### Harcro s Chemical s Inc . 520 0 SpeakerRoa

d Kansa s City , K S 6610 6 Telephone : 913/621-774

7 Fax : 913/621-774

6 E-mail : OrganicsCS@Harcros.co m Dat e 03/19/1 3 

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Documen t Contro l Offic e (DCO ) (7407M ) Offic e of Pollutio n Contro l an d Toxic s (OPPT) U.S

. Environmenta l Protectio n Agenc y(EPA ) 120 0 Pennsylvani a Ave

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RE : Acut e Toxicit y i n th e Rat - U p an d Dow n Procedur e CASR N 31138-65- 5 C O er a C O ZX y_< r,
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yConcern : I n accordanc e wit h EPA' s fina l rule , Testin g o f Certai n Hig h Productio n Volum e Chemicals ; Secon d Grou p o f Chemicals , publishe d i n th e Federa l Registe ro n Januar y7,201 1 at 7 6 fed

. Reg

. 1067 , pleas e fin d enclose d th e fina l repor t fo rth e Acut e Toxicit yi n th e Ra t - U p an d Dow n Procedur e o n D
gluco-Heptoni c acid , monosodiu m salt , (2.xi.)
- [CAS # 31138-65-5]

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cc : Pete rRadford Howard Stevenso n Jame s Grantha m Rand yBuckne r Do n Meuschke Joh n Mile s Fil e 4 0 1 3000003 0



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Sodiu m Glucoheptonate : ACUT E ORA L TOXICIT Y I N TH E RA T

- UP-AND-DOW N PROCEDUR E PROJEC TNUMBER : 4110468 7

AUTHOR : A Sander s

STUD Y SPONSOR : Harcro s Chemical s Inc

. 345 2 Corporat e Driv e Dalto n G A 3072 0 UNITE D STATE S O F AMERIC A STUD Y MONITOR : Joh n Newlov e J N Consultanc y(International ) Ltd

. 1 Potterto n Lan e Barwic k i n Elme t LS1 5 4D U TES TFACILITY : Harla n Laboratorie s Lt d Shardlo w Busines s Par k Shar d lo w Derbyshire ' DE7 2 2G D - U K Telephone : +4 4 (0 ) 133 2 79289 6 Facsimile : +4 4 (0 ) 133 2 79901 8

41104687.docx/J Op
. 3

PROJEC T NUMBER : 4110468 7 PAG E 2
QUALIT Y ASSURANC E REPOR T Thi s stud ytyp e i s classe d a s short-term

. Th e Genera l Stud yPla n fo rthi s stud ytyp e wa s reviewe d fo rcomplianc e onc e onl yo n initia l production

. Inspectio n o f th e routin e an d repetitiv e procedure s tha t constitut e th e stud yi s carrie d ou t a s a continuou s proces s designe d t o encompas s th e majo rphase s o f thi s stud ytyp e a t leas t onc e ever ythre e months

. Fro m 16 t h Ma y201 2 th e frequenc yo f thes e proces s base d inspection s wa s change d fro m a monthl yt o a thre e monthl ycycle

. Thi s deviatio n i s considere d no t t o affec t th e purpos e o rintegrit yo f th e study

. I n addition , genera l facilitie s ar e inspecte d a t leas t onc e a yea ran d th e result s ar e reporte d t o management

. Thi s report ha s bee n audite d b yth e Qualit yAssuranc e Unit , an d i s considere d t o b e a n accurat e accoun t o f th e dat a generate d an d o f th e procedure s followed

. I n eac h case , th e outcom e o f Q A evaluatio n i s reporte d t o th e Stud yDirecto ran d Managemen t o n th e da yo f evaluation

. Audit s o f stud ydocumentation , an d proces s inspection s appropriat e t o th e typ e an d schedul e o f thi s stud ywer e a s follows :

2 4 Augus t 201 0 Genera l Stud yPla n Complianc e Audi t 1 8 Octobe r201 2 Tes t Ite m Preparatio n 1 8 Octobe r201 2 Anima l Preparatio n 0 4 Octobe r201 2 Dosin g 1 1 Octobe r201 2 Assessmen t o f Respons e 0 3 Octobe r201 2 Necrops y § 2 8 Novembe r201 2 Draf t Report Audi t § Dat e o f Q A Signatur e Fina l Repor t Audi t § Evaluatio n specifi c t o thi s stud y

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DATE : Fo rth e Qualit yAssuranc e Unft t 

## 1 5 MA R 

## 2013

"Authorise d Q A Signatures : Senio rAudi t Staff : J G Rile yBS c (Hons ) MRQA , J M Crowthe rMISc T MRQA , G Wre n ON C MRQA , S Beva n BS c (Hons ) MRQA , L Blane yMRQ Ap
. 4

PROJEC T NUMBER : 4110468 7 PAG E 3
GL P COMPLIANC E STATEMEN T Wit h th e exceptio n note d belo w th e wor k describe d wa s performe d i n complianc e wit h U KGL P standard s (Schedul e 1 , Goo d LaboratoryPractic e Regulation s 199 9 (S11999/310 6 a s amende d b yS I 2004/0994))

. Thes e Regulation s ar e i n accordanc e wit h GL P standard s publishe d a s OEC D Principle s o n Goo d LaboratoryPractic e (revise d 1997 , ENV/MC/CHEM(98)17) ; an d ar e i n accordanc e with , an d implement , th e requirement s o f Directive s 2004/9/E C an d 2004/10/EC

. N o analysi s wa s carrie d ou t t o determin e th e homogeneity , concentratio n o rstabilit yo f th e tes t ite m formulation

. Th e tes t ite m wa s formulate d withi n tw o hour s o f bein g applie d t o th e tes t system ; i t i s assume d tha t th e formulatio n wa s stabl e fo rthi s duration

. Thi s exceptio n i s considere d no t t o affec t th e purpos e o rintegrit yo f th e study

. Thi s report full yan d accuratel yreflect s th e procedure s use d an d dat a generated

.

DATE : 

## 1 1 MA

R 

## 201 3 A Sander s Stud yDirecto r

Thi s repor

t ma yb e presente d i n fina l for m a s a digita l (pdf) document

. Suc h documents ar e prepare d b

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yt o version s produce d b yoptica l photocopy

. However , i n al l case s th e hand-signe d pape roriginal , hel d i n secur e archives , i s th e definitiv e document

.PROJEC T NUMBER : 4110468 7 p
. 5

PAG E 4
CONTENT S QUALIT Y ASSURANC E REPOR T 2 GL P COMPLIANC E STATEMEN T 3 CONTENT S 4 SUMMAR Y 5 1 . INTRODUCTIO N 6 2 . TES TITE M AN D EXPERIMENTA L PREPARATIO N 6 2. 1 Description , Identificatio n an d Storag e Condition s 6 2. 2 Preparatio n o f Tes t Ite m 6 3 . METHOD S 7 3. 1 Animal s an d Anima l Husbandr y7 3. 2 Procedur e 8 3. 3 Evaluatio n o f Dat a 9 4 . ARCHIVE S 9 5 . RESULT S 1 0 5. 1 Mortalit yDat a 1 0 5. 2 Clinica l Observation s 1 0 5. 3 Bodyweigh t 1 0 5. 4 Necrops y1 0 6

. CONCLUSIO N 1 1 Tabl e 1 Individua l Clinica l Observation s an d Mortalit yDat a 1 2 Tabl e 2 Individua l Bodyweight s an d Weekl yBodyweigh t Change s 1 3 Tabl e 3 Individua l Necrops yFinding s 1 4 Appendi x1 Statement o f GL P Complianc e i n Accordanc e wit h Directiv e 2004/9/E C 1 5PROJEC T NUMBER : 4110468 7 p
. 6

PAG E 5 Sodiu m Glucoheptonate : ACUT E ORA L TOXICIT Y I N TH E RA T - UP-AND-DOW N PROCEDUR E SUMMAR Y Introduction

. Th e stud ywa s performe d t o asses s th e acut e ora l toxicit yo f th e tes t ite m followin g a singl e ora l administratio n i n th e Wista rstrai n rat

. Th e metho d wa s designe d t o b e compatibl e wit h th e following :

• OEC D Guideline s fo rth e Testin g o f Chemical s No

. 42 5 "Acut e Ora l Toxicit y- Up-and-Down-Procedur e (UDP) " (adopte d 0 3 Octobe r2008 ) Method

. A tota l o f fiv e femal e animal s wer e dose d individuall yi n sequenc e wit h sufficien t tim e (a t leas t 4 8 hours ) betwee n eac h animal , a t dos e level s o f 354 , 111 2 o r 404 0 mg/k g bodyweigh t (equivalen t t o 175 , 55 0 an d 200 0 m g activ e ingredient/k g bodyweight , respectively)

. Th e tes t ite m wa s administere d orall yundilute d a t dos e level s o f 111 2 an d 404 0 mg/k g bodyweigh t (equivalen t t o 55 0 an d 200 0 m g activ e ingredient/k g bodyweight , respectively ) an d a s a solutio n i n distille d wate ra t a dos e leve l o f 35 4 mg/k g bodyweigh t (equivalen t t o 17 5 m g activ e ingredient/k g bodyweight)

. Clinica l sign s an d bodyweigh t developmen t wer e monitore d durin g th e study

. A H animal s wer e subjecte d t o gros s necropsy
. Mortality

. Ther e wer e n o deaths

. Clinica l Observations

. Hunche d postur e wa s note d i n th e anima l treate d a t a dos e leve l o f 111 2 mg/k g (equivalen t t o 55 0 m g activ e ingredient/k g bodyweight)

. N o othe r sign s o f systemi c toxicit ywer e noted

. Bodyweight

. Animal s showe d expecte d gain s i n bodyweigh t ove rth e stud yperiod , excep t fo ron e anima l treate d a t a dos e leve l o f 404 0 mg/k g (equivalen t t o 200 0 m g activ e ingredient/k g bodyweight ) whic h showe d expecte d gai n i n bodyweigh t durin g th e firs t wee k

bu t n o gai n i n bodyweigh t durin g th e secon d week

. Necropsy

. N o abnormalitie s wer e note d a t necropsy
. Conclusion

. Th e acut e ora l media n letha l dos e (LD 5 o ) o f th e tes t ite m i n th e femal e Wista rstrai n ra t wa s foun d t o b e greate rtha n 404 0 mg/k g bodyweigh t (equivalen t t o 200 0 m g activ e ingredient/k g bodyweight)

.PROJEC T NUMBER : 4110468 7 p
. 7

PAG E 6
Sodiu m Glucoheptonate : ACUT E ORA L TOXICIT Y I N TH E RA T - UP-AND-DOW N PROCEDUR E 1 . INTRODUCTIO N Th e stud ywa s performe d t o asses s th e acut e ora l toxicit yo f th e tes t ite m followin g a singl e ora l administratio n i n th e Wista rstrai n rat

. Th e metho d wa s designe d t o b e compatibl e wit h th e following ;

• OEC D Guideline s fo rth e Testin g o f Chemical s No

. 42 5 "Acut e Ora l Toxicit y- Up-and-Down-Procedur e (UDP) " (adopte d 0 3 Octobe r2008 ) Th e ra t wa s selecte d fo rthi s stud ya s i t i s a readil yavailabl e roden t species , historicall y use d i n safet yevaluatio n studies , an d i s acceptabl e t o appropriat e regulatoryauthorities

. Th e ora l rout e wa s selecte d a s th e mos t appropriat e rout e o f exposur e an d th e result s ar e believe d t o b e o f valu e i n predictin g th e likel ytoxicit yo f th e tes t ite m t o man
. Th e stud ywa s performe d betwee n 2 5 Septembe r201 2 an d 0 6 Novembe r2012

. 2 . TES TITE M AN D EXPERIMENTA L PREPARATIO N 2. 1 Description , Identificatio n an d Storag e Condition s Sponsor' s identificatio n Sodiu m Glucoheptonat e Descriptio n dar k brow n liqui d Lo t numbe r92100010 0 Purit y: 49.5 % Dat e receive d : 0 9 Februar y201 2 Expir ydat e 1 3 January201 3 Storag e condition s roo m temperatur e i n th e dar k Th e integrit yo f supplie d dat a relatin g t o th e identity , purit yan d stabilit yo f th e tes t ite m i s th e responsibilit yo f th e Sponsor

. 2. 2 Preparatio n o f Tes t Ite m Fo rth e purpos e o f th e 111 2 an d 404 0 mg/k g dos e level s (equivalen t t o 55 0 an d 200 0 m g activ e ingredient/k g bodyweight , respectively) , th e tes t ite m wa s use d a s supplied

. Th e specifi c gravit ywa s determine d an d use d t o calculat e th e appropriat ep
. 8

PROJEC T NUMBER : 4110468 7 PAG E 7 dos e volum e fo rth e require d dos e level

. Fo rth e purpos e o f th e 35 4 mg/k g dos e leve l (equivalen t t o 17 5 m g activ e ingredient/k g bodyweight) , th e tes t ite m wa s freshl y prepared , a s required , a s a solutio n a t th e appropriat e concentratio n i n distille d water

. Th e tes t ite m wa s formulate d withi n tw o hour s o f bein g applie d t o th e tes t system

. I t i s assume d tha t th e formulatio n wa s stabl e fo rthi s duration

. Fo rth e purpos e o f th e study , th e dos e level s wer e adjuste d fo rth e purit yo f th e tes t ite m (49.5%)

. N o analysi s wa s conducte d t o determin e th e homogeneity , concentratio n o rstabilit yo f th e tes t ite m formulation

. Thi s i s a n exceptio n wit h regar d t o GL P an d ha s bee n reflecte d i n th e GL P complianc e statement

. 3 . METHOD S 3. 1 Animal s an d Anima l Husbandr y Femal e Wista r(RccHanTM:WIST ) strai n rat s wer e supplie d b yHarla n Laboratorie s U K Ltd. , Oxon , UK

. O n receip t th e animal s wer e randoml yallocate d t o cages
. Th e animal s wer e nulliparou s an d non-pregnant

. Afte ra n acclimatisatio n perio d o f a t leas t fiv e day s th e animal s wer e selecte d at rando m an d give n a numbe runiqu e withi n th e stud yan d identifie d b ya numbe rwritte n o n a cag e card

. A t th e start o f th e stud yth e animal s wer e eigh t t o twelv e week s o f age
. Th e bodyweight s fel l withi n a n interva l o f ±20 % o f th e mea n weigh t o f an ypreviousl ydose d animals

. Th e animal s wer e individuall yhouse d i n suspende d solid-floo rpolypropylen e cage s furnishe d wit h woodflakes

. Wit h th e exceptio n o f a n overnigh t fas t immediatel ybefor e dosin g an d fo rapproximatel ythre e t o fou rhour s afte rdosing , fre e acces s t o main s drinkin g wate ran d foo d (2014 C Tekla d Globa l Roden t die t supplie d b yHarla n Laboratorie s U.K

. Ltd. , Oxon , UK ) wa s allowe d throughou t th e study

. Th e diet , drinkin g wate ran d beddin g wer e routinel yanalyse d an d wer e considere d no t t o contai n an y contaminant s tha t woul d reasonabl yb e expecte d t o affec t th e purpos e o rintegrit yo f th e study

. Th e temperatur e an d relativ e humidit ywer e se t t o achiev e limit s o f 1 9 t o 25° C an d 3 0 t o 70 % respectively

. An yoccasiona l deviation s fro m thes e target s wer e considere d no t t o hav e affecte d th e purpos e o rintegrit yo f th e study

. Th e rat e o f ai rexchang e wa s a t leas t fiftee n change s pe rhou ran d th e lightin g wa s controlle d b ya tim e switc h t o giv e twelv e hour s continuou s ligh t (06:0 0 t o 18:00 ) an d twelv e hour s darkness

.PROJEC T NUMBER : 4110468 7 p
. 9

PAG E 8
Th e animal s wer e provide d wit h environmenta l enrichmen t item s whic h wer e considere d no t t o contai n an ycontaminan t o f a leve l tha t migh t hav e affecte d th e purpos e o rintegrit y o f th e study

. 3. 2 Procedur e N o informatio n wa s availabl e regardin g th e toxicit yo f th e tes t ite m therefor e th e defaul t value s fo rLD 5 0 an d sigm a wer e entere d int o AOT42 5 Statistica l Program

. Th e statistica l progra m gav e a recommende d dos e progressio n o f 2000 , 550 , 175 , 55.0 , 17.5 , 5. 5 an d 1.7 5 mg/kg

. Th e firs t anima l wa s dose d a t 35 4 mg/k g (equivalen t t o 17 5 m g activ e ingredient/k g bodyweight)

. Furthe ranimal s wer e the n treate d a s follow s base d o n th e short-ter m result s o f th e previousl ytreate d animal : Tes t Sequenc e {Anima l number ) Dos e Leve l

mg/k g Concentratio n

(mg/ml ) Specifi c

Gravit y Dos e Volum e

(ml/kg ) Short-Ter m

Resul t 1 (1-0 ) 354 0 35. 4
- 1 0 0 2 (2-0 ) 1112 ®
- 1.40 0 0.8 0 0 3 (3-0 ) 4040 * - 140 0 2.8 9 0 4 (4-0 ) 4040 » - 1.40 0 2.8 9 0 5 (5-0 ) 4040

. - 1.40 0 2.8 9 0 0 = Anima l survive d Th e tes t wa s complet e afte rth e fift h anima l ha d bee n dose d a s th e followin g stoppin g criterio n wa s met :

• thre e consecutiv e animal s survive d a t th e maximu m dos e leve l (404 0 mg/kg , equivalen t t o 200 0 m g activ e ingredient/k g bodyweight ) Al l animal s wer e dose d onc e onl yb ygavage , usin g a meta l cannul a attache d t o a graduate d syringe

. Th e volum e administere d t o eac h anima l wa s calculate d accordin g t o th e faste d bodyweigh t a t th e tim e o f dosing

. Treatmen t o f animal s wa s sequential

.

© = Equivalen t t o 17 5 m g activ e ingredient/k g bodyweigh t ® = Equivalen t t o 55 0 m g activ e ingredient/k g bodyweigh t
• = Equivalen t t o 200 0 m g activ e ingredient/k g bodyweigh tPROJEC T NUMBER : 4110468 7 p
. 1 0

PAG E 9 Sufficien t tim e (a t leas t 4 8 hours ) wa s allowe d betwee n eac h individua l anima l t o confir m th e outcom e o f th e previousl ydose d animals

. Th e animal s wer e observe d fo rdeath s o rovert sign s o f toxicit yK , 1, 2 an d 4 hours afte r dosin g an d subsequentl yonc e dail yfo rfourtee n days

. Individua l bodyweight s wer e recorde d prio rt o dosin g an d seve n an d fourtee n day s afte r treatment

. A t th e en d o f th e observatio n perio d th e animal s wer e kille d b ycervica l dislocation

. Al l animal s wer e subjecte d t o gros s pathologica l examination

. Thi s consiste d o f a n externa l examinatio n an d openin g o f th e abdomina l an d thoraci c cavitie s fo rexaminatio n o f majo r organs
. Th e appearanc e o f an ymacroscopi c abnormalitie s wa s recorded

. N o tissue s wer e retained

. 3. 3 Evaluatio n o f Dat a Th e ora l LD 5 o wil l b e calculate d b yth e maximu m likelihoo d method

. Dat a evaluation s als o include d th e relationship , i f any , betwee n th e exposur e o f th e anima l t o th e tes t ite m an d th e incidenc e an d severit yo f al l abnormalitie s includin g behavioura l an d clinica l observations , gros s lesions , bodyweigh t changes , mortalit yan d an yothe rtoxicologica l effects

. Usin g th e mortalit ydat a obtained , a n estimat e o f th e acut e ora l media n letha l dos e (LD 5 0 ) o f th e tes t ite m wa s calculate d b yth e statistica l program
. 4 . ARCHIVE S Unles s instructe d otherwis e b yth e Sponsor , al l origina l dat a an d th e fina l report wil l b e retaine d i n th e Harla n Laboratorie s Ltd , Shardlow , U Karchive s fo rfiv e years , afte rwhic h instruction s wil l b e sough t a s t o furthe rretentio n o rdisposal

.p
. 1 1

PROJEC T NUMBER : 4110468 7 PAG E 1 0
5 . RESULT S Individua l mortalit ydat a an d individua l clinica l observation s ar e give n i n Tabl e 1

. 5. 1 Mortality Dat a Th e mortalit ydat a ar e summarise d a s follows : Dos e Leve l mq/k q Numbe ro f Animal s Survive d Numbe ro f Animal s Die d Tota l Numbe ro f Animal s 354© 1 0 1 1112 ® 1 0 1 4040 * 3 0 3 Al l dose s 5 0 5 5. 2 Clinica l Observation s Hunche d postur e wa s note d i n th e anima l treate d a t a dos e leve l o f 111 2 mg/kg (equivalen t t o 55 0 m g activ e ingredient/k g bodyweight)

. N o othe rsign s o f systemi c toxicit ywer e noted

. 5. 3 Bodyweigh t Individua l bodyweight s an d weekl ybodyweigh t change s ar e give n i n Tabl e 2

. Animal s showe d expecte d gain s i n bodyweigh t ove rth e stud yperiod , excep t fo ron e anima l treate d a t a dos e leve l o f 404 0 mg/k g (equivalen t t o 200 0 m g activ e ingredient/k g bodyweight ) whic h showe d expecte d gai n i n bodyweigh t durin g th e firs t wee k bu t n o gai n i n bodyweigh t durin g th e secon d week

. 5. 4 Necrops y Individua l necrops yfinding s ar e give n i n Tabl e 3

. N o abnormalitie s wer e note d at necropsy
.

© = Equivalen t t o 17 5 m g activ e ingredient/k g bodyweigh t ® = Equivalen t t o 55 0 m g activ e ingredient/k g bodyweigh t
• = Equivalen t t o 200 0 m g activ e ingredient/k g bodyweigh tp
. 1 2

PROJEC T NUMBER : 4110468 7 PAG E 1 1 6 . CONCLUSIO N Th e acut e ora l media n letha l dos e (LD50) o f th e tes t ite m i n th e femal e Wista rstrai n ra t wa s foun d t o b e greate rtha n 404 0 mg/k g bodyweigh t (equivalen t t o 200 0 m g activ e ingredient/k g bodyweight)

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7 PAGE 1 5
Appendi x 1 Statemen t o f GL P Complianc e i n Accordanc e wit h Directiv e

2004/9/E C
TH E DEPARTMEN T O F HEALT H O f TH E GOVERNMEN T

O F TH E UNITE D KINGDO M GOO D LABORATOR Y PRACTIC E STATEMEN T O F COMPLIANC E I N ACCORDANC E WIT H DIRECTIV E 2004/9/E C TES T FACILIT

Y TES T TYP£(S } Harla n Laboratorie s Lt d Analytical/Clinica l

DAT E O F INSPECTIO N 1 0 Jul y201 2 A n inepectio n forcomplianc e wit h th a Principles o f Goo d Laborator

yPractic e wa s carrie d ou t a t th e abov

e test facBft

ya s par t of th e U KGoo

d Laborator

yPractic e Complianc

e Monitorin g Programme

. Thi s statemen t confirm s that > o n th a dat e o f issue , th e U KGoo d Laborator

y Practice Monitorin g Authorit ywer e satisfie d that th e abov e test facilitywa

s operatin g i n complianc

e wit h th e OEC D Principle s of Goo d Laborator

yPractice

. Thi s statemen t constitutes a Goo d Laborator

yPractic e instrumen t (a

s define d i n th e U KGood Laborator

yPractic e Regulation s 1999)

. Shardlo w Busines s Par k Londo n Roa d Shar d lo w Darby , 0E2 7 2G D Chemistr y Environmenta l Toxicit y Environmenta l Fate Mutagenicity Phya/Chem

. Test s Toxicolog y

Dr

. Andre w J

. Gra y Head , U K GL P Monitorin

g Authorit y

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