### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON , D

. C

. 20460

MEMORAN D UM Date : 29-SEP-2015 OFFICE OF CHE M ICAL SAFETY AND POL LUTION PRE VENTIO N



### SUBJECT: A lph a - C hloroh yd rin. Human Health Assessment Scoping Do cu m e nt and Draft Human Healt h Risk Assessment in Sup port of Registrati o n Review. PC Code: 117101 DP Barcode: 04 28647 Decisio n No.: 507994 Regi s trati o n No.: 42882-2 Petit io n No.: NA Re g ulat o r y Actio n : Reg i str atio n Review Risk Asse ss ment Ri s k Assess m e nt Type: Scoping and Reg Review Case No.: 4120 TXR No.: CAS No.: 96-24-2 MRID No.: NA 40 CF R: NA 

# j)
F ROM : Joshua Godshall ,

## Bio~**~** 

# O" 

# .fit/ 

# V( Th omas Bloem ,

## Chemi~**~** • _L1 

### Monique M. Perron, Sc.D. , Toxicolog i st

## ~ 

## T ..£,1./V'-- 

### Ri sk Assessment Branch I (RA B 1 ) Health Effects Division (HED , 7509P) 

### THROUGH: Thurston G. Morton , Acting Branch C hief Geor ge F. Kramer , Ph.D. , Sen ior Chem ist**~_,,,--** 

### RAB I/ HED (7509 P) 

### TO: Matthew Manupella, Chemical R eview Manage r Cathryn Bri tton , Team Leade r Ke v in Cos tello, Branch Chief Pesticide Re-Evaluation Di v i s ion (PRD/7508P) Attac hed i s HED ' s human health r isk assessment sco ping d oc ument for a lpha-chlorohydrin (3

- chloro-1 , 2-propanediol) to support R egistration R eview. A s part of R eg istration R ev iew, PRO of the Office of Pesticide Program s (O PP ) has requ ested that H ED eva lu ate the h aza rd and expos ure data and conduc t occupational and residential expo s ure asses s ments , as nee ded , to es timate th e risk to human health that will result fr o m the currently regi s tered u ses of pesticide s . T his memorandum se rves as H E D ' s scop in g docum e nt AND draft human health ri sk assessment of the dietary , occupationa l and residentia l exposure , and aggr egate risk from the registered uses o f a lpha-chl o roh y drin
.

Page I of 1 5Alpha-Chlo rohydrin Human Health Ri sk Assessment D428647

1.0 2.0 

### 2. 1 2.2 2.3 3.0

### 3 .1 3.2 

### 3
. 3 3.4 4.0 

### 4 .1 

### 4.2 5.0 6.0 7.0 8.0 9 .0 10.0 11.0 12.0 

### Tab l e of Co ntent s Exec uti ve Summary
. ...... ........ .......... ......... ..... ............... . .............................. ........ ............. .. .......... .... .... . ..... ...... 3 HED R eco n1111end ations
........... . .................. . ............... . ............... .. ................. . ............. . ... . ......... . ................. .. .. 3 

### Da ta Defici encies
.. .. . .. .. .. .. . ... ..... ... . .. .. ... . .... .. .. ... . ... . ... . ... ..... .. . .. .... .. . . ... . .. ......... . .. . ............... 3 T olerance Co ns iderations
......................................................... . ......... ..... ........ ... . .. . .......... 3 Label Rec ommendatio n s ...... .......... . ..... . ..... .. .. .. ..... ....... ..... .. . ...... . ........................ .. ..... . ..... 3 In troduction
. ............................... .. .. .. ... .... .... .................... . .... ...... ..... . ....... .. . . ........ ......... .... ... . ........ .. .................. 4 

### Che1nical Id e ntity
..... ..... ...... ...... ...... ...... ......... ........ .... ............. . ................ .. ..... ......... .. ...... 4 Ph ys ical/Ch emical Charac t e ris ti cs ............................. ..... ... ... .. ............ . .... . .......... ..... ........ 4 Pe s ticide Use Patte rn ............. . ....... ... . .. ... .. . ... . ... . ..... .. . .. ..... .. .. .. ................ . .. . ...... .. . .. . ....... .. . 4 Con s ideration of Environme nt a l Ju stic e ... .. .................................................... .. . .. ..... .. ..... 5 Hazard C haract eri zat ion and Dose-Response Assessment
.......... . ... ........... .... ............................. .. ................... 5 

### Toxicology Analysi s ........ .. .. .. .. .. . . .. . .. ... .. .. .. ..... . .... .. .............................. .. .... . .... .. . .. .. . .. ...... . 5 Con s ideration of Tox icity to Ch ildren ................................................ .. . ... .. . . ...... .. . .. ..... . . . 6 Di etary Exposure and Ri s k Assessment
............ . ....... . .. .. ............. ... .............. .... ........................... ... .................. 6 Resid ential (Non-Occupa ti onal) Exposure and Ri s k A ssess ment... ... .. .. .. ......... .. ............ ............................. ..... 6 Agg r ega te Expo s ure/ Ri sk C ha rac teri za tion
...................................................................................................... 6 Cumulative Exposure / Ri sk C haracteri za ti on .................................................................................................... 6 Spray Drift
................................................................................ . ....................................................................... 7 Public H ea lth and Pe s ticid e E pidemi o logy Data
................ ... .......... .......... . ................. . .. . . .... ...... ............. .. ....... 7 Occupationa l Exposure / Ri s k Cha racteriza ti on ............................................................................. ... ................. 7 References ........................................................................................................................................................ 7 Appendix A. Toxico logy Protile and Executiv e S umm aries
. . . ....... ...... .. . ........ . .. ..... ...... ...... . ............. . ..... ..... ............ . ... 8 

### A. I To x icolog y Data Req uirement s .. ..... .... ..... .............................................. .. ......... . .. .. .... .. . .. . 8 A.2. Tox ic it y Profi les ..................................................................... ... ......... ......... . ........ .. ......... 9



# . ... . ... 

# . .. . 

# .**~** 

## .. ... . .. 

# . .

Page 2of15A lpha-Chlorohydrin Human H ea lth Risk Assessment 

### 0428647 

### 1.0 E x ec utiv e Summ ary H E D has p repared a qu al i tat ive hu m an- h ealt h risk assessme n t to s u pport reg i strati o n rev i ew for the use of alpha-chlo rohydrin (3-ch loro - 1 ,2- propanediol ; 3-MCPD; U-5897). W h en writ i ng this risk assessment, HED primarily considered the followi n g two documents: (i) AlphaChlorohydrin: Human Health Risk Assessment for Proposed Use as a Rodenticide (R. Mitkus , 17 August 2006; 0326010) and (ii) HED 's Haza rd and Science Policy Council (HASPOC) recommenda t ions (U. H abiba, 29-Septembe r-20 1 5, TXR # 0057207). Alpha-chlorohydrin was fi r st registered in 1983 and was cancelled in 1991 due to m aintenance fee non - pa yme nt ; it was then newly registered in 2006. The only reg i stered use for a lpha

chlorohydrin is as a tamp e r-proof bait station/bait applicat ion delivery system for elimination of Norway rat s. One product (Epibloc® Rodenticide, produced by Gametrics , Ltd.) is currently registered containing a lpha-c hl orohyd ri n , wh ich i s for r eta il sale to and u se o n ly by certi fied applicators or perso n s under their direct supervis i on and only for th ose u ses covered by th e Certified App l icator 's certification. Alpha-chlorohydrin i s approved for use in and around the indoors of commercial/ indu s trial facilities and sa nitary sewers , the label states not to use the product in any faci li ty where ch il dren ma y be present, and the re are no outdoor uses permitted. As a restricted-use pesticide (RUP), there are no proposed or current reg i strations th at a ll ow for res i dentia l use. Because n egl i gib l e exposu re i s expected from the cu rre n t l y - reg i ste red prod u ct, a quantitat ive human h ea lth risk assessment has not been prev iously cond u cted. No data deficienc ies were identified fo r the toxicology, residue chemistry, or occupational / residential exposure databases. Die t ary exposure is not expected and occupational/residential expos ures are anticipated to be negligible from the currently reg i stered u ses of a lpha

chlorohydrin. Based o n the n eglig i ble exposure pote n tia l of the currentl y reg i ste r ed uses of alpha-chlorohyd ri n, no toxicological po i nts of departu re ( P O Os) have been estab li s h ed. As a result , quantitative risk assessments are not necessary to conc lude with reaso n able certa in ty that exposures to the currently reg i stered use s of alpha

- c h loroh yd rin do not pose a s ignificant human health risk. • 

### 2.0 H E D R e comm e ndatio n s HED ha s no objection for continued registration of the current alpha

- chlorohydr in pesticide product. 

### 2. 1 Data Defi c i e nci es

• None. 

### 2 . 2 T o l e r a nc e Con s id e ra tion s Alpha-chlorohydrin is not a food

- use chemical. There are current ly no U.S. tolerances established for a lpha

- c hl orohydri n . 

### 2
. 3 Labe l R e comm e nd a ti o n s HED ha s n o labe l recommendations at th i s time.

Pa ge 3of15

### Alpha- Chloroh y drin Human He alth Ri s k Assess ment 0 42 8 647 

### 3 .0 Intr o du ct i on Alpha-chlorohydrin is a rodenticide regi s t e red to control Norwa y rat s . The acti v e ingredient ( ai ) e x i s t s as a racemic mixture of R- 

### and S -alpha-chloroh y drin causing reversible inf e rtility in mal e animals at relative l y low do s es . The structure , chemical name, and other identifiers are found in th e chemical ident i ty table (Tab le 3.1.1 ). 

### 3 .1 C h e mi ca l Id e n t i ty
Ta bl e 3.1. 1. No m e ncl a tur e o f a-C h l o r o h y d ri n .

Cit C he mi c al s tructure

# HO,~CI

Co mm o n name a-chl o ro l w <lrin C o mp a ny ex p e rim e nt a l n a me U-5 897 I U P A C Name (RS)-3

- c h lo ro p ro p y lcn c g l y c o l C A S name 3

- c hl o r o -1. 2

- oro o aned i o l C A S regi s tr y num be r 96

- 24

- 2 E n d -u s e product ( E P ) Epibl oc ® Rod e nticidc ( I % alpha-chl o r o hy drin) 

### 3.2 P h ys i cal/C h e mi ca l C h a r a cteri sti cs Alpha-chlorohydrin ' s vapor pressure is not included due to incon s i s te ncies in v alue s between the Food and Drug Administration (FDA) database and the Pesticide Properties Database.

Tab l e 3.2. 1. Phv s icoc h e m ica l Properties of a-C hl o r ohyd rin
. Paramete r Value Reference Me ltin g p o int -4 0 ° C D e n s ity 1
. 322 g/ cm 3 at 20 ° C Th e P esticide pr op ertie s D ata b a s e: W ater so lubility I 00 0 g/ L a t 20 ° C O c tano l/wa te r parti t io n coeffic i en t . htt p : //s it c m . he rts . ac . uk/aeru/ i upac/ i n dcx
. htm L og P ow - 0. 85 a t 20 ° C and p H 7 

### 3.3 P est icid e Use P att e rn A lpha-chloroh y drin is curre ntl y regi s tered under one la b e l as E pibloc ® Rodenticide (1 % a lph a chl o roh y drin p e r 5-gram edible bai t/sach e t ; E PA R eg . N o . 42882- E) to control N orwa y rat s. Each bait-containing sachet (placepack) i s placed by an app li cator in s ide tamp e r - re sistant bait s tations in a n d around comm e rcial/i ndustrial faci l it ie s , and san i tary s ewers . As a RUP , th e product label sp ec ifies that sa le and use i s to and by , re s pectiv e ly , c ertified applicator s or p e r so n s und e r the ir direct s upervi s io n o nl y, and th a t bait

- c o nt a ining sachet s " must be pl a c e d in ta mp e rproof bait boxe s or in location s not acce ss ible to childr e n , pets , dome s tic anim a l s , or wildlif e . " W ith negl igib le exposure and considering that industrial rodenticidc application s are not a cov e red use und e r the Work e r Protection Standards ( WPS) , no p e r s onal-protective equipm e nt ( PPE ) i s requ i r e d for alpha- c hloroh y drin
.

Pag e 4 of 1 5Alpha-Chlorohydrin Human Health Ri s k Asse ss ment 

### 0 428647 

### 3.4 Conside r ati o n o f E n vi r onm e n ta l J u st ice Potential areas of environmental justice concerns, to the extent possible , were cons idered in thi s human health risk asse ss m e nt , in accordance with U.S. Executive Order 12898 , "Federal Actions to Addre ss E nvironmental Justice in Minori ty Populations and Low -I ncome Populations , " (htt p: //www.epa. uov/ compl iance/ environmenta lj ustice / resourc es/ policy/ exec order 12898 .pd 

## D. As a part of every pesticide ri sk assessment, OPP considers a la rge variety of consumer s ub groups according to we ll -established procedures. In line with OPP policy , HED estimates risks to population subgroups from pesticide exposures that arc based on patterns of that subgro up 's food and water consumption , and activities in and around the hom e that involve pesticid e u se in a residential se tting. Exten s i ve data on food consu mption patterns are compiled b y the US DA under the Contin uin g Surve y of Food I ntake by Indi vid ual s (CSF II ) and are used in pesticide risk assessments for all regi ste r ed food uses of a pesticide. These data are analyzed and categorized by subgroups ba se d on age , seaso n of the year , ethnic group , and reg i on of the country. Additionally , OPP is able to assess dietary exposure to smaller, specia l ized subgroups and exposure assessments are performed whe n conditions or circumstances warrant. Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated ri sks for adult applicators and for toddlers, youth s, and adults ente r ing or playing on treated areas post-application are evaluated. Further considerat ions are c urre ntly in de ve lo pm e nt as OPP ha s committe d r eso urces and ex perti se to the development of spec ialized software and models that consider expos ure to by s tander s and farm workers as well as lif es ty le and traditiona l dietary patterns among specific subgroups
. 

### 4. 0 Haza r d C h a rac te r iza ti o n a n d Dose

- Res pon se Assess m e nt 4. 1 Tox ico l ogy An a lys is No g uid el in e st udies are available in the a lpha-ch l orohydrin database; howe ve r , numerous literature s tudies were used to evaluate it s h azard potential. Guideline studies are required for non-food u se pesticides in accordance with th e current 40 C FR Part 158 Toxicology Data Requirements; however , the HASPOC concluded based on a weight-of

- evidence approach that these studies are not requ i red at this time du e to the lim ited exposu re pattern of alp h achlorohydrin and the qualitative nature of th e risk assessment (U. Habiba , 29-September

- 20 1 5, TXR#005 7207). If th e u se patterns were to c hange , or new policies /procedures are put into place , then the need for the se studies ma y be revisited. The TOXLINE (Natio n al Library of Medicine) database lit erature search did n ot id en tify any new to x icological in format ion not already con s id ered. A lph a-c hl orohyd r in exists as a racemic mixture of 

### R- and S -alpha-chlorohydrin. It is moderat e ly toxic fo ll owing acute oral exposure and ha s a low order of ac ut e toxicity via th e dermal route. A lph a-chloro h ydri n is not a dermal irritant , a lth oug h it has been s hown to be a seve re eye irritant. At low doses in subchronic rodent stud ies, alpha-ch loro hydrin causes decreased sperm motility and/or decreased fertility. At hi g her dose s (ap proximately one order of magnitude) , testicu l ar lesions develop leading to permanent infertility. Multi-organ toxicity is also observe d at h i gher doses of alpha -ch lorohydrin following subc hronic exposure , and these include nephrotoxicity , neurotoxicity , and immun otoxicity
. Following chronic expo s ure to alpha-chlorohydrin , nephrotoxicity (c hronic progressive nephr opath y, kidney tubu le hyperplasia) i s observed, and several t ypes of benign tumor s deve lop. Tumor format i on i s believed to occu r through a nonPage 5of15Alpha-Chlorohydrin Human Health Risk Assessment 0428647 

### genotoxic mod e of action
. No developmental tox ic ity s tudies exist in the databa se, although many reproductive toxicity stud ies exist for adult animals, a fact which is consistent with the testing of alpha-chlorohydrin as a chemosterilant in ad ult male rodents, display i ng the critical effects on the male reprodu ct i ve system following exposure to a lph a-chlorohydrin
. 

### 4.2 Consideration of Tox i c i ty to C hild ren Food Quality Protection Act (FQPA) considerations do not apply to alpha-chlorohydrin for the currently regi ste red ( non-fo od) use patterns described in this risk assessment. In addition, no toxicologica l POD s were se lected for a l pha-chlorohydrin and thus, an additional safety factor to protect children is not needed. 

### 5.0 Diet ary Exposure an d Ri s k Assessment Ba sed on the registered rodenticide use, re s idue data are not required and non e have been submitted. In add i tion, based on the reg i stered us e, HED does not antic ipate dietary (food and water) exposure. A quantitative drinking water assessment was not conducted by the E nviro nmental Fate and Effects Division (EFED); therefore, drinking water exposure est im ates were not provided. 

### 6.0 Residentia l (Non-Occ upational ) Exposure and Risk Assessment Residential handler and post-application expos ures from alpha-chlorohydrin are expected to be negligible as th e registered product is a RUP and not approved for u se in res id e ntial settings. Additionally , no toxicological PODs have been established for alpha-chJorohydrin , and when used in above-ground bait stations , the bait formulation is confined inside tamper-resistant plastic bait hou s in g. Therefo re , quantitative residential handler and post-application exposure assessments are not necessary to conclude with rea so nable certainty that residential exposures to the currently registered u ses of alpha-chlorohydrin do not pose a signi ficant human health risk. 

### 7
. 0 Aggregate Ex po s ure /R isk Characterization As quantitative dietary and residential exposure assessments are not required for a lphach lorohydrin and no toxicological POD s have been established, a quantitative aggregate assessme nt is not required e ith er t o conclude w ith re asona ble certainty that aggregate exposures to the currently re gistered uses of alpha-chlorohydrin do not pose a sig nificant human health risk. 

### 8.0 C umulative Exposure/Risk Characterization Un like other pesticides for whic h E PA has followed a cumulative risk approach based on a commo n mechanism of toxicity, EPA has not made a commo n mechanism of toxicity finding as to a lpha-chlorohydrin and any other s ub s tanc es; and alpha-chlorohydrin doe s not appear to produce a toxic metabolite produced by other substances. For the purposes of this action , therefore, EPA h as assumed that alpha-chlorohydrin does not have a common mechanism of toxi c ity with other substances. For information regarding EPA 's efforts to determine which chemica ls hav e a common mechanism of toxicity and to eva lu ate th e cumulative effects of s uch chemicals, see the policy statements released by EPA ' s Office of Pesticide Pro g rams concerning common mechanism determinations and procedures for cumulating effects from substance s found to have a common mechanism on EPA ' s website at http ://www.epa.gov / pesticides/ cumulati ve/
.Page 6 of 15

### Alpha-Chlorohydrin Human Health Risk Assessment 0428647 

### 9. 0 S pr ay Dri f t The alpha-ch lorohydrin end use product Epib loc ® Rodent ic ide is fo r mulated as a bait-containing sachet and is un l ike ly to result in spray drift due to its application method in tamper-proof ba it boxes. 10. 0 P ubli c H ea lt h and Pes tici de Ep id e mi o l ogy D a t a A s ummary report l isting incidents for a lpha

- chlorohydr in reported to the OPP Incident Data System (IDS) has been previously conducted (S. Recore, I 3

- August

- 2015; 0428663)
. The report represents incidents occurring in th e U.S. from 1998 to 2015. The evaluation of incident data for alpha-chlorohydrin ind icates no reported incidents. Therefore, at this time , there are no remarkabl e case reports that suggest a plausible association between a moderate or severe health outcome and exposure to a lpha

- chlorohydrin. The 2015 review of the incident data does not warra nt further investigations at this time. 11. 0 Occ up a ti o n a l Ex p os u re/Ri sk C h a r acte r iza ti o n As mentioned in Sect i on 3
. 3 , a lpha

- chlorohydrin is registered for use in products to be used by certified applicators or persons under their direct supervision and only for those uses covered by the Certified Applicator ' s certification. Occupationa l handler and post-applicatio n exposures are not anticipated since the products are packaged in an enclosed system. Alpha-chlorohydrin is approved for use in and around th e indoors of commercia l / industrial faci li ties and sanitary sewe rs, the label states not to use the product in any fac ili ty where children may be present , there are no outdoor uses permitted. Additionally, no toxicolog ical POOs have b ee n estab li shed for a lpha-ch lorohydri n. Therefore , quantitative occupational hand ler and post-application exposure assessme n ts are not necessary to co nclud e with rea so nab l e c e rtainty that occupational exposures to the currently reg i stered use s of alpha

- chlorohydr in do not pose a significant human hea l th risk. 1 2. 0 R efe r e n ces Memo, R. M itku s 

### et al
. , 17 August 2006, D326010 Memo, S. Recore 

### e t al. , 13

- August-2015 , 0428663 Memo, U. Habiba , 29-September-2015, TXR#0057207

ROI: RAB I (08 / 19 / 15 ) J. 

### Godshall: PY-S I 0941: (703)347 -8068:7509? : 

### RAB I

Page 7of15Alpha

- Chloro hydrin Human Health Ri s k Assessment D4286 47 

### Appendix A. Toxico logy Profile and Executive S ummarie s. A.1 Toxicology Data Requirements Study re quirem ents (40 C FR 1 58.340) for use of a lpha- c hlorohydrin
. Use of th e n ew g uid e lin e numbers do es n o t imply th a t the n ew ( 1 998) gu id e lin e protoco l s we r e u se d. Table A.I.I. Toxi co l oev Data R equirement s . S tud y T ec hni cal Required S ati s fied 870.1100 Acut e Oral Toxicity
........ ..... ...... ........ ................. . ... . ... . . No 1



### -- 870.1200 Acute Derm a l Tox icity
....... ........ ................................... No 1



### -- 870.1300 Acute Inh alatio n Toxicity
..................... ........................ No 1



### -- 870.2400 Acute Eye Ir ritation
......... ...... ............. ............... .. .. ........ No 1


# -- 870.2500 Acute D ermal Irri tation
.............................. .......... ......... No 1



### -- 870.2600 Skin Se n s iti za tion
........... ............ ................................... No 1



### -- 870.3 100 90-Day Ora l Toxicity in Rodent s ............................... ... No 

# -- 870.3 150 90- D ay Ora l Toxicity in Nonrodent s ............................ No 

# -- 870.3200 21 /28 -D ay Dermal Toxicity
.......................................... No 

# -- 870.3250 90-Day Dermal Toxicity
........... .......................... .... ..... . No' 

# -- 870.3465 90 -D ay In hal ati o n Toxicity
........................................... No 

# -- 870.3700a Prenatal Developmental Toxicity (rod ent )
.................... No' 

# -- 870.3700b Prenatal D eve lo pmental Toxicit y ( nonrod ent)
.............. No 1



### -- 870.3800 R eproduc t io n and Fertility Effects
......... ....................... No 1


# -- 870.4 100a C hronic Toxicity (rode nt )
............................. .. ........... .... No


### -- 870.4 I OOb C hro n ic To x ic ity ( nonr oden t)
....................................... No 

# -- 870.4200a Car c in ogenic it y (ra t)
.. .. ............. . ........... ..................... ... No 

# -- 870.4200b Ca rcin ogenicity (mo use)
................. .............................. No


### -- 870.4300 Comb in ed C hr o nic Toxicity/ Carcinoge nicit y ............... No 

### -- 870.5100 Mu tage ni ci ty- Bacterial Re verse Mut a tion Test..
........ No'


### -- 870.5300 Mu ta ge ni ci t y - Mammalian Cell Gene Mutation Te st ... No' 

### -- 870.5385 Mu tagenic it y- ln vivo cytogenetics
.............................. No' 

### -- 870.5395 Mu tagenici ty- ln vivo cytogenetic s ............................. No 1



### -- 870.6200a Ac ut e Neurotox icity Sc re ening Batter y (rat)
..... ............ No'


### -- 870.6200b S ub c hroni c Neurotoxicity Screenin g B att ery (ra t)
........ No 1



# -- 870.6300 D eve lopm e nt a l N e urotoxicity
.... ................................. .. No 

# -- 870.7485 M e taboli s m a nd Pharmacokinetic s ............................... . No 

# -- 870.7600 D erma l P e ne tra ti o n .... ........... . ....................................... No 

### -- 870.7800 l mmun o tox icit y .......... . ...... .. .......................................... No 1



# --

I. HA SPOC concluded lhe se s 1ud1cs are not r eqm r ed a l llllS tun e ( U
. Hab1ba, 29

- Sep tcmbc r- 2015 , TXR # 0057207)
.

Page 8 of 15Alpha-Chlorohydrin Human Health Ri sk Assessment 0428647 

### A.2
. 

### Toxicity Profil es

Ta bl e A.2. 1. Ac ut e T ox ic it y Profil e -Aloh a-C hloro h yd r in
. G uid e lin e No./S tud y T y p e• Res ult s To xicit y Ca tego r y MRID /Re f c r c n ce No . 870.1100 / Ac ute oral toxici t y LD so = 159 mg/kg (M / F) II G lenn and Burr ( 1 968) (mouse) 870.1100 / Acute oral toxicity L D so = 13 I mg/ kg (M / F) II Glenn and Burr ( 19 68) (rat) 870.1200 / Acute dennal LDso**~** 2000 mg/kg ( M / F); s li g ht toxicity ( rabbit ) dermal irritation at 24 hrs. clearing by 111 Me ye r ( 1980) day 6 870.2500/Primary derm a l Not a demrnl irritant IV Meyer ( 1980) irritation (ra bbit ) 870.2400 / Primary eye Corrosive; severe eye irrit a nt I G len n and Burr ( 1968) irritation (rabb it) 870.2400 / Pri mary eye M ini ma ll y i rr ita t ing to irrit a tion (rabbit) was hed/unwashed eyes at 48/ 24 hrs. Ill Meyer ( 1 980) re s p ., clearing by 72 hr s. a No subm ined acute tox ic ity s tud y was acceptable according to current ( 1998 ) OPPTS g uid e line requirements (see e.g., Memo , B
. H anson, I 0 / 26 /2004, DP # 308393). T a bl e A. 2
. 2 . S ubch ro ni c a nd C hronic To x ici t y a n d Cc n o tox ic it y Profil e - A lp ha -C hl o r o h y drin
. S tud y T y p e• Doses Res ult s MRID/R e fer e nce No. NOAEL no t obse rved. LOA EL = 52 mg/ k g/day based on foci of 7-day oral toxici ty (dog; demyelinati o n , capsu le ) 0, 52, 83 , or 13 1 m g/

k

g/day vacuolization , and Glenn and Burr ( 1969) degenerative neurons and glial cells in thal a mu s and hippocampu s a nd decreased bod y weight. NOAEL not observed. LOA EL = 720/ 365 / 522 mg/kg/d ay ba se d o n p neumonitis, foca l p u lmonary h e morrhage , alveolar edema, s li g ht bronchiti s and hepa tic conge s ti o n (dogs); 0 or 4 m g/L (4 hrs / day) (equiva l en t pulm onary focal 5-day inhalation to x i c ity ( rat , to 0 or 720/ 365/ 522 mg/kg/day for hemorrha ge and Glenn and Moe ( 1 969) rabbit, dog) rat/rabbit/dog, re s pective l y') conge s tion , cloudy swelling of th e hepatocytes, t es t icu lar hypogenesis, and focal pol i oencephalomalacia (inflammation a nd softening of th e g re y maner of the brain) (rabbi t s); and testi cu lar hypogene s i s, r e nal tubular

1 Es timate d in the absence of a physio logica ll y based t oxicokinetic (PBTK) m ode l as follows: [ (Co ncentrat i on in mg/ L ) x I00 % absorpt io n x (45 L/h r /kg fo r a rat; 22.8 L/hr /kg fo r a rabbit; and 32.6 L/hr/kg fo r a dog) x 4 hrs]. Page 9of15A lpha-Ch lorohydrin Hu man H ea lth Risk Asses s ment 04 2 8647 Tab le A.2.2
. S u bc hr o ni c a n d C hr o ni c Tox i c it y a nd Ge n o t ox ic i ty Pro fil e - Alph a-C hl oro h y d r in
. Stu d y T y p e • Do s e s Res ults MR ID/ Re f e r e n cc No . cas t s, renal cystic tubular d il atation, and pul monary co nge s t io n (ra t s). NOA EL = 25 m g/kg/day. LOAEL 

## = 30 mg/k g/day based on death cau se d by severe bone marrow 5 60-day ora l tox ic ity 0, I 0 , 25, 30, 50 , 150, or 200 depressio n (ne utropen ia, R ay a nd Ceru ( 1968 ); ( m o n

key; di e t a ry) mg/kg/day thr o m bo cyto pe ni a, and Kirt o n e t a l
. ( 1 970) anem ia) a nd secondary hemorrha g ic pneumonia , ent eri t is, pleurit is , and pe r it o ni ti s . 55- d ay o ra l tox ic it y 0 o r 25 mg/kg/day NO A EL = 25 mg/kg/d ay. R ay e t al. ( 1967) (monkey; gavage) LOAEL not o bse r ve d
. NOAE L no t observed
. LOA EL = 35 mg/k g/da y 30-day ora l tox ic it y (dog; 0 o r 35 mg/kg/day based on decreased G len n e t al. ( 1969) d ieta r y) pro s t a t

e and testis we ig ht and decrease d b ody weigh t. NOA E L not observed
. LOAEL 

## = 30 mg/k g/day b ased on increased re lative kidn ey weig ht (F) o n day 2; increased scrum ALT 4-week oral toxicit y (rat ; (F), decre ased Hb and March es ini and Stalder 0, 30, or 60 m g/

k

g/da y MCV ( M&F) , and gava ge) in crea se d rela ti ve kidn ey (1983) a nd li ve r we i g hts o n day 25; and mil d tub ul e di l atation of teste s and decrea sed bod y-wei g ht 

# . ga in at tem1ination
. NO A EL no t ob se r ve d. L

OAEL = 9/ 11 m g/k g/day (M / F) based on increa se d 90-day ora l toxicit y (rat; 0 , 9 / I I , 27/3 1 , or 43 /46 mg/k g/day re lative kidney weigh t , March es ini and Stald e r decreased serum drinking wa ter) (M/ F) c rea tini ne, and increased ( 1989) num ber ofex foli ated epididyma l spe rmato zo id s ( M only)•. NOA E L = 20 mg/k g/da y. Ca rc in oge ni c it y ( m o u se; 0 o r 2 m g/ mo use (eq ui va le nt to 20 LOAEL no t obse r ved. Va n Duure n et al. de rm a l ) m g/

k

g/d ay; 3X / week) fo r 83 weeks No sk in pap ill oma s or ( 1974) carcinomas observed
. NOAEL not observed. 0 , 30, o r 60 m g/

kg/day (2X/ week) ; LOAEL 

## = 30 mg/kg/day Ch roni c Ora l b ase d o n severe t es t icu la r Toxicity/ Carcinoge ni c ity doses in creased to 0 , 35, or 70 dege nera tio n a nd atrop h y. W eisb urge r et al. ( rat ; ga vage) mg/kg/day (after I0 wee ks) up to ( 1 98 1) week 72 Marginall y p ositive trend ( P=0.044) only for Page 10of 15Alpha-Chlorohydrin Human Health Risk Assessment 0428647 T ab le A.2.2. Subc hr on i c and C hr o ni c Toxicity a nd Ge n otoxicity Profile - A lph a-C hl orohydrin. St ud y Type • Doses Results MRID/Refe r e n ce No. parathyroid adenomas in males. NOA EL not observed. LOAEL = 1.1 / 1.4 mg/kg/day (M / F) based on decreased absolute kidney weight (in the absence of decreased body weight) Chronic Oral 0, 20, I 00, or 500 mg/L [equivalent and increased incidences Toxicity/ Carcinogenicity to 01 0, 1.1 / 1.4 , 5.2/7.0, or 281 35 of Leydig cell adenomas, Sunahara et al. ( 1993) (rat ; drinking water) mg/kg/day (M/ F)] for I 04 weeks mammary glandular hyperplasia, chronic progressive nephropathy, and kidney tubule hyperpla s ia in males ; and increased incidences of kidney tubule hype rpla sia in females*. NOAEL not observed. LOA EL= 25 mg/kg/day based on decreased sperm Non-guide line

- Ma le motility after 3 days Kreider and Dutt reproductive function and 0 or 25 mg/kg/day (25 days) (revers ible) , increased# (1970) perfom1ance (sheep; capsule) abnormal spem 1 (irreve rsibl e), and dec reased fert il ity (reversib le). NOAEL not observed. Non-guide lin e - Male LOA EL = I mg/kg/day reproductive function and I , 5, 25 , or 50 mg/kg/day (25 days) based on decreased sperm Johnson and Pursel performance (boar; dietary) moti li ty and concentr at ion ( 1972) after 3 days (reve rsible) and infertility (reversible). Non-guideline

- Male reproductive function and 0 or 1 5 mg/kg/day (6 months) NOAEL = 15 mg/kg/day. Ericsson et al. ( 1969) perfonnance (monkey ; LOA EL not observed. drinking water) NOA EL= 30 mg/kg/day. LOAEL = 35 mg/kg/day (8 days) based on sterility Non-guide line

- Male 0 , 30, 35 , 45 , 60, or 90 mg/kg/day (I from lesions in caput reproductive function (rat; epididymis. Ericsson ( 1970) gavage) or 8 days) Epid idymal lesions also obse rved at 35 mg/kg/day afler s in gle dose. Non-gu id e lin e - Male and 0, I, 1.5, 2, 3, 5 , I 0, 15 , or 30 mg/rat NOA EL= 2.9 mg/kg/day. female reproductive function (equ ivalent to 0, 2.9, 4.3 , 5.7, 8.6, LOA EL = 4.3 m g/kg/day Ericsson and Baker and performance (rat; 14 , 29, 43, or 86 mg/kg/day; I , 2, or based on in fertil ity (8 (1970) gavage) 8 days) days). NOAEL = I mg/kg/day. Non-guidel in e - Male and 0, 0.2, 1, 1.25, 2.5, 5, I 0, or 25 LOA EL = 1.25 m g/kg/day female reproductive function mg/rat (2 weeks-4 months) based on decreased (30%) Vickery et al
. ( 19 74) and performance (rat ; oral) fertility and percentage of fertilized eggs. Page 11 of 15Alpha-Chlorohydrin Human Health Risk Assessment 0428647 Tabl e A.2. 2. Subchronic and C hron ic To xi cit y and Gcnotoxicitv Pr o file

- Alph a-C h l o r o h vdrin. Stu d y T y p e• Do ses Res ult s MR ID/Rc f crence No. Non-guideline

- Male NOAEL not observed. reproductive function (rat; 0,**5~** 100 , 150,200,250 , or300 LOAEL = 50 mg/ kg/day Kennelly er al. ( 1970) dr in king water) mg/kg/day ( 1 0 days) based on ep id idyma l les ions. NOAEL not observed. LOAEL = 140 mg/k g/day Non-guideline

- Male 

### • based on sloughing of reproductive function (ra t ; 0 or 140 mg/kg epididymal epi th elium Hoffer e t al. ( 1973) gavage) after 2 hrs., followed by obstruction of epididymal tract. NOAEL = 2 mg/k g/ day. Non-guidel in e - Male and LOAEL = 3 mg/kg/day fema le reproductive 0, 0. 1 , 0.5, 1 , 2, 3,4, 5 , or I0 mg/ kg* based on increase d Pari s h ( 1989) perfo nn ance (rat; gavage) in cidence of preimplantation lo ss. NOAEL not observed. Non-guideline

- Male and LOA EL = 5 mg/k g/day based on decreased sperm Woods and Garside female reproductive 0, 5 , I 0 , or 20 mg/kg (5 o r 14 days) motility , altered sperm (1996) performance (rat; gavage) motion, and decreased pregnancy rate (0%). NOAEL not observed. Non-guidel in e - Mal e and LOAEL = 5 mg/kg/day Kawaguchi e r al. fema le reproductive 0, 5, o r 20 mg/ kg (3 or 18 day s) based on altered spe rm (2004) perfonnance (rat; gavage) motion and decreased pregnancy rat e. Non

-guideli ne - Male and NOAEL = 0.05 mg/kg. female reproductive 0, 0.0 I , 0.05, 0.25 , I , or 5 mg/kg (28 LOA EL = 0.25 m g/

kg/day Kwack e t al. (2004) perfonnance and function days) based on decreased spenn and fetal effects (rat; gavage) count and motility. NOAEL = 5 mg/ kg/day. LOA EL = I 0 mg/k g/day based on reduc ed Non-gu id e lin e - Ma le pe rcentage of motile repro ductive function (rat; 0 , 5, I 0 , or 20 mg/kg (8 days) sperm , curvilinear Toth et al. (1992) drinking water) velocity, s trai g ht-line velocity, lateral head displacement , and linearity. NOAEL = I mg/k g/day. Non-guideline

- Male LOA EL = 5 mg/ kg/day based on reduced reproductive function and 0 , I , 5, or 25 mg/kg ( 14 days) percentage of mo ti le Hoyt e t al. ( 1994) perfo rmance (rat; gavage) spe rm and decrea sed fertility
. NOAEL = 1 mg/k g/day. LOA EL= 3 m g/

k

g/day Non-guideli ne - Male and based on decrea se d female reproductive function 0, I, 3, or 10 mg/kg (9 days) fertilization and pregnancy Ban e t al. ( 1999 ) and performance (rat; rate s, # spem1 reaching gavage) oviducts of females , sperm velocity , and lateral head displacem e nt. Non-guide line

- Male and 0, 2, o r 8 mg/k g (14 days) NOAEL not observed. Yamada e t al. ( 1995) female reproductive function Pa ge 12o f15Alpha-Chlorohydrin Human Hea lth Risk Assessment 0428647 Ta bl e A.2.2. S ub c hroni c a nd C hr o ni c T o xicit y a nd Ge n oto x ic ity Pro fil e - Alph a-C hl o roh ydrin
. St ud y Type• Doses R es ult s MRID /Refere n ce No. and perfo rm ance (ra t ; LOA EL = 2 m g/

k

g/ day gavage) ba se d on dec reased sperm activity when incubated for 2 hrs
. NOAEL = 50 m g/

k

g/da y . LOA EL = I 00 m g/

k g/d ay based on decreased No n- guide lin e - ab sol ute and relative 0, 25, 50 , or I00 mg/kg ( 14 d ays) th y mu s weight ( in the Lee e t a l. (2004 , 2005) lmmun otox ic it y ( rat ; gavage) abse nc e of d ec r ease d bod y weight), # ce ll s in s pleen and thymus , and ant i body form ing response. I n vivo dominant letha l 125 m g/

kg i .p. or 20 mg/k g/d ay mutation (JCR/Ha Swiss Negative* Epstein e t a l. ( 1972) mice) (oral; 5 days) In v i vo dominant lethal 0 , 5 , or I 0 m g/kg/day (o ral ; 5 d ays) Negat ive* Jone s e t a l
. ( 1 969) mutation ( mal e mi ce) In v ivo dom inant lethal 0, 5, I 0 , or 20 mg/kg/da y (o ra l ; 5 Negative* Jon es and Jackson mutation (ma le Wistar rats) da ys) (1976) In vivo micronucleus tes t 40- 120 m g/

k g Negative* Jaccaud and (bo ne marrow, OF 1 mice ) Ae sc hb ac he r ( 1 989) N ega tiv e* In v ivo mi c ronucl e us test 0 , 15 , 30, or 60 mg/ k g/day (ora l ; 2 Pi loerection and b o ne ( bo ne marrow , mal e Han days) marrow cytotox icity Marshall (2000) Wi s tar rat s) obse rved after 2 days at 60 mg/ k g/day
. In vivo un sc he du led DNA synthesis (ma l e Han Wistar 0, 40 , or 100 mg/kg (ora l ) Negative* Fellows (2000) rats) In vitro reverse mutation 2-200 μmol /plate (0.2

-22 mg/p late) Po s itiv e wit h a nd without Silhankova e t al. (S. cyQhimuri um TA 1535) metabolic activation * ( 1982) In vitro reve r se mutation Negative with and w ithout Silhankova e t al. (S. cyphimurium TAl5 37 , 2-200 μm o l /pl ate (0
. 2

-22 m g/

plate) TAl538 , TA98) metabo l ic activation * (1982) In v itr o reve rse mutat io n I0-1000**nol/pl ate**  ( I
. 1-1 I0 Po s it ive w ith and without S to lzenberg and Hine (S. cyp himurium TA I00, TAl535) mg/p late) metabolic ac tiv at io n*. ( 1979; 1980) Ne ga tive with metabolic In vitro reve rse mutation I 00- IOOO μmo I / pl ate ( I 1-1 10 act ivation. Stolzenberg and Hin e ( S. typ himurium TA98) m g/pla te) E qu ivocal w ithout ( 1 979) m

e tabo li c act ivation*. In v itro re verse mutation Po siti ve with and without (S. tyQ himurium TA I 00, 0.1-10 mg/p lat e metabolic activation*. Ze ige r e t a l
. ( 1988 ) TA 15 35) Negative with metabo l ic ln vit ro r e ve rse mutation act iva tion
. ( S. cyphim urium T A97) 0. 1-10 mg/plate Zeiger e t al. ( 198 8) Not tested wi thout m

e tabol ic act ivation*.

Pa ge 1 3of 15Alpha-Ch loro hydr in Human Health Ri s k Assessment 04 28647 Tab le A.2.2
. S u bc h ro ni c a nd C h ro n ic T ox ic it y a nd Ge n otox i ci ty Pro fil e - Alp h a-C hl oro h y d rin
. St u d y T y p e • Do ses Re s u lt s MR I D /Re f ere n ce No. Negative wi th metabo lic In vitro reverse muta t ion activation. (S. typhimurium TA98) 0.1 -10 m g/

plat e Zeiger et al. ( 1988) Positive wi th ou t metabolic act i vation•. Negative with m etabolic In v itr o reve rse mutation act iva ti o n . Majeska and Ma the s on Not reported (S
. typ himurium TA I00) No t tested without ( 1983 ) m

e tab o lic act ivation*
. In vitro reve rse mutat ion 0.01-1.25 mg/ plate Pos itive with and wit hou t Ohkubo e t al. ( 19 95) (S. typhimur ium T A I 00) m e tabolic act iva tion *. Nega tiv e w ith m e tabo lic In v itro rev e r se mutation ac tiv ati on. (S. typhimurium TA677 , 0.01-1.25 mg/p late Ohkubo e t al. ( 1 995) TA98) Po s iti ve without metabolic ac ti vatio n •. In vi tr o muta ti o n (E. co li 2-200 μmo l/ plate ( 0.2-22 m g/plat e) Nega tive with and without S ilh ankova e t al. WP2 , TM930 , TM I080) metab o lic act ivation *
. ( 198 2) In vitro mutation (E. co li 2

-200 μmol/plate (0.2

- 22 mg/plate) Nega ti ve with and without Ohkubo e t al. ( 1995) WP2 , TM930 , TM I080) metabolic ac ti vation•. Negative wi th metabolic In vi tro fo rward mu tati on act i vation. (Schizo s accharomyces I 00

- 300 mmo l/L ( 1 1- 33 m g/

ml) Ro ssi et al. ( 1983) p lombe ) Posit ive witho ut metabolic ac ti va ti on• . Po s itive with metabolic I n vi tr o gene mutation ac ti va ti o n . ( Mou se lymp h oma ce ll s , Tk 2 -9 mg/ ml H e nd ers on e t al. ( 1987) loc us) Negat iv e withou t metaboli c ac t ivat ion*. In v it ro mut ati o n (HeLa No t reported Neg ative with and without Paint e r and H oward ce ll s) metabo li c ac tiv a tion • . (1982) I n vitro mutation (Mo use 0.1-2 mg/ ml Po s itive * Piasecki e t al. ( 1990) fibrobla s t s, M2 cl o ne) I n vitro s is te r chromat id Po si tiv e wit h and wi th out exc ha nge (Chinese hamster 0.7-2 .8 m g/ ml May ( 19 9 1) V79 ce ll s) m e t

abolic activation*. In vitro gene mut at io n W eak posit ive a t tox ic (Chi nese hams t er V79 ce ll s , 0.3-70 mmo l/ L (0.033

-7.7 m g/m l ) conce ntratio n of 50 GOrlitz ( 1 99 1) hprt locu s ) mmol / L (5.5 m ?/

ml)*.

Pa ge 1 4of15Alpha-Chlorohydrin Human Health Risk Assessment 0428647 Table A
. 2
. 2
. Subchron ic and Chronic Toxicitv and Genotoxicitv Profile

- Alph a-C hl orohvdrin
. Study T y pe • Do ses Resu l ts MRID/Refe r e nce No. After 24 hrs , 9% 

### o.- ch lorohydrin excreted unchanged in urine; 30% exhaled as C02 (although much of dose unaccounted for); P-ch lorolactate comprised**23%** of urinary metabolites. Jones et al. ( 1978) *; 0 or I 00 m g/

kg (i.p.) Evidence for tissue- Miller and Krake Metabolism 0, I 0 (rats, rabbits) or 17 (monkeys) spec i fic localization of is ( 1968) ; Krake and mg/kg (oral) equivoca l. Parent is Miller (1969) detoxified by conjugation with glutath ione and then by acetylation to form the corresponding mercap turic acid; compound also und e rgoes oxidation to P

chlorolactic acid and then oxalic acid. * Denotes as reported in Schlatter J, Baars AJ, DiNovi M, Lawrie S, and Lorentzen R. (2002). 3-chloro-1,2- propanediol. In : Proceedings of the Fifty-seventh Meeting of the Joint FAO / WHO Expert Committee on Food Additives (JECF A) of the Safety Evaluation of Certain Food Additives and Contaminants. WHO Food Additives Se ries No. 48 , 401-432.

Table A.2.3. Parentera l Toxicity Profile - Alpha-Ch l orohyd rin
. Study T y pe • Do ses Resu lt s MRID/Reference No
. Acute/ 4-day toxicity NOAEL not observed. (s ubcut a neou s inj ection ; 0 or 35 mg/kg/day LOAEL = 35 mg/k g/day G Jenn et al. ( 1969 ) based on decreased dog) prostate and testis weights. NOAEL not observed. 30-day toxicity LOAEL = 35 m g/

k

g/day based on decrea sed Glenn and Sokolowski (subc utaneous injection; 0 or 35 mg/kg/day prostate and testis weights (1969) dog) and decreased body we i e. ht. Male and female NOA EL= 0.5 m g/kg/day reproductive function and 0 , 0.5, 1.5 , or 3 mg/rat (equivalent to LOAEL = 1.5 mg/kg/day Ericsson and Baker pe rfonnance 0 , 1.4 , 4.3, or 8.6 mg/kg/day; 8 days) based on decreased ( 1970) (subcutaneous injection; rat) fertility Male and female reproductive function and NOA EL = 35 mg/ k

g/day
. Glenn a nd Sokolowski performance 0 or 35 mg/kg/day (I or 4 days) LOAEL not observed 4-5 ( 1 969) (subcutaneo us inj ect ion ; months post-dose. dog) NOA EL not observed
. LOAEL = 25 mg/kg/day Neurotoxicity based on moderate to 0 , 25 , 50 , or I 00 mg/kg/day (5-9 days) severe paresis, ataxia, and Cavanagh et al. ( 1993) ( intrap eritoneal ; mouse) tremors and severe le s ions in the central nervous sys tem. Page 15of15