AD-A252 109 :'•': P I! :l - DTIC · (Sources): Hazleton Research Products, Denver, PA Buckshire Corporation, Perkasie, PA Sex: Male and female Age at Initiation: 8-12 weeks Weight

AD-A252 109 A_ _:'•': " P I! :l "A D

CONTRACT NO: DAMDI7-91-C-1140

TITLE: LIMITED TOXICITY AND MUTAGENICITY TESTING OF FIVEUNICHARGE PROPELLANT COMPOUNDS

SUBTITLE: Evaluation of Five Unicharge Propellants in the AcuteExposure Dermal Toxicity

PRINCIPAL INVESTIGATOR: Vincent B. Ciofalo, Ph.D.

CONTRACTING ORGANIZATION: Pharmakon Research International, Inc.P.O. Box 609Waverly, PA 18471 IDT, iC

REPORT DATE: January 31, 1992 ý__ V -

jUtA12 1992~

TYPE OF REPORT: Final Report W

PREPARED FOR: U.S. ARMY MEDICAL RESEARCH AND DEVELOPMENT COMMANDFort Detrick, Frederick, Maryland 21702-5012

DISTRIBUTION STATEMENT: Approved for public release;distribution unlimited

The findings in this report are not to be construed as anofficial Department of the Army position unless so designated byother authorized documents.

92-17928t l l I I 11 tl d I 1 0

Form ApprovedREPORT DOCUMENTATION PAGE OMB No 0704.0188

P- 0 1,C reoom~ q oytaem -or th% 3~clteclOn 0f ,'fo,'nat* %n res ate to ai~vaqi I our oef e'wi-ur MlC'IONq the time to( rev-e-mgl inutruniomn seartn~mq ex s!nq osta jorc

paine,'l and •".o'I"'.•q the 'ta r. nee0.e and como ie " alq Jn d & 'e -"en • the , it¶le On OF 0 ntOVitO fl ' om entl 'egrthenq thin tdrfe e.mate 0r any ow e Se*'co Of th,cOJlec-tl•o O* iflt0'hatOn ndin. d , n g•fl ni lent toe 'ed i in ,h Oa ntoen to v&%hanqton me'ontlrem cenKe% [)11-o'g t of Oriai O e.ratlO• o n es orin 210 ,aiISIetl• eDasMs •gqhvt . Suite 1204 ArIngrton J& A222021302 arn tO the Ot cC et M0 •dn4Kcm.! v 8.indel POalO 'oft Aeduti.n" ProeC-t (0704-0188) wAn•.inqtoin DC 20104

AGENCY USE ONLY (Leave blank) 2. REPORT DATE 3. REPORT TYPE AND DATES COVEREDJanuary 31, 1992 Final Report (9/20/91 - 12/31/91)

4. TITLE AWK51019=r S. FUNDING NUMBERS

LIMITED TOXICITY AND MUTAGENICITY TESTING OF FIVE Contract No.UNICHARGE PROPELLANT COMPOUNDS DAMDl7-91-C-1140

6. AUTHOR(S)

Vincent B. Ciofalo, Ph.D.Victor T. Mallory, B.S.

7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATIONREPORT NUMBER

Pharmakon Research International, Inc.P.O. Box 609Waverly, PA 18471

9. SPONSORING/MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSORING/MONITORINGAGENCY REPORT NUMBERU.S. Army Medical Research and Development Command

Fort DetrickFrederick, Maryland 21702-5012

11. SUPPLEMENTARY NOTES

Subtitle: Evaluation of Five Unicharge Propellants in the AcuteExposure Dermal Toxicity

12a. DISTRIBUTION,, AVAILABILITY STATEMENT 12b. DISTRIBUTION CODE

Approved for public release; distribution unlimited

13. ABSTRACT (Maximum 200 words)

N-methyl-,n-ethyl- and n-butyl-2nitratoethyl nitramine (MeNENA,EtNENA and BuNENA) and bis (2,2-dinitropropyl) acetal/formal(-50/50 mixture) ± diphenyl amine stabilizer (BDNPA/F±DPA) weretested for dermal toxicity. One group of ten rabbits per studyreceived the test article once by topical application and washeld in contact with the skin for 24 hours. Animals wereobserved for clinical signs and mortality daily for 14 days.One animal receiving BDNPA/F-DPA died during the study. Nomortality was observed in any other treatment groups. Basedupon the results of these assays, the estimated acute dermalLD50 for MeNENA, EtNENA, BuNENA and BDNPA/F±DPA, was determinedto be greater than 2000 mg/kg.

14. SUBJECT TERMS 15. NUMBER OF PAGESDermal toxicity, unicharge, propellants, methyl-NENA, ethyl-NENA, butyl-NENA, bis-(2,2-dinitropropyl) acetal bis- 16. PRICE CODE( 2 ,2-dinitropropyl)formal, lab animals, RAIII

"17. SECURITY CLASSIFICATION 18. SECURITY CLASSIFICATION 19. SECURITY CLASSIFICATION 20. LIMITATION OF ABSTRACTOF REPORT OF THIS PAGE OF ABSTRACT

Unclassified Unclassified Unclassified UnlimitedNSN 75a0-01 280.5500 2 Slaridard Form 298 (Rev 2-89)

P U O , NOin St(3*'q~ 'ý

FOREWORD

Opinions, interpretations, conclusions and recommendations arethose of the author and are not necessarily endorsed by the US

Where copyrighted material is quoted, permission has beenobtained to use such material.

Where material from documents designated for limiteddistribution is quoted, permission has been obtained to use thematerial.

___Citations of commercial organizations and trade names inthis report do not consLitute an official Department of Armyendorsement or approval of the products or services of theseorganizations.

I/< In conducting research using animals, the investigator(s)adhered to the "Guide for the Care and Use of LaboratoryAnimals," prepared by the Committee on Care and Use of LaboratoryAnimals of the Institute of Laboratory Resources, NationalResearch Council (NIH Publication No. 86-23, Revised 1985).

For the protection of human subjects, the investigator(s)adhered to policies of applicable Federal Law 45 CFR 46.

In conducting research utilizing recombinant DNA technology,the investigator(s) adhered to current guidelines promulgated bythe National Institutes of Health.

In the conduct of research utilizing recombinant DNA, theinvestigator(s) adhered to the NIH Guidelines for ResearchInvolving Recombinant DNA Molecules.

In the conduct of research involving hazardous organisms,the investigator(s) adhered to the CDC-NIH Guide for Biosafety inMicrobiological and Biomedical Laboratories.

Acoession For

NTIS GRA&IDTIC TAB J0 ýUni•v(--xced 0 PI - Signature / DAte/

By

Am •a l ,.t ) CodOs

Dist ,pO____a

ll a R i f irt

im • l i3

TABLE OF CONTENTS

FRONT COVER ................................................... 1

SF 298 ........................................................ 2

FOREWORD ...................................................... 3

TABLE OF CONTENTS ............................................. 4

SUMMARY ....................................................... 5

STUDY DESCRIPTION ............................................. 6

TEST ARTICLES .................................................. 7

TEST SYSTEM ................................................... 8

HUSBANDRY ..................................................... 9

METHODS ....................................................... 9

RESULTS ...................................................... 11

CONCLUSIONS .................................................. 11

TABLESTable I - Summary of Clinical Observations .................. 12Table II - Summary of Mortality ............................ 14Table III - Summary of Body Weights ........................ 16Table IV - Necropsy Observations (Incidence Values) ........ 19

QUALITY ASSURANCE STATEMENT .................................. 21

COMPLIANCE STATEMENT ......................................... 22

4

Evaluation of Five Unicharge Propellants in the

Acute Exposure Dermal Toxicity

EXECUTIVE SUMMARY

In Dermal Limit Tests, one group of ten (10) rabbits (fivemales and five females) per study was exposed to the test articleat 2000 mg/kg. Animals were observed for clinical signs andmortality once daily for fourteen days.

Clinical signs observed in the bis-(2,2-dinitropropyl) formalwithout diphenyl amine stabilizer treated animals includeddecreased activity, decreased muscle tone, abnormal gait, abnormalstance, diarrhea and dyspnea. No clinical signs were observed inany animal receiving n-methyl-2-nitratoethyl nitramine, n-ethyl-2-nitratoethyl nitramine, n-butyl-2-nitratoethyl nitramine and bis-(2,2-dinitropropyl) acetal with diphenyl amine stabilizer. Withthe exception of a slight decrease in mean body weight on Day 7 inthe n-methyl-2-nitratoethyl nitramine females, there were noapparent effects on mean body weight throughout any other treatmentgroup. One of ten rabbits died in the bis-(2,2-dinitropropyl)formal without diphenyl amine stabilizer treated group. None ofthe animals died in any of the other treatment groups. Necropsy ofthe animal that died during the study revealed a red, distendedcecum and distended intestines. Terminal necropsy revealeddistended intestines and stomach in animals administered bis-(2,2-dinitropropyl) acetal with diphenyl amine stabilizer and pale andenlarged kidneys, enlarged spleen and ascites in bis-(2,2-dinitropropyl) formal without diphenyl amine stabilizer treatedanimals. No visible lesions were observed in any other animal inany treatment group at terminal necropsy.

Based upon the observations made in the Acute Exposure DermalToxicity studies in rabbits, the estimated acute dermal LD5 0(combined sexes) for n-methyl-2-nitratoethyl nitramine, n-ethyl-2-nitratoethyl nitramine, n-butyl-2-nitratoethyl nitramine and bis-(2,2-dinitropropyl) acetal with diphenyl amine stabilizer and bis-(2,2-dinitropropyl) formal without diphenyl amine stabilizer wasdetermined to be greater than 2000 mg/kg.

5

Evaluation of Five Unicharge Propellants

in the Acute Exposure Dermal Toxicity

PH 422-US-001... 005-91

STUDY DESCRIPTION

Sponsor: U.S. Army Medical Research andDevelopment Laboratory

Fort DetrickFrederick, MD 21702-5010

Testing Facility: Pharmakon Research International, Inc.P.O. Box 609Waverly, PA 18471

Test FacilityStudy ConductS.O.P. No.: PH-422

Study Numbers: PH 422-US-001-91PH 422-US-002-91PH 422-US-003-91PH 422-US-004-91PH 422-US-005-91

Purpose of To evaluate the dermal toxicity of the testthe Study: article when administered to rabbits at 2000

mg/kg.

Ownership of The sponsor owns the study. All raw data,the Study: analysis and reports are the property of the

sponsor.

Study Monitor: Major Nathaniel Powell, U.S. Army MedicalResearch and Development Laboratory

Study Director: Victor T. Mallory, B.S., RLAT, PharmakonResearch International, Inc.

Technical Susan E. Armondi, LAT, Thomas O'Neill, B.S.,Performance: LAT, Kim DiLeo, B.S., LAT, Maura J. Bieszczad

and Shirley Chappuis, A.S., AVT, LAT

Q.A.U.ResponsiblePersonnel: Leslie J. Pinnell, M.S.

Date StudyDirector SignedProtocols: Setptember 23, 1991

6

Evaluation of Five Unicharge Propellantsin the Acute Exposure Dermal ToxicityPH 422-US-001... 005-91

Dates of Technical PH 422-US-002-91 - November 15, 1991 throughPerformance: November 29, 1991

PH 422-US-003-91 - November 15, 1991 throughNovember 29, 1991PH 422-US-001-91 - December 4, 1991 throughDecember 18, 1991PH 422-US-004-91 - December 6, 1991 throughDecember 20, 1991PH 422-US-005-91 - December 10, 1991 throughDecember 24, 1991

Good Laboratory These studies were conducted in compliance withPractices the Good Laboratory Practices Regulations.Statement: There were no deviations from the GLP

Regulations which affected the quality orintegrity of the study. Q.A.U. findings fromthe inspections conducted of this study andfrom the audit of the final report aredocumented and have been provided to the studydirector and the test facility management.

Records All raw data, final report documentationMaintained: and protocol will be maintained in the archives

of Pharmakon Research International, Inc.

Recordings: Standard Pharmakon Notebook

Notebook Notebook #1539, pages 116-118, 120-122, 227-Reference: 229, 253-255, 260-262

TEST ARTICLES

DESCRIP- DATE(S)TEST ARTICLE TION LOT # CAS # SUBMITTED

n-methyl-2-nitratoethyl whitenitramine (MeNENA) solid XAP-MeNENA 17096-47-8 9/19/91

n-ethyl-2-nitratoethyl yellownitramine (EtNENA) liquid XAP-EtNENA-4B 85068-73-1 9/19/91

n-butyl-2-nitratoethyl yellownitramine (BuNENA) liquid XAP-BuNENA-15B 82486-82-6 9/19/91

7


DESCRIP- DATE(S)TEST ARTICLE TION LOT # CAS # SUBMITTED

bis-(2,2-dinitropropyl)acetal withdiphenyl amine yellowstabilizer liquid Set #1 5108-69-0 9/19/91(BDNPA/F+DPA) 87 12/5/91

bis-(2,2-dinitropropyl)formal withoutdiphenyl aminestabilizer yellow(BDNPA/F-DPA) liquid Set #2 5917-61-3 9/19/91

87 12/5/91

Analysis of The purity, identity, strength andPurity: stability of the test articles were the

responsibility of the sponsor.

Stability: There was no apparent change in the physicalappearance of the test articles duringadministration.

TEST SYSTEM

Species: Rabbit

Strain: New Zealand White

Suppliers CAMM Research Lab Animals, Wayne, NJ(Sources): Hazleton Research Products, Denver, PA

Buckshire Corporation, Perkasie, PA

Sex: Male and female

Age atInitiation: 8-12 weeks

WeightRange: 1.814 to 3.188 kilograms

No. on Study: Ten (10) (five males and five females) perstudy

Method andJustificationfor Randomization: Randomly assigned to study by health status

AcclimationPeriod: Minimum of five (5) days

8


System of Cage cards were marked with the study number,Identification: animal number, dose level and sex. Rabbits

were ear tagged.

HUSBANDRY

Research Facility U.S.D.A. Registration No. 23-R-107 under theRegistration: Animal Welfare Act 74: SC 2131 et sea.

Animal Rooms: Separate isolation by test systemLight cycle - 12 hours light, 12 hours darkTemperature/Relative Humidity - Every attemptwas made to maintain a temperature of 20°C ±3°C (63-73°F) and a relative humidity of 30 to70%.

Any excursions outside the temperature orhumidity ranges were of small magnitude and/orbrief duration and did not adversely affect thevalidity of the study.

Housing: Rabbits were housed individually in cages sizedin accordance with the "Guide for the Care andUse of Laboratory Animals" of the Institute ofLaboratory Animal Resources, National ResearchCouncil.

Sanitization: Waste material was removed twice weekly. Cagesand feeders were sanitized every two weeks.

Food: Purina Lab Rabbit Chow H.FR ad libitum, food

was checked daily and added or replaced asneeded. Feeders are designed to reducesoiling, bridging and scattering.

Food Analysis: There were no contaminants that were reasonablyexpected to be present in the dietary materialknown to be capable of interfering with thepurpose or conduct of the study.

Water: Fresh tap water, ad libitum.

Water Analysis: Water is monitored for contaminants at periodicintervals according to Standard OperatingProcedure PH-018.

METHODS

Rationale for The albino rabbit is preferred because of itsTest System: size, skin permeability and extensive database.

9

Evaluation of Five Unicharge Propellantsin the Acute Exposure Dermal T~xicityPH 422-US-001... 005-91

Compound All test articles were dosed as received fromPreparation: the sponsor with the exception of l-methyl-2-

nitratoethyl nitramine. l-Methyl-2-nitratoethyl nitramine was placed in adesiccator approximately 24 hours prior toadministration.

DoseAdministration: 2000 mg/kg

Rationale forDose Selection: As required by the regulatory agencies.

Route of The test material was applied directly onAdministration: intact skin sites.

Rationale forRoute of The study is designed specifically for theAdministration: assessment of dermal absorption and resultant

toxicity.

Frequency ofAdministration: Once (1) per test article

No. of AnimalsPer Dose Group: Ten (10)

Length of Studies: Fourteen (14) days

Method of Study Approximately 24 hours before testing, fur wasPerformance: clipped from the dorsal area of the trunk of

the test animals. The test article was applieddirectly onto the exposed intact skin of theanimals taking care to spread the substanceevenly over the entire area. A square gauzepatch was placed on the animals to cover thedosed area. The animal.s were wrapped withrubber dam and an elastic bandage to retardevaporation. The test article was heldin contact with the skin for twenty-four hours.Following the twenty-four hour period ofexposure, the wrappings were removed and theskin sites were wiped with water and gauze oracetone and gauze (n-methyl-2-nitratoethylnitramine) to remove any residual test article.Observations were recorded daily through Day14. Body weights were recorded at initiationand on Days 7 and 14. All rabbits weresacrificed by a lethal injection on Day 14 anda gross necropsy was performed.

10


RESULTS

Clinical signs observed in the bis-(2,2-dinitropropyl) formal without diphenyl aminestabilizer treated animals included decreasedactivity, decreased muscle tone, abnormal gait,abnormal stance, diarrhea and dyspnea. Noclinical signs were observed in any animalreceiving n-methyl-2 nitratoethyl nitramine, n-ethyl-2 nitratoethyl nitramine, n-butyl-2nitratoethyl nitramine and bis-(2,2-dinitropropyl) acetal with diphenyl aminestabilizer. One of ten rabbits died in thebis-(2,2-dinitropropyl) formal without diphenylamine stabilizer treated group. None of theanimals died in aniy of the other treatmentgroups. Necropsy of the animal that diedduring the study revealed a i&d, distendedcecum and distended intestines. Terminalnecropsy revealed distended intestines andstomach in animals administered bis-(2,2-dinitropropyl) acetal with diphenyl aminestabilizer and pale, enlarged kidneys, enlargedspleen and ascites in bis-(2,2-dinitropropyl)formal without diphenyl amine stabilizertreated animals. No visible lesions wereobserved in any other animal in any treatmentgroup at terminal necropsy.

CONCLUSION

Based upon the observations made in the AcuteExposure Dermal Toxicity studies in rabbits,the estimated acute dermal LD5 0 (combinedsexes) for n-methyl-2 nitratoethyl nitramine,n-ethyl-2 nitratoethyl nitramine, n-butyl-2nitratoethyl nitramine, bis-(2,2-dinitropropyl)acetal with diphenyl amine stabilizer and bis-(2,2-dinitropropyl) acetal with diphenyl aminestabilizer was determined to be greater than2000 mg/kg.

ACT/RP31

11

m LOL U LO LA cl) LA LAr4 r- H

(V in LA N~ L Ln Ng ILnLnCfl r4 r4

.-4 LA LO H- L LA H- Ln Lo

0 tnALA 0 LoALA 0 LALA)

5.4

la a t LnL ON L) LA 0) ALA L

N ) 0 LOALA >1 coO LnL > co LA LA

u x0 -H )r N LnL Idr Ln Ln

4.1 54 5.4

.H r,.4

(L4A' LA)LO . LA LA)LA LA LoALA00 H 41 41

42 0 0ooh 'r LA LO .41 1- LA LA 41.)z In LOL

0 04 5. 44 $ .4

.4m 0 ' 4. 4' iL f 1 Ot> (14 LAL zr ~ LL r ~ L

0 N LA LA IN LoALA I N LO LAI

0< A >14m) .0 .

41.

u 0 0 N

44.

0

>45.4

UU2

HH 0 '4H 0 -4H 0uC, cn z Uc/ z u i2 Z

LALAL tn lw -t-; 00 HO4 00c 00 00 00H4 H-

in LAL (11 LOA 00 00 00 00 00 00HT 1

N% LOL In 1 N U) W 00 00 00 00 00 00En H S4J 14

-H V4L i-O H r 00 00 00 00 00 00

00 to v-

ON) LA'tnON ) q 00 00 00 00 00 00ONH

-44.M

w 0

0 .94

E4L LA r Ln 4: 00 00 00 00 00 00

r-4-4

> intD L-L LO - 00 00 00 00 00 00

4J LO LOA 0. Ln UAL qb 00 00 00 00 00 000 40

S4 0 :r LO LOL LA; Ln- 00r- 00f 00V- 00r 00ý 00T4r

0.00Id

> ml L AO O H O H- 0 T4 0 0 O H O H O H-4 0

a) N

3QQ uW 0-4

ade 044)04 0

0 4

H ~jl LA Ln : 0 Lnv OH OH 0 0 0 0 0 0 0 0 09F4

M C4

E x - xe9 m ) w r4 4 ) 4Z4 4I4 ra. rx.. pL w4

0H U) H U) 4J 441) H

U)-4- V) 41o u iil to> c a - 0U 0 ~ u Q)

M 4t U)4 Q) -..4- I.. Q) O*.-41 Pt r. rtr0 14 m~ u~ u 1 4.) M)-..,4 0 H* -4 0 Q)~ m.4 0 ~ .O~.Cl

W(J z wU z a

>4~

m r-4 LAUm1-

0Q41 00 41 41 0 43E-Oý 0i 00 E-4~ 000 E-O 0

Nr 00 00 00

Cl00 Cl00 Cl00H Hl

(N 00 (N 00 (N 00U.)

0 H00 H00 H00HH H H-

340 00 0 00 0 00

0 0 104 .040 H -

x 0 -4 (3) 00 ..4 C% 000 0i 0 0 0

E- H 1 U)54 U 4 )rj >co 00 41 >c oo 41 co 00

z (ar4 (a "4 (aLAq p 0

> r4 N % 00 0 %D 00 0 No 00H 0 .0 .0

M8 41 41

00 d(ae 44 cn LA 00 54 Lo 00 14 tn 00

.94 V4. r4j

41 Q) NIz 00 11 00 *IV 00

fa 0 -4r4.) U C 00 >.q (n 00 >4 ( 00

48 41

(N 00 I N 00 1 (N 00

,'qH 00 H 00 H 00

4-44.) 4-4 4J0 O-Ho.H0- O*.-4 ..0 LoL .0 LnL *. LofLn

.0~ (a 000( 00MzC

x xU) U

00 o ) 00 U 000~00 00 r 00 0R 00

Im - (N(4 0-4 (NN 0'- r4N(

J41 4 00 4-)4.j o

E-40 E-40

S00 00

* i00 N (n 00

.r .94 H0ca 0r-4 f-

cr.a 00 r- 00

.4) 4.1

41H 00

ý4 H

H O 0 ON 00

O N0 0

E-44

0) >~ Hco 00 12 o 00

0 H 0

0 w L 00 H1 %D OH

C) -

0 00 0 10

F4J 4- Q) C1 00 H 10 00

too~4-14 o C 00 r-4 ( ~00

H) 00 no 0

.. 94

CM 4 l4) 1 44S0-4 N 0'

Q LnL t.%C t LAL

0 ro0t

x x

.~00 .~00

W 00 a-00U)O 00 (1) 000 ~ C~j 0 R (4 C,4

Table III. Summary of Body Weights (g) of Five Unicharge

Propellants in the Acute Exposure Dermal Toxicity

PH 422-US-001... 005-91

N-Methyl-2 Nitratoethyl Nitramine

Animal Number Sex Initial Day 7 Final5521 M 2238 2244 23755522 M 2018 1932 19975523 M 2130 2098 23955524 M 1984 2046 21405525 M 1990 2073 2086

x 2072.0 2078.6 2198.6S.D. 109.89 112.16 177.80N 5 5 55526 F 2158 2115 23465527 F 1935 1967 22785528 F 2007 1948 22345529 F 2000 1928 20235530 F 1991 1801 1935

x 2018.2 1951.8 2163.2S.D. 83.16 112.01 175.60N 5 5 5

N-Ethyl-2 Nitratoethyl Nitramine


x 2051.6 2194.0 2338.0S.D. 211.97 210.86 212.87N 5 5 55276 F 2340 2503 26135277 F 1866 1990 20845278 F 2444 2636 27555279 F 1865 1984 21155280 F 2160 2284 2396

x 2135.0 2279.4 2392.6S.D. 266.17 295.04 296.74N 5 5 5

16

Table III. (cont'd) Summary of Body Weight6 (g) of Five Unicharge


PH 422-US-001... 005-91

N-Butyl-2 Nitratoethyl Nitramine


x 2029.8 2227.0 2474.2S.D. 171.53 126.32 126.60N 5 5 55286 F 2181 2381 26315287 F 1990 2114 22505288 F 2150 2326 24895289 F 2051 2301 25005290 F 1900 2029 2166

x 2054.4 2230.2 2407.2S.D. 115.29 150.76 192.54N 5 5 5

Bis-(2,2-Dinitropropyl) Acetal with Diphenyl Amine Stabilizer


x 2853.2 3016.6 3114.0S.D. 281.11 344.16 390.34N 5 5 55546 F 2839 3002 31075547 F 2108 2228 24155548 F 2830 3030 31655549 F 2634 2824 30295550 F 2758 2907 3095

x 2633.8 2798.2 2962.2S.D. 305.16 328.97 309.69N 5 5 5

17

Table III. (cont'd) Summary of Body Weights (g) of Five Unicharge


PH 422-US-001... 005-91

Bis-(2,2-Dinitropropyl) Formal without Diphenyl Amine Stabilizer


x 2300.8 2474.4 2557.2S.D. 135.12 124.82 158.23N 5 5 55586 F 2241 2393 25215587 F 2012 2258 23965588 F 2207 2375 25005589 F 2335 2442 24485590 F 2051 - -

x 2169.2 2367.0 2466.3S.D. 134.87 77.99 55.99N 5 4 4

18

Table IV

Necropsy Observations (Incidence Values) of FiveUnicharge Propellants in the Acute Exposure Dermal Toxicity

PH 422-US-001... 005-91

M-Methyl-2 Nitratoethyl Nitramine

Interim Death Terminal NecropsyObservation Incidence Incidence

M F M

No visible lesions 5 5

N-Ethyl-2 Nitratoethyl Nitramine


M F M F

No visible lesions - - 5 5

N-Butyl-2 Nitratoethyl Nitramine


M F M F

No visible lesions 5 5

- Not applicable

19

Table IV (continued)

Necropsy Observations (Incidence Values) of FiveUnicharge Propellants in the Acute Exposure Dermal Toxicity

PH 424-,-U';--001...O005-91

Bis-(2,2-Dinitropropyl) Acetal with Diphenyl Amine Stabilizer

Interim Death Terminal Necropsy

Observation Incidence Incidence

M F M F

No visible lesions -- 2 4

Stomachdistended -- 1 0

Intestinesdistended -- 3 1

Bis-C2,2-Dinitropropyl) Formal without Diphenyl Amine Stabilizer


M F M F

No visible lesions - 0 5 3

Cecumdistended - 1 0 0red - 1 0 0

Intestinesdistended - 1 0 0

Kidneyspale - 0 0 1enlarged - 0 0 1

Spleenenlarged - 0 0 1

Ascites - 0 0 1

- Not applicable

20

QUALITY ASSURANCE UNIT STATEMENT

Study Nos.: PH 422-US-001-91PH 422-US-002-91PH 422-US-003-91PH 422-US-004-91PH 422-US-005-91

Study Director: Victor T. Mallory

The Quality Assurance Unit conducted the inspections listedbelow and reported the results to the study director and tomanagement on the dates indicated.

The following inspections were performed:

Interval Date

In Life Phase 12/4/91, 11/15/91, 11/15/9112/6/91, 12/10/91

Necropsy Phase 12/18/91, 12/20/91

Reporting Phase 1/28/92

Date OAU Report Issued

To Study Director To Management

1/28/92 1/28/92

Quality Assurbce Date

21

COMPLIANCE STATEMENT

This study was conducted in compliance with the Principles of GoodLaboratory Practices (GLP) as promulgated by the followingregulatory agencies:

EPA as stated in the Federal Register, 40 CFR Parts 160 and792.

Organization for Economic Co-operation and DevelopmentGuidelines for Testing Chemicals (OECD), ISBN 92-64-12221-4,adopted by the council at its 535th meeting on May 12, 1981.

U.S. Food and Drug Administration as stated in 58 CFR Part 21.

Study Nos.: PH 422-US-001-91PH 422-US-002-91PH 422-US-003-91PH 422-US-004-91PH 422-US-005-91

To the best of my knowledge, this study was conducted in accordancewith applicable Good Laboratory Practice regulations; there were nodeviations from these regulations that impacted on studyconclusions.

Study Director -Date /

22

Documents

AD-A252 109 :'•': P I! :l - DTIC · (Sources): Hazleton Research Products, Denver, PA Buckshire Corporation, Perkasie, PA Sex: Male and female Age at Initiation: 8-12 weeks Weight