# i

**E P**  **A R E**  **G I**  **ST RA**  **T ION DIVI**  **S ION CO**  **M PA**  **N Y NO**  **T ICE**  **OF F**  **I L**  **I N**  **G F**  **OR P**  **EST ICIDE**  **P ET**  **I T**  **IONS P**  **U BL**  **I S**  **H E**  **D IN T**  **HE F**  **E D**  **E RAL**  **R E**  **G I**  **STER E**  **P A**  **R e**  **gis tr**  **a t**  **ion Division**  **c o**  **n t**  **a ct**  **: P**  **.V. Sh**  **a h**  **, 703 -**  **308 -**  **1846 IN**  **S T**  **R U**  **C TION**  **S :**  **P l**  **e a**  **se u**  **t ili**  **z e**  **t h**  **is o u**  **t li**  **n e**  **in p**  **re p**  **a r**  **i n**  **g t**  **h e**  **p e**  **s t**  **i c**  **i d**  **e p**  **et i**  **t io**  **n . In**  **c as**  **es w**  **h er**  **e t**  **h e**  **o u**  **t li**  **n e**  **e l**  **e m**  **en t**  **d o**  **e s**  **n ot**  **a pp**  **ly, p**  **l e**  **ase i**  **n s**  **er t**  **“N A**  **- R**  **e m**  **o v**  **e ”**  **a n**  **d m**  **ai n**  **t ain**  **t h**  **e o**  **u t**  **li n**  **e .**  **P l**  **e ase**  **d o**  **n ot**  **ch a**  **n ge**  **t h**  **e m**  **a r**  **gi n**  **s, f**  **o n**  **t , or**  **f o**  **r m**  **a t**  **in yo**  **u r**  **p e**  **s t**  **i c**  **i d**  **e p**  **et i**  **t io**  **n .**  **S i**  **m p**  **ly re**  **p la**  **c e**  **t h**  **e i**  **n s**  **tr uc**  **t io**  **n s**  **t h**  **at a**  **pp e**  **ar in**  **g ree**  **n , i.**  **e ., “**  **[ i**  **n s**  **er t**  **c o**  **m p**  **a n**  **y n**  **a me]**  **,” w**  **i t**  **h t**  **h e**  **i n**  **f o**  **r m**  **a t**  **ion s**  **p ec**  **i f** 

**ic t**  **o yo u**  **r a**  **ct io**  **n .**  **T E**  **MPL A**  **T E**  **:** B A S F C o r

po r ation P P I N - 10545 E P A h a s re c e iv e d a p e sti c ide p e tition ( I N - 1054 5 ) fr om B A S F C o r po ration, c /o L e wis & H arr ison, L L C , 122 C S tree t N W , S uite 740, W a s hin gton DC 20001, re qu e s tin g , pur su ant to s ec tion 408 ( d) of the Fe d era l F oo d , D r u g , and C o s m e tic A c t ( F F D C A ) , 21 U. S . C . 346 a( d ) , to am e nd 40 C F R p art 180 t o e st a blish an e x e mption fr om the re qui r e m e nt of a tol eran c e f or Al k y l ( C 8 - C 1 0 ) po l y

g lu c osid e s ( C AS R e g . No. 68515 - 7 3 - 1) und e r §180.940 ( a ) wh e n us e d a s an i n ert in gre d i e nt a s a sur fac t ant without limit at ion in ant imi cr obi a l p e sti c ide f o r mul ations . E P A h as d e t er min e d th at the p e tit i on c ont a ins d ata or in f or m ation re g ar di n g the e l e m e nts s e t f o rth in s ec tion 408 ( d )( 2 ) of F D D C A; how e v er , E P A h a s not f ul l y e v a l u at e d the s u ff

i c i e n c y o f the submitt e d d ata at this ti m e or wh e th e r the d at a suppo rts gr anting o f the p e ti t ion. Addition a l d ata m a y b e n ee d e d b ef

o r e E P A r ul e s on the p e tition. A. R esidue C

h e mistry R e sidue d at a , in c ludi n g an an a l y t i ca l m e thod, is not p ertin e nt or re qui r e d f or this p e tition sin c e an e x e mption fr om tol er an c e is re qu e st e d. B. T ox i c ologi c al Profile An e x t e nsive s afe t y d ata b a se h a s b e e n c ompli e d o n the a l k y l po l y g l yc osid e s. The s afe t y d ata b a se in c lud e s a c ut e , sub c hr oni c , d e v e lopm e nt a l t ox i c i t y, mut a g e ni c i t y , and m e t a bolism studi e s. 1. A c ute tox i c ity Al k y l po l yg l yc osid e s ar e of low to x i c i t y via the or a l and d er m a l r out e . At h i gh c o n ce ntrations, the a l k y l po l y g l yc osid e s can be i rr it ating to e ye s and skin. The a l k y l po l y g l yc osid e s ar e n ot d er m a l s e nsiti z er s.2

a. A c ute oral tox i c ity P r im ar y limit t e sts w er e p erf o r m e d with v ar ious a l k y

l po l y g l yc osid e s, using dos e s o f 2,000 or 5,000 m g /k g bw in thre e gr oups o f anim a ls. Th e se dos e s w e r e c hos e n to c o mp l y with the r e g ul ato r y r e qui re m e nts i n Eur ope and the Unit e d S t at e s us e d to d ef ine individu a l c l a ssi f

i ca tion limits f or c h e mi ca l subst an ce s. T h e ac ut e to x i c i t y t e st re sults ar e shown b e low.

A c ute O r a l To x i c i t y o f A l k y l P o l y g l y c osid e s C h a in L e n gth C 8 - 10 C 12 - 14 C 10 - 16 P o l y m er i z ation 1.6 1.5 1.6 P erce nt S ubst an c e 50 60 50 Dose ( m g /kg b w) > 5,000 > 2,000 > 5,000 T e st Anim a ls S p ra g u e - D awl e y r at 5 m a l e /5 fe m a le W ist ar rat

2 m a l e /2 fe m a le S p ra g

u e - D awl e y r at 5 m a l e /5 fe m a le Mo rt a liti e s 0/10 0/4 0/10 Anim a ls with G r oss N ecr op s y F indin g s 0/10 0/4 0/10 C h e mi ca l str

u c tur e a pp e ar s to h ave little in f

lu e n c e on the ac ute o r a l to x i c i t y of a l k yl po l y g l yc osid e s with a ll t e sting showi n g an LD 5 0 of great e r th an 2,000 m g /k g bw at a minimum. The p r odu c ts t e st e d c ov e re d a b r o a d ran ge of lin e ar C 8 - 16, with d e gr ee s of po l y m er i z ation b e tw ee n 1.5 and 1.6. F o r the dose ran ge us e d, no n e of the anim a ls show e d an y a dv er s e e f f e c ts in re sponse to a l k y

l po l y g l y c oside c h a ll e n g e , i rre s p e c tive of f ine c h e mi ca l str

u c ture . Thus i n g e stion of a l k y l po l y g l yc osid e s d o e s not re p re s e nt an a c ut e h ea lth r isk. b . A c ute d

e rmal tox i c it

y . F ive m a le and fe m a l e N e w Z ea l and white ra bbits r ece iv e d si n g le limit dos e s of e ith e r 2,000 m g /k g bw of C 8 - 10 or C 10 - 16 Al k y l P o l y g l yc osid e s a

ppli e d d er

m a l l y . F or C 8 - 10 a l k y

l po l y g l yc osid e s, c lini c a l si gns r e c o r d e d in individ u a l anim a ls dur ing th e obs er v ation p er iod of 14 d a ys in c lu d e d mild to mod erate i rr it ating ef f ec ts d ue to the hi gh c on ce ntr ation. One anim a l rece ivi n g the t e st subst an c e di e d. This w a s not t e s t - subst an c e r e l at e d but r ath e r w a s d u e to T y zze r’ s dis ea s e , an in f

e c tious dis ea se c ondition th at w a s c on f i r m e d b y mi cr os c opic e x amin ation. At the e nd of the 14 - d a y ob s er v ati o n p er iod, a ll sur

viving an im a ls w er e kill e d. G r oss n ecr op s y re v e a l e d spott y ar ea s of h e mo rr h a g e on th e lun g s o f f

ive r abbits. The s ame p r oto c ol w a s a

ppli e d us i ng C 10 - C 16 a l k y l po l y g l yc osid e s. No d eaths o cc u rre d and no p atholo g i c a l f

indin g s w e r e re po rt e d. The ef f ec ts on the lun g w ith C 8 - 10 a l k y l po l y g l y c osid e s w er e not s e e n wi t h the c los e l y re l at ed C 10 - 16 a l k y

l po l y g l yc os i d e s in the ac ute d er m a l t o x i c i t y stu d y ( s e e a

bov e ) , n e ith e r with C 8 - 10 a l k y l po l y g l yc osid e s in a sub ac ute d e r m a l stu d y, n or with C 12 - 16 a l k y l po l y g l y c osid e s in a sub c hr onic o r a l stu d y . As a c ons e qu e n ce , the ef f e c ts obs er v e d in the lung in the ac ute d er m al stu d y ar e a ss e s s e d a s b e i ng a si n g le ob s er v ation, possib l y d

u e to an unint e nd e d e x posur e via inh a l ation, or due to the hi gh pH of th e p r odu c t w ithout re l e v an c e to the hum an e x posu r e s ce n ar io. c. E

y e irritation.3

An in v i v o stu d y w a s c ar

r i e d out acc o r di n g to OE C D Guid e line 405 using an a liquot of 0.1 m L a qu e ous solution of C 12 - C 16 a l k y l po l y g l y c oside ( 50% ac tive subst an ce) . E ye s w e r e s c o r e d at 24, 48, and 72 hour s af

t e r a ppli cation. The c onjun c tiv a e displ a y e d mod e rat e to str ong re a c tions th at did not a

b ate c ompl e t e l y a f

t e r 21 d a ys in two anim a ls. Anoth e r s er i e s o f v a lid at e d e ye i rr it ation t e sts using C 12 - 16 Al k y l P o l y g l y c oside ( a dose of 0.1 m L of l a u r y l g l u c oside [ n e utra li z e d, 12.5% ac tive subst an ce ] ) f ound no i rr i t ant re a c tions and on l y sli ght c o r

n e a l re a c tions whi c h p er sist e d f or l e ss th an 48 hour s in one anim a l. d . D e rmal irritation. The t a ble b e low summ ar i z e s the re sults of skin i rr it ation t e sts und er t ak e n ac c o r ding to OE C D Guid e line 404, using lin e ar Al k y l P o l y g l y c osid e s a s the t e st subst an ce . S h o rt - c h a in ( C 8 - 1 0 ) Al k y l P o l y g l yc osid e s ar e si gni f

i cant l y l e ss of an i r r it ant th an th e ir c o rre sp o nding lo n g c h a in ( C 10 - 16 or C 12 - 16) ho m olo g u e s. T h e p r im ar y d e r m a l i rr it a tion ind e x ( P D II ) and m e an v a lu e s f or the 24 - , 48 - , 7 2 - hour e r y th e ma d at a re v ea l an a lmost lin ear in crea s e with in crea si n g c on ce ntr ation, a re l ation s hip ind e p e nd e nt of the d e gr e e of po l y m e r i z ation. Ev e n mi x ture s of sho rt - c h a in and lo n g - c h a i n Al k y l P o l y g l yc osi d e s f

i t this s ce n ar io w e ll, a ll o wing m e aning f ul e x t ra pol ations f

or l a b e ling issu e s. A p r od

u c t t e st e d at both pH 7 and pH 11 re v ea l e d th at i rr it ating p r o p erti e s w e r e a lmost un affec t e d b y a l k a lini t y . S yst e mic to x i c i t y af t e r a sin g le d er

m al a ppli cation in ra

bbits w a s not obs er

v e d in an y of t he t e sts with lin ear Al k y l P o l y g l yc osid e s. F urth er m o re , it h a s b e e n shown in d er m atolo g i ca l studi e s th at Al k y l P o l y g l yc osid e s u s e d a s s ec ond ar y s u rf

a c t ants signi f

i cant l y e nh an c e the s k in c omp atibili t y of p r im ar y s u rf a c t ants. D er m a l I rr it ation of Al k y l P o l y

g l yc osid e s C h a in L e n gth P o l y

m er i z ation P erce nt

S ubst an c e P D II E r y th e ma ( M ean) Ed e ma

( M ean) C 8 - 10 1.6 70 0.8 0.9 0.0 C 8 - 10 1.6 35 1.3 1.1 0.3 C 8 - 10 Not sp ec i f

i ed 15 0.0 0.0 0.0 C 10 - 16 1.4 60 4.6 2.9 2.1 C 12 - 16 1.4 50 3.7 2.2 1.6 C 12 - 16 1.4 50 3.0 2.1 0.9 C 12 - 16 1.6 50 3.0 1.9 1.1 C 12 - 16 1.4 30 2.8 1.7 0.9 C 10 - 16 1.4 20 0.4 1.2 1.1 C 8 - 10/ C 12 - 16 Mixtur e Not sp ec i f

i ed 35 ( C 12 - 16) 21 ( C 8 - 10) 2.7 1.8 0.8

e. S k in s e nsitization. B oth anim a l ( g

uin e a pig) and hum an skin s e nsiti zation t e sts w er e c ond u c t e d. None of the t e sts with C 12 - 16 Al k y

l P o l y g l yc osid e s displ a ye d s i gn i f i cant pot e nti a l f

or skin s e nsiti z ation e ith e r with the B u e hl e r t e st or t he M a gnusson - Kl i gm an p r oto c ol.4 S kin S e nsit i z ation f

or C 1 2 - 16 Al k y

l P o l y g l y c osid e s T e st P r oto c ol Ind u c tion C h a ll e n g e P ositiv e s S e nsiti z e r B u e hl e r Epid er

m a l: 20% Epid er

m a l: 20% 1/20 No M a gnusson - Kli gm an Intr ac ut an e ous: 1%

Epid er m a l: 60% Epid er

m a l: 10% 0/20 No 2. G e notox i c ity No e vid e n c e of g e noto x i c i t y or c hr omosom a l e f f e c ts w a s obs er

v e d in mut a g e n i c i t y studi e s c ondu c t e d with the a l k y

l po l y g l yc osid e s. a. R eve rse M

utation. A re l at e d c ompound c ont a ini n g C 12 - 16 a l k y l po l yg l y c osid e s, w a s t e st e d on S a lmon e lla t y phimur ium TA 98, TA 100, TA 15 3 5, TA 1537 and TA 1538 in two ind e p e nd e nt e x p erim e nts, both with a

nd without S 9 m i x m e t a

b olic ac tiv ation acc o r di n g to the OE C D g uid e line 471. T e st c on c e ntrations w e r e : 8, 40, 200, 1000, and 5000 μ g /pl at e ( 1 st t e st ) . Due to c y toto x ic ef f ec ts st arti n g at 900 μ g

/pl at e , t e st c o n c e ntrations w e r e a djust e d to 11.1, 33.3, 100, 300 and 900 μ g

/pl ate ( 2 n d t e st) acc o r di n g to the t e st g uid e lin e . S olutions of the Al k y l P o l y g l yc osid e s w e r e p r e p are d in d e ioni z e d double distill e d w at e r p rior to us e . C omp are d with c on c ur r e nt n e g ative c ontr ols, no p rec ipit ations or e nh an ce d r e v e rt ant rat e s w er e ob s er v e d in a ll stra ins t e st e d in the p re s e n c e or a b s e n c e of m e t a

b o lic ac tiv ation. 4 - Nitr o - o p h e n y l e n e di am e , 9 - amino acr idin e , and sodi um a z ide c ontr ols w er e p o sitive without S 9 ac tiv at i on, and the amino anthra c e ne c ontr ol w a s positive with S 9 ac tiv ation. C 12 - 16 Al k y l P ol y g l yc oside did not indu c e re v er se mut ations and w e r e not mut a g e nic in this t e st s y st e m ( W illin g , M e ssi n g e r and Aulm ann, 2004 ). B a s e d on th e f

a c t th at di f

fere nt Al k y

l P o l y g l yc osid e s show a simil ar m e t a b olic p athw a y re sulti n g in the o cc ur

r e n c e of s u g ar and di ff

e re nt f att y a l c o h ols and fatt y a l c ohols can be s ee n a s a cat e g o r y with c omp ara

b l e to x i c olo g i ca l p r op e rti e s with re g ar d to mut a g e n i c i t y , Al k y l P o l y g l yc osid e s is r e g ar d e d a s a gr oup with simil ar to x i c olo g i ca l p r op erti e s. As a c ons e qu e n ce, re sults fr om the mut a g e n i c i t y studi e s obt a in e d wi t h C 12 - 16 Al k y l P o l y g l y c osid e s ar e re p r e s e nt ative f o r the whole gr oup o f Al k y l P o l y g l y c osid e s i n c luding C 8 - C 10, the subj ec t of this p e tition.

b . C hromosomal Ab e rration. C ulture d C hin e se h amst e r V79 lung f ib r obl a sts w e r e e x pos e d re p e at e d l y to C 12 - 16 Al k y l P o l y g l yc osid e s e v e r y 4 ho u r s p e r OE C D Guid e line No. 473 ( EU Guid e line B 10 ) . No biol o g i ca l ef f e c ts, with re sp ec t to a

b e rrat ion indu c tion, w er e obs e rv e d at an y tim e , e ith e r with or without S 9 ac tiv ation. Thus it w a s c on c lud e d th at C 12 - 16 A l k y l P o l y g l y c osid e s w er e not c l a stog e nic un d e r the c onditions of the t e st d e si gn ( W illin g , M e ss i n g e r and Aulm ann, 2004 ) . B a s e d on th e f

a c t th at di f

fere nt Al k y

l P o l y g l yc osid e s show a simil ar m e t a b olic p athw a y re sulti n g5

in the o cc ur

r e n c e of s u g ar and di ff

e re nt f att y a l c o h ols and fatt y a l c ohols can be s ee n a s a cat e g o r y with c omp ara

b l e to x i c olo g i ca l p r op e rti e s with re g ar d to mut a g e n i c i t y , Al k y l P o l y g l yc osid e s is r e g ar d e d a s a gr oup with simil ar to x i c olo g i ca l p r op erti e s. As a c ons e qu e n ce, re sults fr om the c hr omo s ome a b e rration stu d y ob t a in e d with C 12 - 16 Al k y l P o l y g l y c osid e s ar e r e p re s e nt ative f

or the wh o le gr oup of Al k y l P o l y g l y c osid e s i n c luding C 8 - C 10, the subj ec t of this p e tition. 3. R e produ c ti v e and d

eve lo pm e ntal tox i c it

y . No re p r od

u c tive or d e v e lopm e nt a l ef f ec ts w e r e n o t e d in an y o f the t e sts c o n du c t e d. a. R e produ c ti v e tox i c it

y . Using OE C D Gui d e line No. 421, an a ss e ssm e nt o f the re p r od u c tive to x i c i t

y of C 12 - 16 Al k y

l P o l y g l yc osid e s w a s c ondu c t e d in 10 m a le and 10 fe m a le rats/gr oup f ollowing d a i l y a dministr ation b y o r a l g a v a ge of 1 00, 300, and 1000m g /k g bw/d a y do s e s ( W illin g , M e ssin g e r and Aulm ann, 2004 ) . No e f f e c ts indi cative of g e n era l t o x i c i t y w e r e obs er v e d in p are nt a l an i m a ls. R e l ative and a

bso l ute w e i ghts of t e st e s, e p i di d y mid e s and s e min al v e si c l e s did not di ffe r b e tw ee n t e st and c ontr ol an i m a ls. W ith re g ar d to r e p r odu c tive p aram e t er s, no t e st subst an ce r e l at e d s y mptoms w e r e obs er

v e d . M ean litt e r w e i ghts, p up w e i ghts, s e x ratios, and g e st ation p er iods did not di ffe r s i gni f i cant l y among a ll gr oups. No c lini ca l p re - w eani n g eff e c ts w e r e not e d and n e cr op s y or histolo g i c a l e x amin ation did not re v ea l an y ef f ec ts in p ar e nt a l or F 1 pups. On the b a sis of th e se re sults, a NOA E L of 1,000 m g /k g bw/d a y w a s d e t er

min e d. b . D eve lop m e ntal tox i c it y. C 12 - 16 Al k y

l P o l y g l yc o s id e s w er e t e st e d in a s e g m e nt I I stu d y p e r OE C D Guid e line No. 414 at do s e l e v e ls of 0, 100, 300, and 1,000 m g /k g bw/d a y i n p r e gn ant C D - R ats. The subst an c e w a s a dm i nist ere d d a i l y b y g a v a ge fr om d a ys 6 to 15 of g e s t ation. A st and ar d dose volume of 10 m L /k g bw w a s us e d. C lini ca l c ondition and re a c tion to treat m e nt w er e rec o r d e d at l ea st on c e d a i l y . M at er

n a l w e i ghts w er e re po rt e d o n d a ys 0, 6, 16, and 20 of g e st ation. All d ams tol erat e d the a ppli e d do s e l e v e ls of up to 1000 m g/kg bw/d a y without l e th a li t y . M at er n a l bo d y w e i ght g a in w a s not a f

f e c t e d b y treatm e nt. F or m at er n a l to x i c i t y a N O A E L of 1,000 m g/k g bw w a s d e du c e d. All fe m a l e s h a d vi a

ble fe tus e s, and p re - and post - impl ant ati o n loss e s a s w e ll a s m ean numb er s of re so r p t ions w er e not a ff

e c t e d b y treatm e nt at an y do s e . S k e l e t a l and vis c e ral e x a min ations a lso did n o t d e t ec t an y tr e atm e nt - r e l at e d m a l f o r m ations. F o r e mb r yo / fe toto x i c i ty and t erat o g e n i c i t y , the N OA E L w a s a lso d e t er mi n e d to be 1,000 m g

/k g bw with no eff

e c t obs er v e d at an y dose l e v e l t e st e d. B oth the d e v e lopm e nt a l to x i c i t y and t e rat o g e ni c i t y NOA E L f ar e x cee d an y rea son a

b l e f o re s e ea ble e x posur e to Al k y

l P o l y g l yc osid e s in hum ans. F urth e r mo re , th e d ata f

o r th e se surfac t ants p r ovide a ssur an c e of a l ac k o f e f f e c t on m at er

n a l to x i c i t y o r re p r odu c tive ca p ac i t y . B a s e d on th e f

a c t th at di f

fere nt Al k y

l P o l y g l yc osid e s dis c uss e d in this do c um e nt show a simil ar m e t a bolic p athw a y r e sulting in the o c c ur r e n c e o f s u g ar and di f

f e r e nt fatt y a l c ohols and th at fatt y a l c ohols can be s ee n a s a cat e g o r y with c omp ara b l e to x i c olo g i ca l p r op e rti e s with re g ar d to s yst e mic to x i c i t y, Al k y

l P o l y g l yc osid e s ar e r e g ar d e d a s a gr oup with simi l ar to x i c olo g i ca l p r op erti e s on r e p eat e d d o se to x i c i t y . As a c ons e qu e n ce , r e sults fr om re p eat e d a ppli cation studi e s6

obt a in e d with C 12 - 16 Al k y l P o l y g l yc osid e s ar e re p r e s e nt ative f or the whole gr oup o f Al k y l P o l y g l y c osid e s in c luding C 8 - C 10, the subj ec t of this p e tition. 4. Sub c hronic tox i c ity B a s e d on th e f

a c t th at di f

fere nt Al k y

l P o l y g l yc osid e s show a simil ar m e t a b olic p athw a y re sulti n g in the o cc ur

r e n c e of s u g ar and di ff

e re nt f att y a l c o h ols and fatt y a l c ohols can be s ee n a s a cat e g o r y with c omp ara

b l e to x i c olo g i ca l p r op e rti e s with re g ar d to mut a g e n i c i t y , Al k y l P o l y g l yc osid e s is r e g ar d e d a s a gr oup with simil ar to x i c olo g i ca l p r op erti e s. As a c ons e qu e n ce, re sults fr om re p eat e d a

p p li cation studi e s obt a in e d with C 12 - 16 Al k y l P o l y g l y c osid e s ar e re p r e s e nt at i ve f

or the who l e gr oup of Al k y l P o l y g l yc osid e s i n c luding C 8 - C 10, the subj ec t of this p e tition. a . Sub c hronic oral tox i c it y . C 12 - 16 Al k y

l P o l y g l yc o s id e s w er e inv e sti g at e d in c ompli an c e with OE C D Guid e line 408 f or sub c hr onic to x i c i t y ( W il l in g , M e ssi n g e r and Aul m ann, 2004 ) . T e n m a l e and 10 fe m a le S p r a g u e D awl e y r ats p e r dos a ge g r oup w e r e a dminist ere d d a i l y with 250, 500 and 1 0 00 m g /k g bw/d a y b y g av a g e f o r 90 d a ys. An u ntreat e d gr oup s er v e d a s the c ontr ol. No si gni f i can t c h an g e s w e r e s e en due to treatm e nt in bo d y w e i ght g a in, f ood c ons u mption, re l ative o r g an w e i ghts, bio c h e mi c a l, ophth a lmolo g i ca l or h e m atolo g i c a l p aram e t er s d u e to treatm e nt. G r oss p atholo g y at n e cr op s y re v ea l e d ul c e rations and e d e ma r e str i c t e d to the f o re stom ac h in the h i gh - d o se gr oup. P atholo g i ca l and histol o gi ca l e x amin ations re v ea l e d th at no st atisti ca l l y s i gn i f i cant or biolo g i ca l l y re l e v ant sub st an ce - r e l at e d c h an g e s h a d o cc ur r e d in an y of the o r g ans e x ce pt the f o re stom ac h. Histop atholo g y r e v ea l e d dos e - d e p e n d e nt m ani fe st ation of ul c er s and in f l a mm ato r y e d e ma a cc omp ani e d b y a canthosis and p r oli fe r ation of the mu c osa c o n f in e d to the mu c ous m e mb rane of th e f o r e stom ac h of both m a le and f e m a le hi gh - do s e gr oup an d to a l e ss e r e x t e nt in the mid - dose gr oup. No s ubst an ce - sp e c i f ic histop atholo g y w a s e vid e nt in the f o re stom a c hs of the low - dose gr oup. E x amin ation of the f o re stom a c hs of a r e c ov e r y gr oup fr o m the hi gh - dose show e d th at th e se e ff

e c ts w er e re v e r sible a lb e it slow l y . S in c e e ye c ont ac t with Al k y l P o l y g l yc osid e s p r odu c e s i rr it ation, i rr it ative ef f ec t s on the mu c ous m e mb r an e s of the g a str oint e stin a l tr ac t w e r e not un e x p ec t e d and this w a s c on f i r m e d in the 90 - d a y stu d y . A f t e r dis c ontinu ation of s a

mple a ppli cation ( r ec ov e r y g r oup ) , e x a min ation of the f

o re stom ac hs g ave e vid e n c e th at the ef

f ec ts w er e re v e r sibl e . The inh e re nt i rr it ation pot e nti a l r e qui re s sp ec i a l tho u ght in the r isk a ss e ssm e nt p r o ce ss. B a s e d on the dos i ng r e g ime us e d in the 90 - d a y o ra l to x i c i t y stu d y , sp ec i f ic p r obl e ms can ar ise if the dosing r e g ime is bolus - lik e , a s w a s the ca se in this stu d y . Oth e r a utho r s h ave p re vious l y r e po rt e d th at r e sults fr om g av a g e studi e s di f f e r f r o m those of a mo r e c ontinuous int ake ( di e t, dr inking w at er) ( H a ye s, 1 994; G reav e s, 1990; and E C ETO C , 2003 ) . Th e y d e monstrat e d th at g av a g e a dministration of i rr it ating subst an ce s p r o d u ce d lo ca l ul c erations in the r od e nt f

o re stom ac h due to p eak c o n ce ntr ations of a t e st subst an ce . I f the s ame dose w as a ppli e d in fee di n g or dr inking w at e r studi e s, or in c o r po rat e d into the di e t v i a mi cr o e n c a psul ation a s h a s b ee n re po rt e d f

or C itra l ( Di e t er , 1993) and c inn am a ld e h y de ( H e b ert , 1994 ) , no l e sions w er e ob s er

v e d in the f

o r e stom ac h. I

n a ll th e se c a s e s, dilution of the subst an c e p r ovid e s a g ood e x pl an a tion f or the di ffe r e nt re spons e s. Altho u gh f ee di n g studi e s would mimic di e t ar y e x posur e mo r e r e a listi ca l l y, bolus - like a ppli cations ar e a st at e - o f

- th e - art t ec hnique to e nsur e a c c ur ate dosin g . In o t h e r wo r ds, the boluslike a ppli cation ref

l ec ts a mo r e s e v e r e th a

n wo r st - ca s e f

ood e x posur e c ondition.7

F urth er m o re , the pH o f the raw Al k y l P o l y g l y c oside m at er i a l is a djust e d to a pH 12 to avoid mi cr obi a l c ont amin ation whi c h f urth e r e nh an ce s the i rr it ation pot e nti a l. Thus, sin c e on l y lo c a l re v er sible ef

f ec ts on the f

o re stom ac h b a s e d on i rr i t ation w er e ob s er v e d, the No - Obs er

v e d Adv er s e - E f

f ec t L e v e l (N OA E L ) f

o r s ys t e mic o ra l to x i c i t y w a s th e ref o r e c a l c ul at e d to be 1,000 m g /k g bw/d a y . b. Sub c hronic d e rmal to x i c i t y . A d er m a l stu d y f

or sub a c ute to x i c i t y with C 8 - 10 Al k y l P o l y g l y c oside ( 6 0 % ac tive subst an c e ) w a s c ondu c t e d in N e w Z ea l and white r a bbits with dos e s b e tw ee n 60 m g an d 3000 mg /k g bw/d a y a ppli e d to the int ac t skin f or 14 d a ys. Do s e s at 1500 m g /k g bw/d a y and a

bove indu c e d s e v er e skin i rr it a

tion a f t e r re p e at e d a

ppli c ation a s w e ll a s s e v e r a l c h an g e s i n h e m atolo g i c a l and c lini ca l p aram e t er s and t e sti c ul ar atr op h y . Mini m a l to mild skin i rr it ation w a s s ee n in dose gr oups st arting fr om 540 m g /k g bw/d a y , wh er e a s no c lini ca l, h e m atolo g i c a l or o r g an c h an g e s w er e re po rt e d at this dos e . At and b e low 180 m g / kg bw/d a y , no n e of the d e s cr ib e d a dv er s e e v e nts w e r e obs er

v e d. A NOA E L f

or s yst e mic ef

f ec ts w a s s e t at 540 m g

/k g bw/d a y . 5. C hronic tox i c it

y . Th er e ar e no c hr oni c /on c o g e n c i t y studi e s av a il a b l e on the a l k y

l po l y g l y c osid e s. How e v e r , c hr onic studi e s should not be re qui re d f or the a l k y

l po l y g l y c osid e s sin ce : 1 ) th er e w a s no s yst e m atic to x i c i t y obs e r v e d in the sub - c hr onic s tudi e s; 2) the a l k y l po l y g l yc osid e s ra

pid l y d e gra de to s u g ar and fatt y a c ids, both of whi c h do not p re s e nt an y to x i c i t y issu e s of c on c er n; and the a l k y l po l y g l yc osid e s ar e not mut a g e ns, r e p r o d u c tive to x ins or e ndo crine dis r upto r s. Th e r e is nothing to indi cate th at C 8 - 10 a l k y l po l y g l y c osid e s will h ave an y a dv e r se c hr onic ef f ec ts on hum ans or the e nvi r onm e nt. C 8 - 10 a l k y l po l y g l y c osid e s ar e a l rea d y c l e ar e d f or use and ar e e x e mpt fr om tol eran c e w ithout num er i ca l re str i c t i on und e r 40 C F R §§180 . 910 and 180.930. Oth e r a l k y

l po l y g l yc osid e s ( C 10 - 16 - a l k y

l g l y c os i d e s and C 9 - 11 - a l k y

l g l y c osid e s) ar e lik e wise c l ear e d und e r 40 C F R §§180.910 and 180.930 without num er i ca l re st r i c tion. F urth er , s e v e r a l F D A c l e aran c e s f or a l k y l po l y g l y c osid e s e x ist in c luding those f or m eat - r oom d e grea si n g , p e sti c ide a d

j uv ants und e r 21 C F R § 1 82.99 ( C 8 - 10 and C 9 - 11 a l k y l po l y g l y c osid e s ), and indi rec t f

ood c ont ac t (fe lt c l e aning o p erations) und e r 21 C F R P art 176. 6. Animal m e tabolism. Anim a l m e t a

bolism stud i e s show th at the a l k y l pol y g l y c osid e s ar e ra

pid l y h y d r o l y z e d into sug ar s and lon g - c h a in a l c ohols. W e b e r and B e nni n g ( 19 8 4) e v a lu at e d th e m e t a bol i sm of thre e a l k y

l g l y c os i d e s: o c t y

l g lu c oside (car bon c h a in of a l c ohol is C 8 ) , dod e c y l m a ltoside (car

bon c h a in of a l c ohol is C 12 ) , and h e x a d e c y l g l u c oside ( c arbon c h a in of a l c ohol is 1 6 ) . The ra diol a b e l e d sub s t an ce s w e r e a dminist ere d b y g av a ge t o fe m a le NM R I mi c e . T wo hour s af t e r tr e atm e nt the anim a ls w e r e s acr i f i c e d and r e l e v ant o r g ans w e r e an a l y z e d to d e t er

mine distribution in s p ec i f ic o r g ans. S tom ac h, int e stin e s, liv er , and kidn e y show e d the hi gh e st c o n ce ntr ations of ra dio ac tivi t y f or the c ompounds. Using e x tra c tion m e thods, it w a s shown th at Al k y l P o l y g l yc o s id e s ar e r ea di l y8

c l eav e d into g lu c ose and fatt y a l c ohol, whi c h is f u rth e r o x idi z e d to the c o rre sponding f att y ac id and p art l y in c o r

po r at e d i n no r

m a l fat m e t a

bolism. O c t y

l g lu c oside w a s r a

pid l y trans f

o r m e d into h y dr ophilic m e t a

bolit e s d ur ing int e stin a l and liv e r p a ss a g e , wh er e a s h e x a d ec y l g lu c oside sh o w e d a mu c h gr e at e r t e n d e n c y tow ar ds lipophilic m e t a bolism, re sultin g , e . g ., in p ref e re nti a l id e nti f i cation in the liv e r of ra diol a b e l e d p a lmit o y

l g l y c er id e s. Th e s e f

indi n g s ar e und e r lin e d b y the fac t th at D - o x id ation o cc ur s mo r e ea si l y in m e dium - c h a in fatt y a c ids th an in lon g - c h a in f att y ac ids ( S c h e i g ( 196 8 ) and P e tit e t al., ( 1982 )) . The f ollowing summ ar i z e s the m e t a bolic p a thw a y of Al k y

l P o l yg l y c osid e s. F i r st, the 8 - g l y c osidic bond b e tw ee n g lu c ose and lo n g - c h a in a l c ohol is h y dr o l y z e d. Gl u c ose and g lu c o s e oli g om er s e nt e r the c ar

b oh y dr ate m e t a

bolic p athw a y and ar e c at a boli z e d. L on g - c h a in a l c ohols ar e a c y l at e d to w ax e st er s, th e n e ith e r in c o r p o rat e d into e th e r g l y

c er olipids or o x id i z e d to fatt y ac ids. F in a l l y, the f

att y a c ids ar e e ith e r e st e r i f i e d t o e st e r g l yc olipids or o x i di z e d to ace t at e. Th e se t e st subst an ce s ( C 8 - , C 12 - and C 16 - Al k y l G l y c osi d e s) re p re s e nt the whole ran g e of possible c h a in l e n gth of non - b ran c h e d fatt y a l c o h ols ( C 8 - 16) f or c omm e r c i a l Al k y

l P o l y g l yc osid e s whi c h ar e c h ar a c t er i z e d in T a ble 1 A. Al k y

l P o l y g l y c osid e s with b ran c h e d fatt y a l c ohols ( C 9, C 11) will a lso ra pid l y d e gra de af

t e r o ra l int ake due to the h y d r o l ysis of the D g l y c osidic bond. T h e b r an c h e d fatt y a l c ohol will not in f lu e n c e the h y

dr o l ys is. Thus, a ll Al k y

l P o l y g l yc osid e s ar e trans f

o r m e d into g lu c o s e and f

att y a l c ohol ( b ran c h e d or non - b ran c h e d ) . T h e m e t a bolism of fa

tt y a l c o hols is dis c uss e d in mo r e d e t a il in the f ollowing p ar a gr a

ph while the m e t a bolism of g lu c ose is not f urth e r dis c uss e d. G l u c ose is r e g ar d e d a s s a f e af t e r o r a l int ak e . Fatt y a l c ohols r e p re s e nt the m a in di ffe r e n c e in the str u c tur e of the di f

fe r e nt Al k y

l P o l y g l yc osid e s. Th e r ef

o r e , di ffe r e nt fatt y a l c o h ols o cc ur a f t e r h y dr o l ysis of Al k y

l P o l y g l yc osid e s. The m e t a

bolism of th e se fa

tt y a l c ohols is d e s cr ib e d in mo r e d e t a il to show th at the re sulting f

att y a l c oh o ls ( C 8 lin ear , C 9 b ran c h e d, C 10 lin ear , C 11 b ran c h e d, C 12 lin ear , C 14 lin ear and C 16 lin ear ) b e l ong to a cat e g o r y with c o mp ara ble to x i c olo g i ca l p r op erti e s. The initi a l st e p in the m amm a li an m e t a bolism of p r im ar y a l c ohols is the oxid ation to t he c o r r e spondi n g car bo x y lic a c id, with the c o rre spondi n g a ld e h y de b e ing a transi e nt int er

m e di at e . Th e se car bo x y lic a c ids ar e sus c e ptible to f urth e r d e gra d a tion via a c y l - C oA int er

m e di at e s b y the mito c hondr i a l P - o x id ati o n p r o ce ss. This m ec h anism re mov e s C 2 units in a st e pwise p r o c e ss and lin ear ac ids ar e mo r e e f

f i c i e nt in this p r o ce ss th an the c o r r e sponding b ran c h e d ac ids. I n the ca se of uns aturat e d car

bo x y lic ac ids, c l eav a g e o f C 2 - un its c ontinu e s until a double bond is reac h e d. S in c e double bonds in uns aturat e d f att y ac ids ar e i n the c is - c on f i g ur ation, wh er e a s the uns aturat e d a c y

l - C oA int er

m e di at e s in the P - o x id a

tion c y c l e ar e trans, an a

ux i l i ar y e n z y

m e, e n o y l - C oA isom e ra se cat a l ys e s th e shi f t fr om c is t o trans. Th e r eaf t e r , β - o x id ation c ontinu e s a s with s aturat e d c ar

bo x y lic ac ids [ W HO, 1999 ] . An a lt er n ative m e t a

bolic p athw a y f

or a liph atic ac ids e x ists thr ou gh mi c r osom a l d e gra d ation via ω or ω - 1 o x id ation f oll o w e d b y β - o x id ation. This m ec h anism p r ovid e s an eff i c i e nt st e pwise c h a in - sho rt e ni n g p athw a y f or b ran c h e d a liph atic ac ids ( V e r

ho e v e n, e t al., 1998 ) . The a c ids f o r m e d fr om the long e r c h a in e d a liph atic a l c ohols can a lso e nt e r the lipid bio s y

nth e sis and m ay b e in c o rpo rat e d in phospholipids and n e utra l lipids ( B andi e t al, 1971 a &b an d Mukh er j e e e t al, 1980 ) . A sm a ll frac tion of the a liph atic a l c ohols m ay be e limin at e d un c h an g e d or a s the g lu c ur onide c o nju g ate ( K amil e t al, 19 5 3 ) . S imil ar to the d er m a l a bso r ption pot e nt i a l, o ra l l y a dminist ere d a l iph atic a l c ohols a lso show a c h a in - l e n gth d e p e nd ant pot e nti a l f

o r g a str o - int e stin a l a

bso r pti o n, with sho rt e r c h a in a lip h atic a l c ohols h avi n g a hi gh e r a bso r ption pot e nti a l th an lon g e r c h a in a l c ohols. W ith re g ar ds to th e blood - b ra in b arr i er,9

a c h a in - l e n gth d e p e nd ant a bso r ption pot e nti a l e x i s ts with the low e r a liph a tic a l c ohols and a c ids mo r e r e a di l y b e ing t ak e n up th an a liph atic a l c oho l s/ ac ids of long e r c h a in - l e n gth ( G e lm an, 1975 ) . The long c h a in a liph atic car bo x y lic a c ids ar e e f

f i c i e nt l y e limin at e d so th at a liph atic a l c ohols will not h ave a tissue re t e ntion or bio acc umul ation po t e nti a l ( B e v an, 2001 ) . L o n g e r c h a i n e d a liph atic a l c ohols within this cat e go r y m a y e nt e r c ommon lipid bio s y nth e sis p athw a y s and will be indistin g uish a ble fr om th e lipids d er iv e d fr om oth e r sour c e s ( in c ludi n g di e t ar y g l y ce r id e s) ( K a bi r , 1993; 1995 a , b ) . I n summ ar y , lo n g c h a in e d a l c ohols ar e eff i c i e nt l y m e t a

bolis e d and th e r e is limit e d pot e nti a l f

or re t e ntion or bio acc umul a ti o n f or the p ar e nt a l c ohols and th e ir biotrans f o r m ation p r odu c ts. 7. Me tabolite tox i c olog

y . Th er e ar e no m e t a

bolit e s of to x i c olo g i ca l c on c er n. 8. Endo c rine disruption . B a s e d on av a il a

ble studi e s, th er e is no in f o r m a tion or e vid e n c e to indi cate th at the a l k y l po l y g l yc osid e s ( C 8 - C 10 ) ar e e nd o cr ine dis r upto r s. a. I mpairm e nt of Hormonal Fun c tions -E- s c r e e n and r e porte r ge ne assa

y . The M C F - 7 p r oli f

eration a ss a y ( E - Sc ree n Ass a y ) and the M C F - 7 r e po rt e r g e n e a ss a y w e r e us ed a s p re di c to r s o f pot e nti a l e str og e nic a c tivi t y ( W illin g , M e ssi n g e r and Aul m ann, 2004 ) . I n the E s cree n, th e indu c tion of c e ll p r oli feration ( mitog e n ic ef f ec t) in M C F - 7 ce lls, an e str og e nd e p e nd e nt hum an b rea st tumour ce ll lin e , is d e t er min e d. A wide r an g e o f c on c e ntrations of the t e st subst an c e is c o mp are d to a n e g ative c o n tr ol ( m e dium) and to re f e re n c e subst an ce s ( 17 - 0 - e stra diol and bisph e nol A ) . C 12 - 16 a l k y l po l y g l yc oside c on ce ntr ation ran g e s of 0. 1 - 10,000 nmol w er e t e st e d in this a ss ay . No ef f ec ts w e r e not e d with Al k y l P o l y g l yc oside c on c e ntrat ions up to 10 tim e s hi gh e r th an the 0.1 nmol positive c ont r ol. The ef f ec ts of C 12 - 16 Al k y

l P o l y g l yc osid e s w er e a lso inv e sti g at e d in a re po rt e r g e ne a ss a y . In th is a ss ay , th e indu c tion of lu c i fera s e ac tivi t y in st a b l y trans f ec t e d M C F - 7 ce lls ( pl a smid p V I T tk - Lu c) , whi c h e x p re ss the l u c i fe r a se g e n e und e r t h e c ontr ol of wild t y pe vit e llo g e nine A2 p r omot e r ( d e r iv e d fr om X e nop u s l ae vis ) , is a ss a ye d. T h e lu c i fera s e ac tivi t y c o rre l at e s di r e c t l y with t he e str o g e nic po t e n c y of the t e st e d li g and ( t e st sub st an ce) . I n c ontra st to the E - S cr e e n a ss a y in wh i c h on l y c e ll p r oli fe r ation is an a l ys e d, in this a ss a y an e str o g e n - s p ec i f ic re sponse on the g e ne e x p re ssion l e v e l is m ea sur e d . T ran s g e ne re po rt e r g e n e s yst e ms ar e c onsid ere d su p er ior to the hum an M C F - 7 ce ll line s yst e ms due to th e ir b e tt e r sp ec i f i t y and h i gh e r thr ou ghput. In the g e ne r e po rt e r a ss a y , no c o n ce nt ration - d e p e n d e nt indu c tion of lu c i fe r a se w a s not e d with the C 12 - 16 Al k y l P o l y g l yc osid e s at c on c e ntrations up to 100,000 tim e s hi gh e r th an th e positive c ontr ol. B a s e d on th e se r e sults, th er e is no indi cation th at Al k y l P o l y g l y c osid e s, i n c luding C 8 - 10 a l k y l po l y g l yc osid e s, m i ght a c t a s an e ndo c r ine modul ato r .10

C. Aggre gate E x posure As p art of the tol e r an c e r ea ss e ssm e nt p r o ce ss f or the a l k y

l po l y g l y c osid e s, t he A g e n c y re vi e w ed the s afe t y d at a b a se and c on c lud e d th at the a l k y l p o l y g l y c osid e s ar e low e r t o x i c i t y subst an c e s. In gre di e nts th at the A g e n c y c l a ssi f i e s a s b e ing o f l ow e r to x i c i t y ar e g e n e ra ll y c onsid e re d to pose no c on cer ns to hum ans o r the e nvi r onm e nt. Addi n g us e s in antimi cr obi a l f o r mul ations will a dd little if a n y in c r e m e nt a l r i sk c omp are d to the unr e s tr i c t e d use of C 8 - 10 a l k y l po l y g l y c osid e s in p e sti c ide p r odu c ts a

ppli e d di rec t l y to f

ood cr ops b oth p re - and posth ar v e st. 1. Di e tary ex

posu r e. Di e t ar y (f ood and dr ink i ng w at er) and re si d e nti a l ( d er m a l and inh a l a

tion) e x posure s ar e possible fr om the use of C 8 - 10 a l k y l po l yg l yc osid e s a s an in ert in gr e di e nt in antimi cr obi a l f o r mul ations. Al k y l po l yg l yc osid e s, i n c luding C 8 - 10, h av e b ee n d e monstrat e d to be r e a di l y biod e gra d a bl e , whi c h re du c e s the lik e li h ood of re sidu e s on f ood. F or the s am e r e a son, no s i gni f i cant c ontr ibutions to drinking w at e r ar e e x p ec t e d fr om the use of C 8 - 10 a l k y l po l y g l y c osid e s a s in ert in gre d i e nts in p e sti c ide p r odu c ts. Al k y l po l y g l y c o sid e s h ave low to x i c i t y and e x posur e to re sidu e s a bo v e to x i c i t y l e v e ls of c on c er n ar e not anti c ip at e d. A qu antit ative di e t ar y r i s k a ss e ssm e nt f or the a l k yl po l y

g l y c osid e s is not n e ce ss ar y sin c e th e r e ar e no to x i c i t y e ndpoints of c on c e r n th at ar e a sso c i at e d with di e t ar y i n g e sti o n of the a l k y l po l y g l yc osid e s. The g a s t r ic i rr it ation th at re sult e d in the sub c hr onic o ra l stud y is p arti c u l ar to the n atur e of the stu d y ( dosi n g b y g av a g e with a s u rf a c t ant) and would not o cc ur fr om di e t ar y int ak e of low l e v e ls of the a l k y

l po l y g l yc osid e s. Nonth e l e ss, a qu antit ati v e r isk a ss e ssm e nt h a s b e e n c ondu c t e d usi n g the s y st e mtic NO E L fr om the sub c hr onic stu d y . S p ec i f i ca l l y, a Re fe r e n c e D ose ( R f D) of 10 m g

/k g / d a y w a s c a l c ul at ed b a s e d on a N OA E L of 1 , 000 m g /k g /d a y in the sub c hr onic o r a l to x i c i t y stu dy in rats usi n g a 10x un cert a int y f

ac tor f o r int er - and intr a - sp e c i e s e x tra pol ation. The c hr on i c P opul ation Adjust e d Dose (c P A D ) is a lso 10 m g /k g /d a y . No a ddition a l un cert a int y f a c tor w a s a dd e d to the c P AD ca l c ul ation a s the re p r o d

u c tive and d e v e lopm e nt a l toxi c i t y studi e s do not i ndi cate an y a ddition a l sus ce ptibili t y f

or in fants and c hildre n. The c hr onic d i e t ar y e x posur e due to C 8 - 10 a l k y l p o l y g l y c osid e s use a s an i n ert ingre di e nt in disin fec t ants ( s aniti z er) u s e d on f ood - c ont ac t sur f

a ce s w a s a ss e ss e d. This a s s e ssm e nt ca l c ul at ed the D a i l y Di e t ar y Do s e ( DDD) and th e Estim at e d D a i l y Int ake ( ED I) . T h e a ss e ssm e nt c onsid ere d: a

ppli c ation r at e s, re sidu a l solution or qu anti t y of solution re m a ining on the tr e at e d surfa c e without r insing w ith pot a ble w at er , sur fa c e are a o f the tr e at e d sur fa c e whi c h c om e s into c ont ac t with f

ood, p e sti c i de mi gr ation fr a c tion, an d bo d y w e i ght. T h e se a s s umptions ar e b a s e d on F DA g uid e lin e s ( F DA , 2003 ) . The E D I c a l c ul ations p r e s e nt e d in this a ss e ssm e nt a ssume th at f ood can c o nt ac t e ith e r 2,000 c m 2 or 4,000 c m 2 ( 50% and 1 00% of the F DA wo r st - c a se s ce n ar io) of t reat e d surfa c e s, and th at 10% of the m at er i a l would m i gr ate to f ood. The 1 0 % mi gration r ate is b a s e d o n Ag e n c y R e sid e nti a l S t and ar d Op e r ation P r o c e dure s. Th e s e d a i l y e stim at e s w e r e c ons e r v ativ e l y us e d to a ss e ss c hr onic di e t ar y r isks ( i. e . , p e r c e nt c hr onic popul ation a dju s t e d dose or % c P AD ) .11

2 x

2 x Assuming a l e v e l of 2,1 0 0 ppm of C 8 - 10 a l k y l po l y g l y c osid e s in the use di l ution solution, the f ollowing E D I is ca l c ul at e d: E D I: 10 0 % F DA W o r st C a se E D I = 1 m g

/solution cm 2,100 μg

1,000 mg x 4,000 cm 2

p er son/d a y x 10% = 840 μ g /p er son/d a y OR 0.84 m g /p er son/d a y E D I: 5 0 % F DA W o r st C a se E D I = 1 m g

/solution cm 2,100 μg

1,000 mg x 2,000 cm 2

p er son/d a y x 10% = 420 μ g /p er son/d a y OR 0.42 m g /p er son/d a y The a bove ca l c ul ation is f

or use of the subst an c e i n p r odu c ts th at ar e u s e d i n publi c - eati n g fac iliti e s, whi c h is wo r st - ca s e . U s e in f ood - p r o ce s s ing pl ants would y i e ld dr am ati ca l l y l o w e r e x posure s. Assuming bo d y w e i ghts f or m e n ( 70 k g ) , wom e n ( 60 kg ) , and in f ants and c hildre n ( 15 k g ) , the f ollowing p e rce nt D DD v a lu e s ar e ca l c ul at e d: DDD: 100% F DA W o r st C a se

• M a l e : 0.84 m g /p er son/d a y ÷ 70 k g

/p er son = 0.012 m g

/k g/d a y • Fe m a l e : 0.84 m g /p er son/d a y ÷ 60 k g

/p er son = 0.014 m g

/k g/d a y • In fants/ C hildre n: 0.84 m g /p er son/d a y ÷ 15 k g

/p er son = 0.056 m g

/k g/d a y DDD: 50% F DA W o r st C a se

• M a l e : 0.42 m g /p er son/d a y ÷ 70 k g

/p er son = 0.006 m g

/k g/d a y • Fe m a l e : 0.42 m g /p er son/d a y ÷ 60 k g

/p er son = 0.007 m g

/k g/d a y • In fants/ C hildre n: 0.42 m g /p er son/d a y ÷ 15 k g

/p er son = 0.028 m g

/k g/d a y B a s e d on th e ca l c ul at e d DDDs and the c P AD v a l ue of 10 m g /k g /d a y , th e f

ollowing p e r ce nt c P AD e stim at e s ar e d er i v e d: % c P AD: 100% F DA W o r st C a se

• M a l e : 0.012 m g /k g /d a y ÷ 10 m g

/k g /d a y = 0.1 2 % c P AD • Fe m a l e : 0.014 m g /k g /d a y ÷ 10 m g

/k g /d a y = 0.1 4 % c P AD • In fants/ C hildre n: 0.056 m g /k g /d a y ÷ 10 m g

/k g /d a y = 0.5 6 % c P AD % c P AD: 50% F DA W o r st C a se

• M a l e : 0.006 m g /k g /d a y ÷ 10 m g

/k g /d a y = 0.0 6 % c P ad12

• Fe m a l e : 0.007 m g /k g /d a y ÷ 10 m g

/k g /d a y = 0.0 7 % c P ad • In fants/ C hildre n: 0.028 m g /k g /d a y ÷ 10 m g

/k g /d a y = 0.2 8 % c P ad i. Food. F ood c ont a c t e x posure s ar e w e ll b e low 10 0 % of th e c P AD, and ar e th ere f o r e b e low E P A ’ s e st a blish e d l e v e l of c o n c er

n f or a ll U. S . subpopul ations. The c ombin e d e x posur e f or m a l e s, fe m a l e s, and in f

ants and c hildre n is < 1% of th e cP AD, e v e n f or th e 100% wo r st ca se s ce n ar io. ii. Drin k

ing w ate r. D r inking w at e r e x posur e is hi gh l y unlik e l y f r om the use of Al k y

l ( C 8 - C 10 ) P o l y

g l yc osid e s a s an in ert in gr e di e nt in antimi cr obi a l p e sti c ide p r od u c t s. Mo re ov er , a l k y

l po l y g l yc osid e s ar e r e a di l y biod e gr a d a

ble a c c o r di n g to OE C D cr it er i a , wh i c h re du c e th e lik e lihood of r e sidu e s on f ood. F urth er m o re , the A g e n c y did not anti c ip ate si gni f i cant c ontr ibutions to dr inking w at e r wh en a ss e ssing the r isks fr om t h e se c h e mi c a ls a s in ert i n gr e di e nts in p e sti c ide f o rmul ations a

ppli e d to gr o wing cr ops and anim a ls. E x posu re s to re sidu e s a

bove to x i c i t y l e v e ls of c on cer n ar e not anti c ip at e d. D. C umulati v e Eff

ec ts Al k y l ( C 8 - C 10 ) po l y

g l yc o sid e s do not sh ar e a c ommon m ec h anism of to x i c i t y with an y oth e r p e sti c ide ac tive and/or in ert ingre di e nt. E. Saf e ty D e te rmination The p r opos e d use o f a l k yl ( C 8 - C 10 ) po l y g l y c osid e s will not in crea se the c ur r e nt e x posur e due to oth e r non - p e sti c ide e x posure s. The f oo d - c ont a c t s aniti z e r use f or a ll popul ation sub gr oups c ombin e d is < 1% of the c P AD. As p art of the tol e r an c e r ea ss e ssm e nt p r o ce ss f or the a l k y

l po l y g l y c osid e s, t he A g e n c y re vi e w ed the s afe t y d at a b a se and c on c lud e d th at the a l k y l p o l y g l y c osid e s ar e low e r t o x i c i t y subst an c e s. W ith the e x ce ption of lo c a li z e d i rr it ation at hi gh c on ce ntrations, the s a fe t y t e st d ata c l e ar l y shows th at the a l k y

l po l yg l yc osid e s ar e p rac ti c a l l y non - to x ic af t e r both ac ut e and re p eat ed e x posure s. The one e ff

ec t th at w a s obs er

v e d in the sub - c hr onic stu d y – i rr i t ation of the f o re stom ac h

– is t y

pi ca l of surf

a c t ants, su c h a s th e so a

p s a lts, whi c h ar e list e d in §180.950. In gre di e nts th at the A g e n c y c l a ssi f i e s a s b e ing o f l ow e r to x i c i t y ar e g e n e ra ll y c onsid e re d to pose no c on cer ns to hum ans o r the e nvi r onm e nt. Addi n g us e s in antimi cr obi a l f o r mul ations will a dd little if a n y in c r e m e nt a l r i sk c omp are d to the unr e s tr i c t e d use of C 8 - 10 a l k y l po l y g l y c osid e s in p e sti c ide p r odu c ts a

ppli e d di rec t l y to f

ood cr ops b oth p re - and posth ar v e st. Addition a l l y, a l k y

l po l y g l yc osid e s sur f

a c t ants in the ran g e o f C 6 - C 1 6 ( C A S Nos. 68515 - 73 - 1, 132778 - 08 - 6, 110615 - 4 7 - 9) ar e c l a ssi f i e d a s G e n e ra l l y Re c o gni z e d a s S af e ( G RA S ) b y F DA f

or use in the c l eani n g of f

o o d p r odu c ts; the c l eani n g of e quipm e nt us e d to p r o ce ss f ood; the m anu fac tur e of p r od

u c ts th at c ome in c ont ac t with f ood, fr uits and v e g e t a

b l e s in c luding m e at and poultr y c ar c a ss e s; the c l e aning of m at er i a ls th at s ubs e qu e nt l y c ome in c ont a c t with f ood, p a p er ,13

car dbo ar d, pl a stic or st a i nl e ss st ee l lin e s and or p r odu c tion v e ss e ls; and the c l eani n g and s aniti z ing of surfa c e s in f ood p re p ar ation ar e a s. 1. U

.S. popu la ti on. T he % c PA D ca l c u l at e d f or ma l e s (0.06 - 0.1 2 %) an d f emale s (0. 0 7 - 0.14%) i s b el ow th e l e v e l of c on c e rn. B a s e d on th e s e c on s e rv ati v e e xpo s ure e s t i mat e s , th e re i s a r e a s on ab l e c e rt a i nty th a t no h ar m w il l r e s u l t t o the U . S . popu lat i on f rom th e a ggr e g at e e xpo s ure t o a l k y l ( C 8 - C 10 ) po l y

g l yc osid e s. 2. In

f an t s and c h ild

re n . FFD CA S ecti on 408 r e qu ir e s an a d d i t i on a l t e n f o l d mar g i n of s a f

e t y f or the pro te c ti on of i n f

ant s and c h il dr e n i n ca s e of thr e s h o l d e ff ect s t o a cc ount f

or pr e n a t a l and po s tn a t a l t o x i ci t y , and an i n a d e qu at e t ox i c it y d atab a s e . W

h e re a n a d e qu at e and r e l iab l e d atab a s e i s av ai l ab l e and th e re i s a la c k of e v i d e n ce f or i n c r ea s e d s u s c e p t i b i li ty , the F Q P A s a f e t y f act or ma y be r e du ce d o r r e m o v e d. An e v al u at i on of s u s ce p t i b il i t y and un ce rt a i nt y i ss u e s a ss o ci ate d w ith a l k y l ( C 8 - C 10 ) po l y

g l y c osid e s h a s b ee n p e r f

orme d, and E P A h a s pr e v i ou s l y r e du ce d the F QP A s a f e t y f act or f rom the d e f

au l t 10x t o 1 f or the f o ll o w i ng r ea s o n s : • T he av ai l ab i lit y o f a s ub s t ant i a l and sc ie nti f ic a ll y s o und mamm a lian t ox i c o l o gy d atab a s e th at i n cl u d e s ac ute , r e p e at do s e , r e prod u cti on, d e v e l op me ntal , and e nd o c r i n e d at a f or a l k yl po l y g l yc osid e s , i n cl ud i ng C 8 - C 1 0 ; • O E CD te s ti ng i nd i c ati n g th at th e re w a s no e v i d e n c e of d e v el op me nt a l t ox i c i ty or mal f orm ati ons i n the d e ve l op i ng of f s pr i n g ; • T h e r e i s no e v i d e n c e t o s u g g e s t th a t a l k y l po l y g l yc osid e s, in c luding C 8 - C 1 0 , w ou l d h av e an a dv e r s e e ff

ec t on the r e pr o du cti v e or g an s ; • Al k y l po l y g l yc osi d e s, in c luding C 8 - C 1 0 , do not b el ong t o a c l a s s of c h e mi cal s k no wn or s u s p ecte d of h av i ng a dv e r s e e ff ect s on the e s tro g e n r e ce p t or or e ndo c ri ne s ys tem . A l k y l po l y g l yc osid e s, i n c luding C 8 - C 10 , h av e b ee n e v al u at e d i n ac ute , r e p e ate d do s e , d e v el op m e nt a l , and c hr o n i c t ox i c i ty s tud ie s cap ab l e of d ete c ti ng e ff ect s on e ndo c r i ne me d i at e d e v e nt s and h av e not d e m on s tr ate d any e ndo c r i n e - r e lat e d e ff ect s . T he % c PA D ca l c u l ate d f or i n f ant s and c h il dr e n (0 . 28 - 0.56%) i s b el ow th e l e v e l of c on ce rn. B a s e d on th e s e c on s e rv ati v e e xp o s ure e s t i m ate s , th e re i s a r ea s on ab l e ce r tai nty th a t no h arm w i l l r e s u l t t o i n f ant s and c h il dr e n f

rom t he a g gr e g at e e xpo s ure t o a l k y l ( C 8 - C 10 ) po l yg l y

c o s id e s. F. I nte rnational T

ole ran ces Th er e ar e no C O D EX MR L s e st a blish e d f o r a l k y l ( C 8 - C 1 0 ) po l y

g l y c osid e s.