llllllllllllllllllllllllllllllllllllllllllllllllllllllllllll • 

OTS0522237 

One Source. One Search. One Solution. 

ACUTE EXPOSURE ORAL TOXICITY STUDY IN RATS 

(83 EPAIOECD) WITH ATTACHMENTS AND COVER 

LETTER DATED 030890 

23 JUL 1985 

U$, Department of Commerce 

National Technical Information Service 
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~~' U.S. DEPARTMENT OF COMMERCE 

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\ 

.- · / National Technical Information Service 

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CODING FORM FOR SRC INDEXING REVISED 10115186 

O'fS052'2237 

ACUTE EXPOSURE ORAL TOXICITY STUDY IN RATS (83 EPA/DECO> 

WITH ATTACHMENTS AND COVER LETTER DATED 03089(> 

HEXABROMOCYCLODODECANE (3194-55-ol 
t: CONTAINS NO CBI 

ETHYL CORPORATION HEALTH and ENVIRONMENT DEPARTMENT 

ETHYL TOWER, 451 FLORIDA 

BATON ROUGE, LOUISIANA 70801 

March 8, 1990 

CERTIFIED MAil RETURN RECEIPT REQUESTED P 131 520 103 

Document Processing Center (TS~790) 

Office of Toxic Substances 

=~,J]Ii~o~~~~!~ls:r~~ection Agency 8(o-C{66oOO 1/.r:>b_ W~iiington, DC 20460 

Attention: B(d) Reporting 

Dear Sir: 

RE: [OPTS-82034; FRl-3666-9] Chemical Name .CAS Registry # 

Hexabromocyclododecane 3194-55-6 

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In accordance with 40 CFR 716.35(a)(4), Ethyl Corporation hereby submits this list of studies previously sent to federal agencies without confidentiality claims. 

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Chemical Name Hexabromocyclododecane CAS number 3194-55-6 

The following studies were sent on May 23, 1988 to: Mr. Robert Brink 

Executive Secretary TSCA Interagency Testing Committee (TS-792) U.S. Environmental Protection Agency 401 M Street, S. W. 

Washington D.C. 20460 

1. Mutagenicity Test of GlS-S6-41A 

lab GSRI 

Date of Study November 17, 1978 

2. Primary Dermal Irritation (Rabbit) Dermal corrosion (Rabbit) Ocular Irritation (Rabbit) Oral LDSO (Rabbit) 

lab-Consumer Product Testing Company Inc. 

Date of Study October 17, 1978 
3. Inhalation LC50 (Rat) 

Dermal LD50 (Rabbit) 

Lab Consumer Product Testing 

Date of Study November 7, 1978 

Submitting Company: 

Submitting Official: 

Ethyl Corporation 451 Florida Blvd. 

Baton Rouge, La 70801 

Ms. Anne B. Lemmon 

Information Specialist Health & Environment Dept. 

451 Florida Blvd. 

Baton Rouge, La. 70801 

All technical questions concerning this submission should be 

directed to IJ'r. L. L. Wen, Regulatory Affairs at (504) 388·7650. 

ABL:pm 

Sincerely, 

ETH~l CORPORATION 

Q,'M~ I)~_,.... Anne B. Lemmon 

Information Specialist 
( .) ·" ' I ! .~·· 

I ,i. t PHARMAI<ON RESEARCH INTERNATIONAL, INC. 

WAVERLY, PENNSYLVANIA, .. , !JS OONTAINS NO CEll 

Acute Exposu~e oral Toxicity Study 

in Rats (83 EPA/OECD) 

PH 402-ET-002-85 

HBCD Bottoms 

Lot # PU 85121 

Submit ted to 

Ethyl corporation 

Baton Rouge, Louisiana 

~ai~mi~ Date 

Director of Toxicology 

oite 

PHONE 

C711J 13815-2411 

oEPA•OTS 

lmm~l~~unmmmmu 000636666X 
Acute Exposure oral Toxicity Study 

in ~ats (63 EPA/OECD) 

PH 402-ET-002-85 

Test article, HBCD Bottoms, LOt # PU 85121, was orally administered to one' 

group of ten animals at a single dose level o~ 5000 mgjkg.. Signs observed 

included poor grooming, ptosis, chromodacryorrhea, lacrimation and S""elling Of 

the facial region. All animals were normal on Day 4 of the study. No other 

signs were observed during the remainder of the study. The study was 

terminated on Day 14. None of the animals died at the 5000 mgfkg dose level. 

No test article related lesions were observed in any of the animals upon 

terminal necropsy. 

Based upon the results from the Acute EXposure Oral Toxicity Study in Rats, 

the estimated acute oral LD50 for HBCD Bottoms, Lot~ JU 85121, was determined 

to be greater than 5000 mg(kg. 

1 
sponsor: 

!,i, 

-.:, 

Testing Facility: 

Test Facility 

s.o.P. No., 

Study No.: 

Purpose of 

the Study: 

Ownership of 

.the . Study, 

study Monitor: 

Study Director: 

Technical 

Performance: 

Q.A.tl. 

Responsible 

Personnel: 

Dates of 

Performance: 

Good Laboratory 

Practices 

Statement: 

Acute Exposure Oral Toxicity Study in Bats 

(83 EPA/DECO) 

PH 402-ET-002-BS 

Ethy 1 Corporation 

BODO GSRI Avenue 

Baton Rouge, Louisiana 70820 

Pharmakon Research International, Inc. 

Waverly, Pennsylvania 19471 ·,:: 

PH-402 

PH 402-ET-002-85 

To evaluate the single dose oral toxicity and/or to 

determine the median lethal dose {to50}. 

The sponsor owns the study. All raw data, analysis, 

and reports are the property of the sponsor. 

Mr. Michael Pinkerton, Ethyl Corporation 

Victor T. Mallory, B.S~, Pharmakon Research 

International, Inc. 

Victor T, Mallory, B.s., Gary G. Bolus, B.A. 

and Yvonne Coccetti. 

Leslie Maas, B~S. 

June 27, 1985 through July 11, 1985 

This study was conducted in compliance with the Good 

Laboratory Practice Regulations as stated in the 

Federal Register, Vol~ 48~ No. 230, Tuesday, November 

29, 1983. There were no siqnificant deviations frqm 

the GLP Regulations which affected the quality or 

2 
,, 

Acute ' Exposure ~Oral Toxicity Study 

in Eats (83 EPA/OECD) ~ 

PH ~02-ET-002-85 

Records 

Maintained: 

Recordings: 

Notebook 

Reference: 

Raw Data: 

statistics: 

Compound 

Description: 

Lot No., 

Ease Factor: 

Amount Submitted: 

Date Submitted: 

Special Handling 

Instructions: 

Analysis of 

Purity: 

Stability, 

Species: 

integrity of the study. Q.A.U. findings derived from 

the inspection(s} during the conduct of this study and 

from the audit of··~fhe final report are documented and 

have been provided to the study director and the test 

facility management. 

All raw data, final reports, documentation and 

protocol will be maintained in the central files of 

Pharmakon Research International, Inc. 

Standard Pharm<lkon Notebook 

Notebook #1062, pages 209-221 

Copies of notebook recordings attached. 

Not applicable 

TEST l\RTICLE 

HBCD Bottoms -- black solid 

PU 85121 

Not applicable 

801 gm 

June 24, 1985 

Standard precautions 

The purity, identity, strength and stabi.lity of the 

test article are the responsibility of the sponsor. 

There was no apparent change in the physical state of 

the test article during administration. Test 

article/carrier mixtures were returned to the sponsor 

for analysis on July 8, 19BS. 

TEST SYSTEM 

Rat 

3 
Acute Expo~ure Oral Toxicity Study 

in ~ats (83 EPA/OECD) 

PH 402-ET-002-BS 

Strain: 

Supplier 

(Sou:rce) : 

Sex: 

Weigllt at 

Initiation: 

No .. on Study: 

Method and 

Justification for 

Randomi:z:a tion: 

Acclimation 

Period: 

System of 

Identification:. 

Research Facility 

Registration: 

Animal Rooms: 

Housing: 

Sanitization: 

Sprague Dawley 

Charles Rivet; Breed;n.9 L~or~tor~,e!i, Wilmington, 

Massachusetts 

Hale and female 

Younq·adult animals 

Single dose level -- Ten (10) 

Selection based upon body weight and apparent good 

health. 

Five (5) days 

Cages marked with an animal number and dose level. 

Rats were identified by .. metal numbered ear tag .. 

HUSBANDRY 

U.S.D.A. Registration No~ 23-107 under the Animal 

Welfare Act 74: SC 2131 !:E_-==:!.:.. 

Separate isolation by test system~ 

Light cycle - ~2 hours light, 12 hours dark. 

Temperature/Humidity •· ~aintained at a temperature of 

22°C ± 3°C and a hum~dity of 30 to 70%. 

Rats housed individually in stainless steel ~n wire 

mesh cages. Size in accordance with the "Guide for 

the Care and Use of Laboratory Animals" of the 

Institute of Laborato~y Resources, National Research 

Council. 

Waste material was remove~ daily. Cages and feeders 

were sanitized every two weeks. 
. ' ., Acute Exposure Oral Toxicity Study 

in aats (83 EPA/OECO) 

PH 402-ET-002-85 

Food: 

Food Analysis: 

Water Analysis: 

Rationale for 

Test System: 

Compound 

Preparation: 

Dose 

~niStration; 

Rationale for 

Dose Selection: 

Volume 

Administration: 

Vehicle: 

Route of 

Administration: 

Rationale for 

Route of 

Administration: 

Frequency and 

Duration of 

Administration: 

No. of Animals 

l?er Dose Group: 

wayne Lab BloxR, ad Libitum, checked daily and added 

or replaced as needed. Feeders were designed to 

reduce soiling, bridging, and scattering. 

There were no contaminants that were reasonably 

expected to be present in the dietary material known 

to be,capable of interfering with the purpose or 

conduct of the study. 

Availability - fresh tap water, ~ libitum. Water is 

monitored 

according 

for p:ontaminants at periodic intervals 

/1 to{!Standard Operating Procedure PH-01.8. \~, 

METHODS 

As required by the regulatory ag~ncies. 

see attached copies notebook recordings 

5000 mgjkg 

As specified by the sponsor 

10 m1jkg 

Corn oil 

Oral, by gavage 

Potential route of human exposure 

Once (1) 

Ten (10) (five males and five females) 

5 
Acute Exposure oral Toxicity Study 

i11.,Rats (83 EPA/OECD) 

PH 402-ET-002-85 

No. and Code of 

Dose Group: 

Length of Study: 

Method of Study 

Performance: 

Results: 

Conclusions: 

AT1983 

Rat No. 

1460-1469 

Fourteen (14) days 

Dose Level 

5000 mqfkq 

In the limit test, one group of ten rats (5 males and 

5 females) was fasted for eighteen hours and orally 

administered the test article at 5000 mgfkg.. The rats 

were observed at one, four and twenty-four hours after 

dosing and once daily for four~een days for 

pharmacotoxic, CNS effects and mortality. On the 

seventh and fourteenth day body weights were recorded 

{Table 1}. The rats were sacrificed by co2 inhalation 

and a gross necropsy performed. 

Signs observed were poor grooming, ptosis, 

chromodacryorrhea, lacrimation and swelling of the 

facial region.. All animals were normal on Day 4 of 

the study. No other signs were observed during ~he 

remainder of the study. None of the animals died at 

the 5000 mg{kg dose level (Table 2). No test article 

related lesions were observed in any of the animals 

upon terminal necropsy. 

Based upon the results from the Acute Exposure Oral 

Toxicity Study in Rats, the estimated acute oral LD50 

for HBCD Bottoms, Lot # PU 85121, was deter.mined to be 

greater than 5000 mgfkg. 

6 
Animal 

No. 

1460 

1461 

1462 

1463 

1464 

-

X 

S.D. 

T<ilile l 

Individual and Group Mean Body Weights (grams) 

Acute Exposure Oral Toxicity Study in Rats 

83 EPA/OECD 

PH 402-ET-002-85 

HBCD Bot toms 

Lot # PU 85121 

Males @ 5000 mg(kg Females @ sooo mg(kg 

Animal 

Initial wee!< I Final No., Initial Week I Final 

177 235 278 1465 172 223 .241. 

1.87 247 302 1466 178 236 241 

179 241 290 1467 172 224 234 

171 238 287 l4C8 169 226 236 

168 226 268 1469 170 215 234 

176.40 237.40 285.00 172.20 224.80 237.20 

(7 .40) ( 7. 77) (12.81) (3.49} (7.53} (3.56} 

7 
I. 

Table 2 

Summary of Mortality 

Acute Exposure Oral Toxicity Study in Rats 

83 EPA/OECD 

PH 402-ET-002-95 

HBCD Bottoms 

Lot # PU 85121 

!' Dose Sex No. of Rats ; 1 2 3 4 5 6 7 8 9 10 ll _"/12 13 14 Total Mortality 

5000 rngfkg M 5 0 0 0 0 0 0 0 0 0 0 0 ''" 0 0 0 0/5 

5000 rngfkg F 5 0 0 0 0 0 0 o,., 0 0 0 0 0 0 0 ,, 0/5 
,. 

,, 

PHARMAKON RESEARCH INTERNATIONAL, INC. 

WAVERLY, PENNSYLVANIA 18 .. 71 .. 

" 

QUALITY ASSURANCE UNIT STATEMENT 

Study No. , _ _,P,_,H"--'4'-'0"2~-_.,E"T_-"'-0"'0"'2--'8"'5"-------

Study Director: Victor T. Mallory 

PHONE 

(7171 &00.2411 

Thi~ study was conducted in compliance with the Principles of Good 

Laboratory Practice~ The Quality Assura_nce Unit conducted the inspections 

listed below and reported the results to the study director and to management 

on the dates indicated. 

The following inspections were performed: 

Interval 

In Life Phase': 

Reporting Phase 

Da!:.e QA6 P.eport Issued 

To Study Director To Management 

7/23/85 7/23/85 

!-!ISC3 

Date 

6/27/85 

7/23/85 

iJLL' dlfrifb Quality Assurance 
,, PHARMAKON RESEARCH INTERNATIONAL, INC. 

WAVERL V, PENNSVLV~NlA 1B.ol71 

Compliance Statement I" HONE 

171 7) !BG-2•11 

This study was conducted in~compliance with the Principles of Good Laborat~ry 

Practice (GLP} as promulgated by the following regulatory agencies: 

U .. S .. Food and Drug Adr.tinistration, as stat,ed in the Code of Federal 

Regulations, Title 21, Part 58, revised as of April 1, 1980. 

u.s. Environmental Protection Agency as stated in th~ Federal 

Register, Vol~ 48, No. 230, Tuesday, November 29, 1983. 

Organization for Economic Co-operation and Development Guidelines 

for Testing Chemicals (OECD), ISBN 92-64-12221-4, adopted by the 

council at its 53Sth meeting on 12th May, 1981. 

S.t u d N PH 402-E'I'-002-85 y o.: __________________________________ __ 

"To the best of my knowledge, the study was conducted in accorCance with 

applicable Good Laboratory Practice regulations; there ·..rere no Ceviatior..s from 

these regulations that significantly im;:acted on stuc!:t .:on elusions • 11 

Date 

CCR?.84 
RJ\H DATA 

?.PPF.NDIX 
Notebook I tr1(/';L 

ACUTE TOXICOrDGY .STUDY ASSIGNMENT FORM 

Study No. :P-11 1./fJ;J.-FT- oo ¢=·[? 

Scale #: I t.isht cycle chocked:_:c;.c..·~::b:f:iZ;t;/L<....;<£c_ __ 

Animals sh~ve/fluorescein._,_.~§.;:;.•:.::-if::z.__,/...~~P.?'-'1-' :_,;_£~"L/L§~(.;~~:t,;~::,i,(__ ____________ ;____ _ 

?h of Test Article: //.1'/,,f.,6u//.kl:>; 

Q «= 

Compo~~c Preparation. __ ~k2~~~p~~~'-~~~4~·c~~~·~A~~~------------------------------

Dose Leve 1: ..i.&,~t;; ' Test Weight: -~fc..~L"""'f""'""-'' __ _ I 

Final Volume: ._"?/! ··""'#.€ 

Comments: 

MISC 
·Notebook 4 /f:/•,.1-

Page t ;".J IC 

Sponsor: f~¥ Cttptrt:M?z 

'rest Articl:. Ji /X.. () 'IJ;,.t#JU) 

Acute Toxicology 

~LDso 

Species: -z1tz;e 

Veh!,cle: ~-::'ct""d'!C<..--::=----­ . ..-:- ' ,-;-;r Study No.: PH tfDd. -ET- QQ;;L-K'[ Room No • : _!tfy' ..1-HRoute:~ IP IV 

Date:_j,o)'.;t ?jLJ)_"':--

Ti.me of Dose: //: 0'? 1/m-/I: !1 ;/!!1 

J: II/ t;fi>l/sJ!.> jC- Dose Level: _ _,v7

:;, 4 //{SJ"1z.:-____ Dose Volume: {Onu./1{, 

''t1 . ;J 

sc 

l!.nimal Ml. Weig~1 (grilllls{fjri-/ Mimal Ml. . we;g~V <grill:lSf"#L 

No. Sex Given Day 0 Day Day ay No. Sex Given Day 0 Day Day ay 

I'IM o':J It /77 c?!J!:' 1\~ 'Ill _;; 7,<! ltij(p!} 9. 17 17il J'.J4 \ h :2'/ J 

!'lfol or f·'l I 'In ~-17 \.§ .Jo;L 11')/h~ 'j- li 17S dlJ& \U Ji/ 

F/6-?- 0'7 Lf /7"! .f;!<// l'f! c190 1'1?-J Cf. n. /7:;!. j~~ /\iY "'3 'i 

;ljffi rFl L7 17/ :?J!J ~7\ ,:;u7 Jl/1/1 :f J.7 /fa9 c:'J,jf, /A ci??~ 

;?f;_..Jf cr7 n IM? <2.JI? '0'/ \ .J6v NM 9- J.7 /70 ;?/5 .~ \ ;!3:( 

Initials ' 1>"/'6 tl • uu :1't:''' 6:;0 ~'$../ \ 7{;:[.•'!> 1-/)7//i G(:OI't~ 7/WS$' I" ; w::__ lfV b' as ''-7-'ilr.. 

I I 

,. '~ _,_ <= " - ?.OURS DAYS 

TOXIC SIGNS 0 I l 2 4 I 24 2 3 4 ~- I 6 7 

-'*~' 615 --~~ o;:+-- ;).), % 50 Sf/( 3j{ "j-{ No Signs ~'frl- .. -.~~ 

• • 1~ 

Activity: Inc. Dec. 

Convulsions 

Paralysis I 

Diarrhea 

Salivation 

.Lacrimation I 9'\ I 

Ptosis lo/1 % 

Poor Grooming :51"! 

chrcmodacryorrhea 1

/o 

File-erection I 

* • Muscle Tone: Inc. Dec. 

~Abnormal Gait 

Abnormal stance 

!Dyspnea I 

Cyanosis 

Tremors 

I..oss of Righting P.eflex: I 

?rcst.:.-ation 

!Mortality (AM) c;o a;o C/c % 0/o % is'::- % c;/0 

Mortality (>{:) .'1 t:jjJ "'/o ofo Y't) ,-. I Jf:- L'Q (?M) ~;.: '-j~.,"'l I •-' 

l::l))\':1' I ·-.-;·•:- i.·ftYP r.{;.Hi$. (,'}ofl'I'I"''"T' 'I' :;(;:~:; rl/ !J.'J:?tJ linitials l •·' j·:.... ',,, ~ 

Ill . .• ·I·' ' I' C.[/) C-G!J !r._.. ir.> ·1j,, I 

Inc. - • 

Increased I ' I ' I I)/ 

n~~ = norrP~~Pn 
Acute Toxicoloqy 

Oboervations (continued) 

Page I._..:J"'-'1..:.1 __ 

,. 

S~]>nBcr: r~ &'(Yl:af:!kz 

Test Art.icle: /JflJC b ]6~) 

study Number: ~# qo.?--f]:.ocs-X£ 

tot Nllllb<!r: Pu t.5-!P1 I 

.. ·· !i'oxic Signs 

{continued) 

INo si<ms 

* * ~ctivity: Inc. Dec. 

Convulsions 

IPa.ralysis 

lniarrbea 

salivation 

Lac:z:·imation 

Ptosis 

Poo:z:· Grooming 

Chromodacryorrhea 

Pilo-erection 

Muscle * * Tone: Inc. Dec. 

~J::mormal Gait 

labnor.mal Stance 

Dyspnea 

Cyanosis 

Tremors 

h:.oss of. Rightinq Refle) 

Prostration 

IMorali ty (liM) 

Mortality (PM) 

Initials 

Necropsy Findings 

* Inc. = Increased 

• ~ec. = Decreased 

oavs 

8 9 10 11 12 13 14 .. 

o/r %. %. 9"1! o/o o/o. 

I I v 6 I 

' ' 

Stucy 

-
-

PHARMAKON RESEARCH INTERNATIONAL, INC. 

WAVERLY, ,.ENNSif"t..VANIA Hl .. 71 

Individual Necropsy Sheet 

. studz: No.(J/jp;J.-F7-C</N0 Species: yj_t;iJ- Is~: cf=7 I Weig~t: _;;;!J.r 

P'HONE 

1117] 58CJo2.C1t 

Joate: 71/J'.:> 

Animal #: JL/(,0 Ear Tag #: /'/6tJ I Reason•: 1 (1) 3 4 (circle one) 

ComFOund:fi_BC j) .f!r.:1/;;n.y I Dose: • -J..,.,. ?f.:z: I Study Director::r'u~/.7,r?.U/-" Tissue E Wt. Tissue ' E i (/ Wt. Tissue E Wt. Other _,;.. 

Brain v Heart IV Cecum :V' ~ 

sp.cord v Liver ILl' _Colon lv" 

Pituitary t/ Cholecyst ~esen.l. node ILl' 

:.;y_es ,v Kidneys I.! Testes v' 

Sal. qlands v Soleen v !pididvmis v 

Submn .1. node v .Pancreas v Prostate 1'-' 

Thyroid ,/ Urocyst v Seminal ves. ' ..... Parathyroid v Adrenals ;/ ovary 

Thymus II/ Stomach / Uterus 

Esophagus ;/ Duodenum v Sternebrae v 

Trachea V' Jejunum IV Sciatic n. v 

Lung IV Ileum IV skel. muscle "'" 

E= examine Wt. - weight (gm) .1 = dead 2 = term sac 3 = sac rnorib 4 = sac ...,~ak 

Necropsy Observations (NVL =no visible lesior.s): 

/lilt-

-,-:Vlt' 

?rosector: 'lltfz~!L &.-u c:.:z:t: /VI' PathologiSt: 

c7 
PHARMAKON RESEARCH INTERNATIONAL, INC. 

WAVERLY, rENNS:.OLVANIA 18471 

PHONE 

t7 I 71 MS..2olt t 

Individual Necropsy Sheet 

' 

.... 
' 

• 

~: 

' 

·-

PHARMAKON RESEARCH INTERNATIONAL, INC. 

WAVERLY. r'ENNS"M..VANIA 121471 

Individual Necropsy Sheet 

P'HONE 

(7171 ,86-2411 

Study No./'1/J/t;J,.B.;J;:J,'(; Species: -lf:zt lsex: ()-/ I Weig~t: ,-;;17/1 .. Toate: 7];k.;-

Animal #: /L/6;}. Ear Tag #: jLj/p,;;}. } Reason•: 1 (2J 3 4 (circle one} 

compound: /J/!C}).;tf', J.I., } I Dose:._?<;' '11..-/fq I Study Director:Jf/.Z:...?/Jn#.n. 

Tissue E Wt. Tissue E 

"' Wt. Tissue E, Wt. Other // 

Brain ./ Heart I/ Cecum II 

Sp.Cord v Liver 1/ Colon I 

Pituitary r/ Cholecyst Mesen.l.node .;, 

Eyes t.. Kid.."'l.evs v Testes 17, 

Sal. glands v Spleen v: Epididymis I .7. 

Submn.l.node v'. Pancreas ./ Prostate 

Thyroid !/'. Urocyst / St::minal ves. ./ 

Para thyroid y Adrenals v Ovary 

Thvmus y' Stcmach ,/ Uterus 

Esophagus v Duodenum / Sternebrae ./; 

Trachea v Jeiunum v Sciatic n • /-

Lung '"' Ileum v Skel. muscle 1/. 

E- examine Wt. = weight(gm) *1 = dead 2 = term sac 3 - sac morib 4 - sac "~.o:eak 

Necropsy Observations (NVL - no visible lesions): 

/VVL 

.~ j 

P:rcsec:tor: 7lzl!7'4LP & .r y-:i!.t:f /i/( , Pathologist: 
PHARMAKON RESEARCH INTERNATIONAL, INC, 

WAVERLY. PENNS"t"lVANIA 11!1471 

Individual Necropsy Sheet 

PHONE 

l7t71 IS86o2•1 1 

study No .-fJI/J/(}7.?-;;tAJt~l'i Soecies:0d I sex: cJ-7 lweig~t:,;;J.f7 loate: 7/;t/!15 

Animal #: {-t/0'3 Ear Tag #: ,/~t} Jneason'*: l (2') 3 

I 

4 (circle one) 

c~mpound: )/J?e_j) ;4Cl2:#z J Dose:. J) 07t /J4 I study Director:Ji~Pz TJJJ~ Tissue E Wt. Tissue " E I' fit. Tissue E Wt. Other // 

1 Brain IV Heart v' Cecum lv 

I Sp.Cord v Liver v Colon lv' 

Pituitary v Cholecyst esen~l~node v 

Eyes I>" Kidneys v Testes v 

sal. glands lv Spleen ./ Epididymis / 

SubiiUl.l.node y Pancreas 'v Prostate ,v' 

Thyroid v Urocyst ·/ Seminal ves. !.v" 

Parathyroid rv. Adrenals / Ovary 

Thymus IV Stomach IV Uterus 

Escohagus v Duodenum I Sternebrae v 

Trachea rv Jejunum I ,_ Sciatic n_ ;/ 

Lung lv Ileum It--- Skel. muscle , 

E= examine wt. - weight (gm) *l - dead 2 - term sac 3 sac morih 4 sac weak 

Necropsy Observations (NVL = no visible lesions): 

fi)l~ 

" ' _;;;!(II\ 

!?rosec:or: 1iFtJftM f!J.Jt tJ!Z(.( . U( , Pathologist: 

rJ 

' 
PHARMAKON RESEARCH INTERNATIONAL, INC. 

WAVERLY. P'ENNSYLV.t.NIA liA71 

Individual Necropsy Sheet 

PHONE 

ll17) &85-:IAU 
PHARMAKON RESEARCH INTERNATIONAL., INC. 

WAVERLY. PENNSY-LVANIA 111!471 

Individual Necropsy Sheet 

Study No./)/fiJ:{-P/-tJ!%N? Species: "lf'd- I sex: J! l Weig~t: ,}7' / 

'HONE 

(7111 58&2-'1t 

Joate: 7/;i;-

Animal #: ;1/!P.tJ Ear Tag #: ;'~~ .. J Reasofi•= 1 (i) 3 4 (circle one) 

Compound: //;!.C./; 7< ,;k · J Dose: ~a'-/14- I Study Director: ~b/~·~}r~/,~. Tissue E Wt. Tissue y E-: lt?'Wt. Tissue E Wt. Other /I Brain il/ Heart v Cecum ,/ 

Sp.Cord ... Liver v Colon v 

Pituitary I"' Cholecyst ~esen .. l .. node ~ 

Eyes ,.,.. Kidneys v Testes 

sal. glands v Spleen v Ecididymis 

Submn .. l. node v Pancreas v Prostate 

Thyroid .......- Urocyst v Seminal ves. 

Parathyroid 1/ Adrenals ;/ Ovacy v Thvmus ,/ Stomach 1/ Uterus v 

Esophagus v Duodenum 1/ Sternebrae ,/ 

Trachea 1/ Jejunum v Sciatic n .. t/ Lung v Ileum v Skel .. muscle w E- examine wt. - weight (gm) *l - de:ad 2 - term sac 3 = sac morib 4 "" sac ¥o"eak 

Necropsy Observations (NVL - no visible lesions): 

jl!Jit 

=..:::: 

Prosector: Z/ t-fl.4-f f?.r:-~u.iic ATlllfl Pathologist: 

(/ 
PHARMAKON RESEARCH INTERNATIONAL, INC. 

WAVEPI.t.Y • .-ENNS~VANIA Hl<l7~ 

Individual Necropsy Sheet 

P'HONt; 

11171 !58!-::I:AU 

Study No./J/Yt)J-Ef-afl.-X? Species:tf/_if- I sex: [2 lweig~t:.?7'/ loate: 7k J-:r 1-"A"'n::::im:::•ool~H:..:::.J./+f' ~""-'~ (;"'-___ _c:Eo:a=.r..,Tra"-'g'-'#'-":-'/+L/t,-"~"-(j;""'----'~'-'R"'e"'a"'s'To"'n'-•.:.: .....;l::..J...: 6J2=. 3 4 (circle one)/ 

Compound: iJff/) . .I:L-"' -A-l I Dose: :::J'/fffi..$(t.. I Study Direc:or: ?J4iz!JFTJ.7k//h 

Tissue E W't. Tissue E VWt. Tissue E Wt. Other ~ 

Brain ~ Heart ~ Cecum V 

Sp .Cord 'V Liver V Colon 1 V 

Pituitary ! V Cholecyst F"~esen .1. node r/ 

Eyes // Kidr.eys V Testes 

SaL cd·ands .~ Spleen V Epididvmis 

Submn.l. node Y Pancreas ,/ r?rosta te 

Thyroid Y Urocyst v' Seminal ves. 

Parathyroid V Adrenals 'V Ovary 

Th:"lnus ! Y E c.omach V Uterus V 

Eso,;:hagus ""' Duodenum Sternebrae V 

Trachea v Jejunum V Sciatic n.. ./ 

Lung I "' Ileum v' Skel.. muscle V 

E examine Wt~ weight (gm} *1 = dead 2 - term sac 3 - sac morib 4 - sac weak 

Necrcpsy Observations (NVL - nc visible lesions): 

' 

Prosector: Pathologist: 
PHARMAKON RESEARCH INTERNATIONAL, INC. 

WAVEALY.I"ENNSV'I..VANIA 18471 

Individual Necropsy Sheet 

Study No.P/M'J.·bf.to;·JJ Species: '1f/d I sex: !j.. I Weig~t;.(tj.y' 

!"HONE 

(1U) M&-2£11 

lom:7k /r-c . / 

Animal #: /@;1 Ear Tag u:N1 I Reason•: 1 (2") 3 4 (circle one) 

Comoound:_& ':iJ :J4? ·L~ 

Tissue E Wt. 

.a) loose: 50 lrh I study Director: zbt177~- ~//,(: · ' ~ 

Tissue E': I"" Wt. Tissue E Wt. Other ..r Brain v Heart II ·Cecum v 

Sp.Cord v Liver v Colon v Pituitary It/ Chole'.cyst .eser .. l.node v Ey_es 'v' Kidneys ·/ Testes 

sal .. alands v: Spleen ./ Epididymis 

Submn.l. node \1. Pancreas //. Prostate ·~ 

Thyroid v, Urocyst v Seminal ves. 

Para thyroid ,.,. Adre:nals ;/ Ovary / Thymus 11 Stor.~ach v llterus - 1 ... 

Esophagus ,; Duodenum ;/ Sternebrae ,/ 

Trachea v Jejunum ;/ Sciatic n. ,/ 

Lung 1/ Ileum v Skel .. muscle L E- examine Wt. = weight (gm) •1 - dead 2 = term sac 3 = sac morib 4 = sac weak Necrcpsy Observations (NVL = no visible lesions): 

;VI~· 

. .,,; • 

:?rosector: n)i - u :u;tiT AJ1 r /, t1e-{Lf/ 1/f!t Pathologist: 

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fi:p}!'ZJ-t-/:-)# j{J(i; 7-

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PHARMAKON RESEARCH INTERNATIONAL, INC. 

lndivid~al Necropsy Sheet 

PHONE 

1717) &B&-2411 

Studv No.f/1'J£f/d~;f{_ Soecies:~l.i~ lsex: ;t lweig~t:230 ·~D~~e:7£,J;-

Animal #; !t/h? Ear Tag #: /4'e;;i I Reason*: 1 V3 4 (ciX:cle one)* 

Compound: i/n ~}) ~t< Lf, . AJ nOse: "?m~ I Study Director:)!~ T .J.J;lcfl.h 

Tissue E Wt. Tissue / E 1?/Wt. Tissue E Wt. Other _,/-

Brain v:; Heart v Cecum v 

Sp.Cord v Liver v Colon v 

Pituitary v. Cholecyst Mesen. Lnocle It/ 

Eyes v Kidneys v Testes 

Sal. glands v. Spleen j/ Epididymis 

Submn .1. node v Pancreas v Prostate 

Thyroid Uroc)-~st ,/ Seminal ves. 

Parathvroid Adrer:als v Ovary lv ' Th~"ll\US Stomach .... Uterus lv 

Esophagus v Duodenum ;/ Sternebrae IV 

Trachea v Jejunum ;' Sciatic n. lv 

Lung 1/ Ileum y Skel. muscle v 

E- exa.-nine Wt. weight(gm) '1 = dead 2 - term sac 3 = sac morib 4 - sac ""eak 

Necropsy observatior.s (NVL - no visible lesions): 

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Prosector: 2f-f0Z/f/ b..,r.~~JZ /UI Pathologist: 

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PHARMAKON RESEARCH INTERNATIONAL, INC. 

WAVEiAl.Y, PENNS't1..VANIA1D411 

Individual Necropsy Sheet 

I" HONE 

(717) ISe&-2~11 

Study No./J/1/t.;?-PT-&;;J.-[') Species: -;l!j I sex, <;;!. I Weig~t' ;J ~t/ loate' 7,4-,d§-

Animal #: /f69 Ear Tag ~: nE/~ I Reason*: 1('2)3 4 {circle one) 

Compound' ?f'&,l),;;4~.?~ Dose: ..:::5f?A.~ !study Director:)Jh.'rJf~a Tissue E Wt. Tissue E Wt. Tissue E Wt. Other ...r 

·.arain ,_/ Heart v Cecum v ~ 

Sp.Cord '"" Liver ·v Colon v 

Pituitary v Cholecyst ~esen.l~node v" 

Eyes j/ Kidne\1 s v" Testes 

Sal. glands o/ Spleen ,/ r.pididymis 

Submn.l.node v Pancreas J/ Prostate 

Thyroid v - Urocyst v Seminal ves. 

Parathvroid v Adrenals 'v Ovarv ..,/ 

Thy'TTIUS v Stomach './ Uterus ./ 

Esophagus y Duodenum .v Ste=nebrae v 

Trachea v Jejur.wn y Sciatic n. 

Lung 'V Ileum v Skel. muscle 

E= examine Wt. - weight(gm) *1 = dead 2 = term sac 3 = sac rnorib 4 = sac ·..:eak 

Necropsy Observations (NVl - no visible lesions): -::: 

fil/l 

I L '"" 

Prosector: zi~?b?(.{'!rl t: ...(~~ -j{:AJ/1' . <.. Pat.hclog~st: // 
PHARMAKON RESEARCH INTERNATIONAL, INC. 

Sponsor: 

Testing Facility: 

Test Facility 

s.o.P. No.: 

Study No.: 

Purpose of 

the Study: 

ownership of 

the Study: 

Study Monitor: 

Study Director: 

Q.A.U. 

Responsible 

Personnel: 

Dates of 

Performance: 

Good. Laboratory 

Practices 

Statement: 

Tentative Date 

of submission of 

Final Report: 

Records 

Maintained: 

WAVERLY, PENNSYLVANIA 16-471 

Protocol - 402 83 £Pl\(OECD 

Acute Exposure Oral Toxicity 

Ethyl Corporation 

8000 GSRI Avenue 

Baton Rouge, Louisiana 70820 

Pharmakon Research International, Inc. 

Waverly, Pennsylvania 18471 

PH-402 

PHONE 

(717) 15815-2411 

To be assigned at study initiation. \) tf 1./D:l.- E:i '-001... ii">'" 

To evaluate the single-dose oral toxicity and/or 

to determine the median lethal dose (L050), its 

statistical limits and slope using a single exposure 

or multiple dose given up to a 24-hour period and a 

14-day post-exposure observation period. 

The sponsor owns the study.. All raw data analysis, 

and reports are the property of the sponsor. 

Victor T. Mallory, B~S~, Pharmakon Research 

International, Inc. 

Leslie Maas, B~S. 

The study will begin within one month of receipt of 

the test article and authorized protocol. 

This study will be conducted in compliance with the 

Good Laboratory Practices Regulations as statPd in 

the Federal Register, Vol. 48, No. 230, Tuesday, 

November 29, 1983~ 

Within one month following the completion of the 

study. 

All raw data, final reports, documentation and 

protocol will be maintained in the central file of 

Pharmakon Research International, Inc. 

Amendments to protocol 

Feed Lot Number 

Body weights, initial, Day 7, and final 

1 
P•otocol--02 83 EPA/OECD 

Acute Exposure Oral Tbxicity 

'' 

Statistics: 

Analytical 

Chemistry: . 

Species: 

Strain: 

Supplier 

~S!:.L:.. 

Sex: 

No. on Study: 

Method and 

Justification for 

Randomization: 

Compound preparation 

Volume administration 

Environmental conditions 

Observed signs 

Observed mortality 

By the method of Litchfield and Wilcoxon, 

JPET 96: 99-114 (1949). 

Analysis and stability of the test article and test 

article/carrier mixture is the responsibility of the 

sponsor. If requested by the sponsor, Pharmakon 

Research Inter'ruiltional, Inc. 1 its subcontractor, 

conduct appropriate analytical analysis and indicate 

the additional cost involved following receipt and 

evaluation of the appropriate analytical method.. In 

the case where a satisfactory method is not provided, 

Pharmakon Research International, Inc., or its 

subcontractor, at additional cost to the sponsor, will 

develop appropriate methods. 

If the sPonsor elects to analyze the test 

article/carrier mixtures, Pharmakon Research 

International, Inc. will collect the sample at 

appropriate designated intervals during the study and 

transmit the samples to the sponsor for analysis. 

TEST SYSTEM 

Rat 

Sprague Dawley 

Charles River Breeding Laboratories, Wilmington, 

Massachusetts or Blue Spruce Farms, Altamont, 

New York. 

Male and female (Equal number of each sex will be used 

for each dose level. The females will be nulliparous 

and non pre\lllant.) 

Younq adult animals will be used.. The ·weight 

variation of animals used in a test will not exceed ± 

20 percent of the mean weight for each sex. 

Ten/group {five males, five females) 

Selection of rats based Upon body Weight. 

2 
Protocol-402 83 EPA/OECD 

Acute Enposure Oral Toxicity 

.· 

Acclimation 

Period: 

system of 

Identification: 

Research Facility 

Registration: 

Animal Rooms : 

Housing: 

Sanitization: 

Food Analysis: 

Water 

Ari'a'i:Ysis: 

Justification for 

Test System: 

Fi.ve (5) days 

Cages marked with an animal group number and dose 

level •. Rats are ear tagged. 

BOSBl\NDRY 

u.s.D.A. Registration No. 23-107 under the Animal 

Welfare Act 74: SC 2131 .!:E_ seq. 

Separate isolation by test system. 

~ight cycle - l2 hours light, 12 hours dark. 

Temperature/Humidity - Maintained at a temperature of 

22°C ± 3°C and a humidity of 30 to 70\. 

Rats housed individually or in groups, according to 

sex, in stainless steel ':In wi.re mesh cages. Size in 

accordance with the "Guide for the Care and Use of 

Laboratory Animals" of the Insti~ute of Laboratory 

Resources, National Research Council~ 

Waste material was removed daily~ Cages and feeders 

were sanitized every two weeks. 

Wayne Lab BloxR, ad li.bi tum, or any other acceptable 

Lab Chow, checked~aily and added or replaced as 

needed~ Feeders were designed to reduce soiling, 

bridging, and scattering~ 

There were no contaminants that were reasonably 

expected to be present in the dietary material known 

to be capable of interfering with the purpose or 

conduct of the study~ 

Availability- fresh tap water, ad libitum. Water 

is monitored for contaminants at-periodic intervals 

according to Standard Operating Procedure PH-018. 

METHODS 

According to the New and Revised Health Effect Test 

Guidelines EPA 560/6-83-00l. 

• 

3 
:1· 

- "PrQtocol-402 63 EPA/OECD 

Acut~ Ex~sure Oral Toxicity 

• 

' ' 

Rationale for 

Dose Selection: 

Limit Test: 

Dose Selection: 

Compound 

Preparation: 

Vehicle: 

Volume 

Administration: 

Route of 

Administration: 

Frequency and 

Duration of 

Administration: 

Based on the results of a dose-range finding study. 

In the event there is no mortality observed ~n the 

dose-range-finding study. ten animals will receive the 

test article at 5000 mgjkq. If a test at 'a dose level 

of at least 5000 mg(kg body weight, using the 

procedures described for the study, produces no 

compound-related mortality, then a full study using 

three dose levels will not be necessary. 

As specified by the sponsor, a sufficient number of 

dose levels will be used to meet the criteria of the 

data analysis system. 

At least three dose levels will be used and spaced 

appropriately to produce test gro~ps with a range of 

toxic effects and mortality rates. The data will he L 

sufficient to produce a dose response curve and, where 

possible, permit an acceptable determination of the 

LDso· 

Proper amounts of test material are ground with a 

,pestle or tissue grinder. Vehicle is then added in 

proper increments to achieve a designated dose level. 

Where necessary 1 the test substance will be dissolved 

or suspended in a suitable vehicle. It is recommended 

that wherever possible the usage of an aqueous 

solution be considered first, followed by 

consideration of a solution in ~ (e.g. corn oil) and 

than by possible solution in other vehicles. For 

non-aqueous vehicles the toxic characteristics of the 

vehicle should be known, and if not known should be 

"determined before the test_ 

The maximum volume of liquid that will be administered 

at one time depends on the size of the test animal. 

In rodents, the volume will not exceed 1 ml 100 q body 

weight. Variability in test volume will be minimized 

by adjusting the concentz·ation to ensure a constant 

volume at all dose levels. 

The test substance will be administered in a single 

dose by gavage, ~sing stainless steel gavage needle. 

The test substance will be administered over a 

period not exceeding 24 hours. 

4 
Pr~ocol-402 B3 EPA/OECO 

Ac~t~ Exposure oral Toxicity 

• • 

Rationale for 

Route of 

Administration: 

Control Groups: 

Length of Study: 

Methods of Study 

Performance: 

Type and Frequency 

of Test, Analysis 

and Measurements 

To Be Made: 

Gross Pathology: 

Treatment of Results: 

ATXPL6 

According to the New and Revised Health Effect Test 

Guidelines EPA 560/6-83-001; 

Neither a concurrent untreated nor vehicle control 

group is required except when the toxicity of the 

vehicle is unknown. 

Fourteen (14) days 

The preliminary range-finding screen will be 

performed by administering three different doses 

to six fasted rats (one male, one female per dose 

level). 

If results do not provide adequate information for 

selecting doses for the LD50 determination, additional 

screening studies will be performed~ Animals will be 

observed daily for 72 hours. Based on results of this 

screen, at least th.t'ee dose levels will be selected 

and each doSe will bP. admini.stered to ten fasted 

animals (5/sex) for a determination of the L050 • The 

rats are observed at approxfmately 1 and 4 hours after 

dosing and daily for fourteen days £or pharmacological 

and toxicological effects.. Viability will be checked 

daily. On the seventh (7th) and fourteenth (14th) day 

body weights are recorded~ The surviving rats will be 

sacrifi~eC by c~2 inhalation and a gross necropsy 

performed. 

Body weight (initial, at death, week one and final) 

Observations - daily 

Mortality (daily) 

Necropsy findings 

LD 50 with 95% confidence limits (An attempt will 

be made to calculate an Lo50 for each sex). 

Consideration will be given to performing 

histopathology animals where indicated by the nature 

of the toxic effects observed. All gross pathology 

changes will be recorded. 

Data will be summarized in tabular form, showing for 

each test group the number of animals at the start of 

the test, time of death of individual animals at 

different dose levels, number of animals displaying 

other signs of toxicity, descripti.on of toxic effects 

and necropsy ~indings .. 

5 
LEGEND •Pre>eocol-402 83 EPA/DECO 

A~t~ EXposure oral TOxicity 

• 

N/A - not available 

Nfl<: - not known 

Chemical Abstract No. 

or Code No.: 

Lot or Batch No.: 

Description: 

lunount Submitted: 

Expiration Date: 

Special Handling or 

Storage Instructions: 

TEST ARTICLE 

C.~.-npov...' '\d.. GM '1"0-.C.-\: e '<1 Z..OC.tl Cl'l rD hYI 

li 

Strength: Purity: 

Analysis of 

Purity/Stability: 

Analysis of the purity and stability of the test 

article is the responsibility of sponsor. 

Test Article/ 

carrier Mixtures: 

Analysis for stability, uniformity and correctness of 

concentration is the responsibility of sponsor. 

~ Return Test Article/Carrier Mixtures to Sponsor 

Dispose of Test Article/Carrier Mixtures 

T-est Article 

Dispasi tion: 

Test article will be disposed of 3 months followi.ng the submission 

of the final report. 

Test article to be returned upon completion of the study. 

~MENTS----------------------~------------------------------

APPROVAL,OF PROTOCOL 

Date _,_A.!.II'~n_,.··.\~_,I...JJ'-,-..!.IJ.9-'5""5"'-- Study Monitor 

~/;/ffs" '{17 Date 

6 ·' ,: 

··,· , .. , .. . ··;· 


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