3666.8 3627.5 35607 3996.0 4070.4 3999.9 3983.0 4025.5 4015.0 35608 3326.0 3334.4 3315.2 3307.7 3332.4 3379.2 35618 3805.0 3749.4 3770.1 3779.1 3752.1 3816.5 35620 3290.0 3442.3 3475.3 3480.1 3417.5 3547.2 35625 3561.0 3575.4 3538.5 3606.2 3597.3 3615.5 35626 3091.0 3173.5 3136.9 3191.8 3150.3 3221.0 35631 3881.0 4069.9 4129.9 4143.9 4145.7 4100.8 35635 3044.0 3120.8 3083.5 3121.4 3130.5 3125.8 35637 3748.0 3887.8 3838.4 3777.2 3788.8 3833.5 35640 3174.0 3257.1 3188. O 3155.4 3205.2 3170.9 35650 4154.0 4137.9 4168 8 4222.5 4221.0 4105.3 35653 3581.0 3546.8 3583.5 3577.5 3586.1 3543.4 35663 3630.0 3536.9 3575.6 3577.3 3594.7 3687.8 35672 3586.0 3306.7 3317.8 3342.5 3370.3 3388.4 35676 3272.0 3195.9 3233.0 3222.4 3201.5 3208.3 35678 3215.0 3207.1 3165.8 3151.3 3211.1 3205.1 DuPont 10657 DAY 9 ANIMAL STATUS 3804.8 3267.8 2905.3 3588.4 3262.7 3667.3 3957.3 3318.0 3786.6 3485.9 3553.0 3150.4 4111.8 3105.8 3812.7 3177.9 4052.3 3567.2 3621.8 3373.8 3206.7 3211.4 NP 98 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits INDIVIDUAL ADULT BODY WEIGHTS GROUP IV: 300 mg/ m3 ANIMAL DAYS OF GESTATION NUMBER DAY 10 DAY 11 DAY 12 DAY 13 DAY 14 DAY 15 35571 3834.0 3833.0 3861.8 3856.6 3858.9 3935.0 35577 3296.9 3313.3 3342.0 3384.8 3400.0 3437.9 35583 2925.6 2927.6 2960.9 2987.7 3026,4 3040.1 35586 3626.2 3623.4 3646.0 3684.8 3716.7 3764.5 35591 3241.4 3266.4 3281.4 3340.9 3399.8 3506.5 35592 3687.0 3725.5 3707.3 3725.7 3729.5 3773. a 35607 3972.4 3956.2 4031.4 3986.9 4075.6 4128.4 35608 3336.0 3355.5 3388.6 3390.3 3442.7 3467.9 35618 3806.3 3760.1 3763.0 3777.3 3825.8 3848.4 35620 3490.9 3498.5 3550.4 3639.6 3601.3 3665.4 35625 3597.4 3556.6 3537.1 3609.4 3655.5 3707.0 35626 3108.2 3209.0 3181.0 3233.3 3286.1 3313.9 35631 4162.6 4155.9 4055.9 4079.3 4161.1 4196.4 35635 3094.9 3116.7 3149.8 3178.2 3258.6 3272. I 35637 3818.4 3821.2 3861.4 3903.4 3917.9 3892.1 35640 3139.2 3145.6 3167.0 3221.7 3270.0 3281.0 35650 4104.0 4133.8 4173.2 4117.3 4119.9 4170.5 35653 3602.9 3604.4 3654.1 3743.4 3745.8 3768.7 35663 3594.3 3600.3 3648.0 3764.7 3798,9 3802.9 35672 3395.9 3365.2 3445.8 3484.0 3448.6 3469.8 35676 3208.2 3191.5 3214.5 3218.5 3260.9 3237.8 35678 3168.5 3184.4 3220.3 3217.5 3224.2 3226.6 DuPont 10657 DAY 16 ANIMAL STATUS 4007.7 3460.4 3038.6 3740.7 3553.4 3751.2 4133.8 3448.8 3837.2 3674.7 3728.9 3331.3 4257.2 3261.8 3909.7 3210.2 4192.0 3742.7 3760.5 3503.4 3230.1 3223.8 NP 99 Dimethvl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits INDIVIDUAL ADULT BODY WEIGHTS GROUP IV: 300 mg/ m3 ANIMAL DAYS OF GESTATION NUMBER DAY 17 DAY 18 DAY 19 DAY 20 DAY 21 35571 4034.9 4037,5 4039.2 4034.9 4067.1 35577 3460.9 3505.6 3498.6 3530.4 3553.3 35583 3028.7 3062.4 3081.4 3139.7 3139.2 35586 3736.7 3719.8 3705.3 3724.8 3733.8 35591 3586.4 3574.4 3596.0 3614.5 3625.2 35592 3786.1 3755.8 3779.0 3802.5 3839.0 35607 4148.3 4131.0 4157.3 4154.2 4181.3 35608 3471.4 3461.5 3428.6 3462.4 3456.4 35618 3798.8 3797.1 3813.6 3812.6 3856.5 35620 3506.3 3639.7 3617.5 3643.5 3700.7 35625 3673.7 3741.4 3729.3 3771.5 3737.5 35626 3308.5 3285.5 3304.8 3311.3 3327.8 35631 4204.9 4196.0 4186.6 4205.2 4218.4 35635 3271.5 3294.6 3332.8 3399.0 3353.2 35637 3882.6 3890.4 3921.2 3931.4 3965.6 35640 3222.9 3233.3 3245.5 3265.9 3284.7 35650 4225.4 4233.2 4226.5 4229.9 4254.3 35653 3751.4 3741.0 3734.5 3754.5 3822.5 35663 3725.6 3738.9 3734.7 3783.5 3752.6 35672 3460.3 3446.5 3474.8 3515.0 3367.1 35676 3265.7 3282.1 3250.2 3266.5 3298.1 35678 3187.2 3189.7 3223.0 3236.2 3227.7 DuPont 10657 DAY 22 STATUS 4096.1 3579.1 3146.8 3773.6 3645.8 3880.5 4192.3 3474.7 3795.4 3762.1 3769.8 3338.8 4208.4 ,3380.1 3950.6 3301.9 4283.9 3755.4 3742.2 3250.6 3300.2 3272.2 NP 100 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits INDIVIDUAL ADULT BODY WEIGHTS GROUP IV: 300 mg/ m3 ANIMAL DAYS OF GESTATION NUMBER DAY 23 DAY 24 DAY 25 DAY 26 DAY 27 DAY 28 35571 4094.0 4140.0 4158.1 4202.9 4230.3 4227.4 35577 3632.5 3642.1 3640.7 3659.6 3647.7 3641.6 35583 3195.1 3228.5 3226.5 3278.4 3293.9 3295.7 35586 3781.3 3794.2 3829.0 3861.0 3867.6 3871.0 35591 3671.2 3642.8 3696.6 3713.7 3727.6 3717.5 35592 3913.1 3951.4 3988.1 4024,5 4073.8 3976.8 35607 4265.4 4306.4 4304.6 4300.3 4302.5 4380.2 35608 3487.7 3475.8 3563 5 3560.2 3602.8 3645.4 35618 3855.4 3877.6 3897.8 3922.6 3904.6 3915.0 35620 3710.6 3767.2 3753.6 3777.8 3826.4 3783.8 35625 3820.8 3824.5 3838.4 3831.9 3869.8 3843.8 35626 3357.8 3411.2 3447.0 3465.8 3477.4 3505.8 35631 4213.4 4219.9 4241.8 4265.2 4272.8 4294.3 35635 3413.3 3438.0 3471.2 3481.7 3495.9 3523.9 35637 4000.7 4038.6 4028.8 4080.8 4073.5 4102.8 35640 3333.3 3337.6 3405.6 3392.0 3401.6 3417.9 35650 4348.6 4353.9 4466.3 4466.2 4447.5 4446.4 35653 3856.6 3880.8 3868.3 3872.5 3875.9 3830.8 35663 3752.5 3608.0 3849.4 3862.5 3856.4 3859.9 35672 3158.4 3551.6 3518.7 3565.6 3568.0 3590.  O 35676 3352.1 3341.4 3359.7 3383.7 3411.6 3414.9 35678 3246.8 3211.2 3227.0 3239.8 3262.8 3268.8 DuPont 10657 DAY 29 ANIMAL STATUS 4253.3 3665.5 3315.2 3868.5 3651.9 4073.5 4458.9 3673.4 3931.6 3772.6 3858.5 3518.6 4294.0 3509.3 4113.7 3434.6 4472.2 3876.8 3964.2 3593.3 3450.2 3270.6 NP 101  Dimethvl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 INDIVIDUAL ADULT BODY WEIGHTS GROUP IV: 300 mg/ m3 ANIMAL DAYS OF GESTATION NUMBER DAY 29a ANIMAL STATUS 35571 3566.9 35577 3235.8 35583 2891.5 35586 3417.6 35591 3115.4 35592 3459.1 35607 3783.2 35608 3131.6 35618 3625.4 35620 3336.9 35625 3424.6 35626 3091.2 35631 3809.5 35635 3064.0 35637 3660.7 35640 3031.6 35650 3988.4 35653 3309.9 35663 3514.4 35672 3237.5 35676 3125.2 35678 NP 102 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 INDIVIDUAL ADULT BODY WEIGHTS GROUP V: 1000 mg/ m3 ANIMAL DAYS OF GESTATION NUMBER DAY 0 DAY 4 DAY 5 DAY 6 DAY 7 DAY 8 DAY 9 ANIMAL 35569 3710.0 3887.8 3861.4 3867.4 3882.3 3874.5 3886.5 35575 3292.0 3348.9 3323.8 3341.3 3334 2 3383.8 3382.2 FD 35581 3133.0 3140.9 3149.8 3143.0 3180.8 3117.6 3193.4 35590 3446.0 3341.6 3290.3 3298.5 3268.1 3316.6 3370.9 R 35598 3672.0 3711.3 3722.6 3668.9 3631.4 3694.2 3622.3 35602 3187, O 3257.4 3238.2 3045.7 3244.3 3185.4 3238.0 35605 2973.0 3112.1 3035.9 3036.7 3091.5 2902.1 3031.3 35612 3424.0 3597.1 3597.0 3533.5 3565.2 3635.3 3581.4 NP 35613 4096.0 3523.4 3665.9 3746.7 3786.0 3636.3 3410.1 35619 3117.0 3072.8 3019.8 3047.7 3017.7 3079.6 3095.4 35623 3764.0 3666.3 3665.2 3708.4 3700.3 3757.0 3766.6 35629 3603.0 3587.7 3606.9 3548.6 3616.0 3569.3 3598.7 35636 3417.0 3478.9 3531.0 3492.2 3474.8 3374 .> 3 3420.5 35638 3145.0 3119.8 3148.4 3158.6 3172.6 3145.2 3100.5 35648 3570.0 3578.4 3592.8 3585.5 3621.8 3467.3 3569.0 35651 3665.0 3622.3 3604.6 3590.9 3664.0 3426.9 3397.9 35655 4202.0 4034.4 4005.0 3994.7 4013.0 4121.3 4117.7 35664 3581.0 3559.1 3570.1 3565.6 3570.0 3553.8 3614.5 35665 3175.0 3231.0 3224.6 3233.4 3229.5 3262.0 3239.2 35668 3632.0 3647.0 3655.3 3699.8 3675.6 3614.1 3761.1 35671 3748.0 3709.0 3734.0 3709.1 3718.6 3607.2 3689.0 SE 35673 3370.0 3411.0 3405.1 3337.9 3351.4 3381.8 3394.0 103  Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits INDIVIDUAL ADULT BODY WEIGHTS GROUP V: 1000 mg/ m3 ANIMAL DAYS OF GESTATION NUMBER DAY 10 DAY 11 DAY 12 DAY 13 DAY 14 DAY 15 35569 3895.5 3877.9 3913.3 3952.9 3957.9 3971.7 35575 3448.0 3476.5 3526.2 __ ___ 35581 3141.1 3188.1 3235.1 3227.6 3277.5 3316.4 35590 3323.9 3327.3 3371.2 3382.0 3371.6 3400.8 35598 3670.1 3674.7 3702.3 3749.7 3775.3 3795.3 35602 3239.8 3238.7 3256.4 3307.7 3310.0 3329.0 35605 3053.4 3032.3 3044.8 3069.1 3089.9 3127.6 35612 3549.9 3581.8 3556.7 3586.0 3574.0 3590.3 35613 3361.1 3331.9 3246.2 3207.0 3212.7 3201.3 35619 3069.6 3092.4 3098.7 3083.2 3117.4 3149.0 35623 3778.9 3750, l 3726.5 3740.9 3762.2 3787.9 35629 3339.6 3595.5 3578.7 3594.0 3628.3 3626.2 35636 3452.1 3450.7 3495.8 3492.3 3525.7 3523.7 35638 3106.2 3162.8 3193.6 3251.3 3307.3 3357.2 35648 3637.9 3632.3 3627.3 3636.3 3667.9 3708.8 35651 3514.0 3527.5 3511.4 3570.9 3607.7 3624.8 35655 4065.4 4077.1 4099.9 4113.8 4126.8 4181.9. 35664 3591.4 3591.8 3650.9 3690.0 3746.8 3789.7 35665 3253.0 3260.6 3312.7 3348.7 3357.5 3330.2 35668 3760.9 3726.5 3782.8 3827.1 3826.5 3805.2 35671 3713.8 3707.4 3691.6 3658.8 3564.2 3526.9 35673 3392.6 3382.9 3438.1 3448.4 3470.9 3493.1 DuPont 10657 DAY 16 ANIMAL STATUS 3997.4 ___ FD 3319.3 3420.8 R 3844.5 3306.0 3144.0 3617.7 NP 3309.3 3181.0 3825.6 3632.1 3564.5 3330.0 3691,8 3603.7 4210.3 3792.8 3350.6 3827.7 3306.8 SE 3511.3 104       Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits INDIVIDUAL ADULT BODY WEIGHTS GROUP V: 1000 mg/ m3 ANIMAL DAYS OF GESTATION NUMBER DAY 17 DAY 18 DAY 19 DAY 20 DAY 21 35569 4017.0 4013.6 4016.4 4002.4 4036.8 35575 35581 3297.1 3326.4 3299.2 3311,7 3348.3 35590 3436.7 3468.3 3450.4 3482.6 3479.1 35598 3830.9 3818.8 3793.6 3813.9 3606.4 35602 3299.7 3078.9 2928.6 2955.6 2831,7 35605 3177.4 3168.8 3183.8 3195.0 3046.9 35612 3644.5 3690.9 3691.9 3634.8 3507.1 35613 3441.9 3520.9 3596.1 3636.9 3630.1 35619 3184.2 3162.6 3188.8 3200.7 3224.3 35623 3792.4 3789.9 3801.6 3822.7 3858.6 35629 3667.7 3709.1 3704.5 3710.0 3822.6 35636 3566.5 3625.2 3607.2 3597.2 3609.8 35638 3345.9 3315.3 3348.8 3351.2 3375.4 35648 3700.8 3722.6 3707.2 3712.3 3711.2 35651 3613.7 3622.2 3621.5 3613.5 3634.2 35655 4274.6 4249.7 4217.1 4295.2 4362.2 35664 3773.4 3803.6 3789.7 3818.7 3824.1 35665 3381.9 3385.1 3383.6 3401.7 3449.6 35668 3877.1 3879.3 3878.8 3905.5 3888.5 35671 3242.7 3247.1 3154.0 3037.8 2944.7 35673 3510.9 3532.0 3531.1 3548.6 3523.4 DuPont 1065  7 DAY 22 ANIMAL STATUS 3813.7 FD 3236.3 3392.2 R 3893.1 3108.5 3248.5 3658.3 NP 3601.5 3227.9 3843.2 3732.1 3631.4 3381.4 3716.7 3636.4 4354.7 3861.4 3481.3 3880.7 2847.9 SE 3537.7

 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 INDIVIDUAL ADULT BODY WEIGHTS GROUP V: 1000 mg/ m3 ANIMAL DAYS OF GESTATION NUMBER DAY 23 DAY 24 DAY 25 DAY 26 DAY 27 DAY 28 DAY 29 ANIMAL STATUS 35569 4099.9 4129.9 4073.3 4120.6 4123.4 4147.5 4130.1 35575 FD 35581 3378.1 3418.0 3441.8 3451.0 3443.3 3428.9 3457.8 35590 3546.9 3581.7 3604.3 3648.5 3682.4 3672.6 3553.9 R 35598 3881.6 3883.6 3924.2 3948.5 3918.5 3953.7 3958.5 35602 2951.0 3174.7 3252.9 3303.2 3305.4 3312.7 3319.0 35605 3320.2 3278.8 3323.7 3367.7 3361.5 3389.1 3414.3 35612 3675.9 3721.1 3739.9 3722.9 3689.3 3728.3 3754.1 NP 35613 3589.4 3657.2 3449.8 3695.8 3661.1 3656.8 3700.5 35619 3277.1 3315.8 3125.2 3374.2 3378.5 3368.0 3375.6 35623 3782.2 3884.0 3703.6 3916.9 3904.7 3911.4 3931.7 35629 3762.9 3767.5 3609.0 3907.0 3874.2 3867.6 3865.0 35636 3609.0 3401.8 3584.5 3613.0 3643.4 3649.2 3641.6 35638 3403.8 3263.1 3464.3 3470.2 3490.2 3512.5 3542.7 35648 3751.1 3597.3 3752.2 3739.4 3757.0 3757.3 3768.6 35651 3675.3 3521.1 3703.6 3708.1 3694.0 3697.2 3759.6 35655 4305.5 4338.8 4348.3 4349.6 4329.9 4274.2 4306.7 35664 3869.2 3872.6 3876.0 3884.4 3875.1 3841.5 3886.6 35665 3526.9 3505.2 3549.4 3579.2 3589.0 3620,7 3626.8 35668 3932.7 3945.4 3961.5 3979.2 3979.1 3972.7 4021.8 35671 SE 35673 3550.9 3540.9 3542.1 3541.7 3566.3 3543.7 3550.8 106

  Dimethyl Glutarate ( DMG): Inhalation Develo~ mentalToxicity Study in Rabbits DuPont 10657 INDIVIDUAL ADULT BODY WEIGHTS GROUP V: 1000 mg/ m3 ANIMAL DAYS OF GESTATION NUMBER DAY 29a ANIMAL STATUS 35569 3770.1 35575 FD 35581 3038.6 35590 3048.6 R 35598 3594.7 35602 2964.9 35605 3060.1 35612 NP 35613 3347.0 35619 2856.2 35623 3721.0 35629 3509.1 35636 3576.5 35638 3146.3 35648 3426.0 35651 3571.8 35655 3873.2 35664 3454.1 35665 3185.1 35668 3464.2 35671 SE 35673 3357.3 107 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 APPENDIX F Individual Body Weight Changes 108  Dimethvl Glutarate ( DMG): Inhalation DeveloDmental Toxicity Studv in Rabbits DuPont 10657 Individual Body Weight Changes Explanatory Notes Footnotes a Weight calculated using the final body weight minus the weight of the products of conception.

Abbreviations = Nodata AB = Aborted NP = Notpregnant ED = Earlydelivery R = Litter totally resorbed SE = Sacrificed in extremis FD = Founddead Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 INDIVIDUAL BODY WEIGHT CHANGES ( grams)

GROUP I: o mg/ m3 ANIMAL DAYS OF GESTATION NUMBER 0 4 4 7 0 7 7 9 9 11 11 13 13 15 ANIMAL STATUS 35570 207.7  167.9 39.8 23.4 45.4 70.3 67.8 35572 135,6  60.4 75.2  37.4 8.5 86.9 29.4 35576 109.4 51.2 160.6 60.4  61.9 73.3 132.1 35578 245.7  189.5 56.2  4.3  44.1 29.0 9.7 AB 35579 250.0  115.7 134.3 55.4  2.4 82.7 85.4 35597 96.6 1.0 97.6 1.0  13.7  1.3 67.4 35599 137.3  280.8  143.5 249.4  13.6 26.2 61.0 35601 111.0  57.1 53.9 78.9 62.2 50.3 43.8 35604 58.6  59.8  1.2 46.3 37.2 86.3 122.3 35616  55.5 4.4  51.1 61.2 8.8 97.1 93.4 35621 8.8  7.2 1.6  20.6 52.3  23.6  110.6 35628  57.3 26.7  30.6 23.1 41.1 64.5 87.5 35632 ,147.7  7.2 ,154.9  13.9 57.6 9.7 57.4 35639 65.9  5.5 60.4 3.7  27.0 45.5 75.6 35644 68.6  40.3 28.3  17.1 23.5 29.7 134.0 35646 49.1 24.0 73.1  52.6  18.6  29.1 159.9 35656  71.7  27.2  98.9 49.8 45.3 5.6 41.1 35658  79.8 12.8  67.0 7.6  0.6 61.1 39.0 35659  5.2 18.7 13.5 63.5 24.1 40.9 60.5 35666 34.1  9.0 25.1 26.8 6.1 32.0 80.7 35675  54.1 31.5 '  22.6 47.4  23.5 150.0 86.1 35677 128.4 34.6 163.0 11.2 24.2 22.1 63.4 110

  Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 INDIVIDUAL BODY WEIGHT CHANGES ( grams)

GROUP I: o mg/ m3 ANIMAL DAYS OF GESTATION NUMBER 15 17 17 19 19 21 21 23 23 25 25 27 27 29 ANIMAL STATUS 35578 35570  6.5 8.3  19.3 51.6 55.0 18.7 64.4 35572 52.5 14.3 13.7  5.8 40.1 2.9  37.2 35576 148.8  65.4 36.4  63.0 48.2 67.8 97.0  20.2 101.8 AB 35579 48.6 8.1 31.9 77.3 47.0 41.2 21.9 35597 37.0  27.1 24.2 60.0 68.7 57.8  8.4 35599 24.4  7.9 87.0 28.2 94.9 49.8 13.6 35601  9.0 31.2 48.2  34.6 71.7 88.5 27.8 35604 59.6 23.3 10.9  35.3 71.0 46.5 28.6 35616 40.7 2.5 21.0 28.8 29.8  10.5 65.7 35621 229.8 19.5  1.1 14.7 28.7 36.1 35628  45.5 86.4 12.5 7.4 49.7 12.6 35632  14.2 30.4 26.5  79.6 33.4 3.4 36.1 35639  5.2 7.9 29.0 58.9 58.3 70.7 76.5 35644 17.6  45.9  40.8 85.2 2.4 42.8 45.8 35646 13.5  15.0 9.2 82.4 45.9 91.8 27.4 35656 49.0 1.3  13.7 53.9  6.7 17.8  3.1 35658 17.1 25.1 15.8 37.0 52.1 30.0 91.9 35659 41.6 57.8 69.7  19.7 107.1  96.7 108.7 35666 34.9 62.2  37.2 89.4 64.9 21.7  10.3 35675  31.1 4.4  25.0 26.1 44.0 100.3 94.3 35677  52.7 46.1  15.2 68.6 4.2 34.7 71.8 111

  Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 INDIVIDUAL BODY WEIGHT CHANGES ( grams)

GROUP I: o mg/ m3 ANIMAL DAYS OF GESTATION NUMBER 7 29 7 29a ANIMAL STATUS AB 53.3  162.7  49.0 35570 35572 35576 35578 35579 35597 35599 35601 35604 35616 35621 35628 35632 35639 35644 35646 35656 35658 35659 35666 35675 35677 379.1 167.9 473.7 497.1 265.6 613.0 459.0 496.7 438.5 901.6 ,278.0 146.8 393.9 277.2 314.8 240.3 376.1 457.5 371.2 473.0 278.4 68.6  187.2 200.4  7.4  52.6  26.5  211.0  109.9  133.3  216.8  156,7  104.4  54.1  81.7  63.6  216.1 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits INDIVIDUAL BODY WEIGHT CHANGES ( grams)

GROUP 11: 30 mg/ m3 ANIMAL DAYS OF GESTATION NUMBER 0 4 4 7 0 7 7 9 9 11 11 13 35573 146.3  108.5 37.8  25.4 40.1 58.2 35574  69.2  70.9  140.1  5.5 32.9 27.0 35584 30.4  3.9 26.5  32.1 6.0 71.4 35585 54.6  134.4  79.8 49.0 7.5" 41.6 35588  132.8  78.3  211.1  47.2  3.8 81.4 35593 31.0  61.7  30.7 69.7  6.4 13.3 35595 132.5 10.3 142.8 10.0 21.5 22.6 35600  106.9 45.4  61.5  0.7  6.9 1.7 35603  32.0  24.4  56.4 68.4 40.5  1.1 35606 97.7  39.2 58.5 36.1 5.8 33.9 35614  138.3  14.2  152.5 38.1 26.5 106.8 35617 73.4  74.2  0.8 14.3 41.2 26.4 35630 50.9  40.5 10.4  9.9 18.2 40.1 35633  93.8 53.4  40.4 35.7  0.5 5.7 35642  1.1 91.1 90.0  86.7  23.2 I 72.6 3564t7 160.9 24.0 184.9  31.5 62.7 152.5 35649 51.4  97.0  45.6 19.5  59.2 65.7 35654 24.8 30.7 55.5  32.2 10.4  29.9 35667  69.8 31.6  38.2 24.2  3.0 47.6 35669  17.1 97.3 80.2  0.9  5.2 65.2 35670 5.0 63.3 68.3  17.5 5.1 96.0 35674  32.9  29.6  62.5 22.8 29.7 96.8 DuPont 10657 13  15 I" I ANIMAL STATUS 92.6 66.9 62.6 72.0 32.8 71.2 93.8 99.5  7.6 NP 87.2 168.2 64.2 85.5 123.8 117.0 159.1 60.3 55.5 NP 22.0 52.6 25.9 109.4 113 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 INDIVIDUAL BODY WEIGHT CHANGES ( grams)

GROUP IS: 30 mg/ rn3 ANIMAL DAYS OF GESTATION NUMBER 15 17 17 19 19 21 21 23 23 25 25 27 27 29 ANIMAL STATUS 35573 101.9 14.5 22.1 27.8 62.9 37.2 9.4 35574 40.2 28.2 22.1 71.0 5.6 69.8 24.2 35584 17.2 9.0 46.6 58.4 26.4  29.1 52.4 35585 48.4 7.8 51.4 33.8  154.5 242.7 40.6 35588 76.8  28.1 20.2 89.6 90.5 79.9 29.1 35593  2.4 32.0 28.3 99.6 34.4 37.3 10.2 35595  4.8  8.2 1.6 80.6 45.9 39.1 63.1 35600 81.8 0.2  6.3 42.4 51.9 85.0 8.4 35603 63.9 28.5  41.2 9.5 34.7 5.3 25.7 NP 35606 3.0 41.3 30.4 35.8 49.9  7.4 86.0 35614 43.9 17.4  26.9 63.1 24.5  5.9  10.5 35617  59.6 7.2 81.2 35.8 39.2 53.3 1.6 35630 25.3 9.0 61.7 37.3 81.0 20.0 98.6 35633  39.5  3.6 34.1 54.6 40.4 38.6 23.0 35642  14.7  34.2  5.6 33.1  2.6 48.7 61.7 35647 83.7  50.0  58.1 71.4 78.7 32.7 98.4 35649 54.6 11.6 4.3 32.4 50.1 21.0 30.9 35654  90.2  25.1  19.3 48.2  5.6  4.5 30.9 NP 35667 38.7 21.7 20.4 27.0 34.3 36.6 71.1 35669 51.7 20.9 15.9 38.1 59.5 65.6 34.0 35670  16.0 29.2 32.3 74.3 65.1 70.8 63.7 35674  43.8  12.9 13.5 10.8 72.6 42.9 40.5 114

 I Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits DuPont 10657 GROUP 11: 30 mg/ m3 ANIMAL NUMBER 7 29 35573 441.3 35574 382.4 35584 288.8 35585 440.3 35588 421.2 35593 387.2 35595 365.2 35600 357.0 35603 226.6 35606 402.0 35614 445.2 35617 304.8 35630 466.8 35633 312.3 35642 166.1 35647 599.6 35649 291.2 35654  61.8 35667 340.6 35669 397.4 35670 428.9 35674 382.3 INDIVIDUAL BODY WEIGHT CHANGES ( grams)

DAYS OF GESTATION 7 2ga ANIMAL STATUS 2.8  181.6  61.7 20.4  128.0  91.2  175.0  207.6 NP  89.2  74.8  21.4 27.2  41.4  222.6 55.4  259.7 NP  73.2 12.1  63.6  85.7 115 Dimethyl Glutarate ( DMG): Inhalation Developmental Toxicity Study in Rabbits INDIVIDUAL BODY WEIGHT CHANGES ( grams)