# llllllllllllllllllllllllllllllllllllllllllllllllllllllllllll 

# • OTS0522237 OneSource. OneSearch. OneSolution. 

# ACUTE EXPOSURE ORAL TOXICITY STUDY IN RATS (83 EPAIOECD) WITH ATTACHMENTS AND COVER LETTER DATED 030890

23 JUL 1985

U$, DepartmentofCommerce 

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### CODING FORM FOR SRCINDEXING 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:CONTAINSNOCBI 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 lO c:::> ::>:: 

# """ :;:) w 

# :: g N c.n



## 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. **·~** 

## "' 

# "' "' Q 

## "'

**~~** 

# -· .•

## .,

**~.**

**-~** 

# - 2. -,



## 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 MStreet, 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

## OONTAINSNOCEll

Acute

**Exposu~e** oral Toxicity Study 

### in Rats (83 EPA/OECD) 

### PH 402-ET-002-85 HBCD Bottoms 

### Lot # 

### PU 85121

Submitted to Ethyl corporation Baton Rouge, Louisiana



# ~ai~mi~ Date Director of Toxicology 

## oite PHONE C711J 13815-2411 

### oEPA•OTS



# lmm~l~~unmmmmu

000636666XAcute 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 Ethy1 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 3Acute

**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:ation: 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.

6Animal 

### 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 Bottoms 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}

7I. 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. WAVERLV, **PENNSVLV~NlA** 1B.ol71 Compliance Statement I"HONE 1717) !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 d N PH 402-E'I'-002-85

u 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 .:onelusions• 11

Date

CCR?.84RJ\H DATA ?.PPF.NDIXNotebook 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 Leve1: 

# ..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-H

### IV

**Route:~** IP Date:_j,o)'.;t

# ?jLJ)_"':-- Ti.me of Dose: //:

## 0'?

# 1/m-

# /I:

# !1 ;/!!1 J: II/ t;fi>l/sJ!.>

### jC- Dose Level:_

# _,v 7

:;, 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 Day0 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: 

# /JflJCb
**]6~)** study Number:



## ~#

## qo.?--f]:.ocs-X£ tot Nllllb<!r: 

# Pu t.5-!P1I

..·· !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 IMorality (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 t7I71 MS..2oltt 

### 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. 

### ./ Parathyroid 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•11 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 

### // 1Brain 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.JttJ!Z(.( . U( , 

### Pathologist: 

# rJ 'PHARMAKON RESEARCH INTERNATIONAL, INC. WAVERLY.P'ENNSYLV.t.NIA liA71 

### Individual Necropsy Sheet PHONE ll17) &85-:IAUPHARMAKON 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 #:



## ;'~~.. JReasofi•= 1 

### (i) 3 4 (circle one) 

### Compound:

# //;!.C./; 7< 

### ,;k · JDose:



## ~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 1V 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?rostate Thyroid Y Urocyst v' Seminal ves. Parathyroid V Adrenals 'V Ovary Th:"lnus ! Y Ec.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~** .a)loose:

# 50 lrh 

# I study


# zbt177~- Director:

**~//,(:** · '

**~** Tissue E Wt. 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. Parathyroid 

# ,.,. 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 AJ1r /, t1e-{Lf/

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## " 

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

# 7-



# -j~ff~/7 ,.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

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# AJnOse:



# "?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):



# ~/V

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# i1fl'\ Prosector: 

## 2f-f0Z/f/



# b..,r.~~JZ /UI Pathologist: 

# ?

# .·

... '. 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/~**  

# IReason*: 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\1s 

### 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

IL '"" Prosector:



# zi~?b?(.{'!rl

# t: -j{:AJ/1' .

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**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.

2Protocol-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.bitum, 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 LD50 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**..

5LEGEND 

### •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.tlCl'l 

# rDhYI 

## 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 Dispasition: 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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## Ill ..I 

# = ..I ..I 

# <C National Technical Information Service Springfield, VA 22161 

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