UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: 29-SEP-2015 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Alpha-Chlorohydrin. Human Health Assessment Scoping Document and Draft 

Human Health Risk Assessment in Support of Registration Review. 

PC Code: 117101 DP Barcode: 0428647 

Decision No.: 507994 Registration No.: 42882-2 

Petition No.: NA Regulator y Action: Registration Review Risk Assessment 

Risk Assessment Type: Scoping and Reg Review Case No.: 4120 

TXR No.: CAS No.: 96-24-2 

MRID No.: NA 40 CFR: NA j) 

FROM: Joshua Godshall, Bio~ ~ O" .fit/ V( 

Thomas Bloem, Chemi~ ~ • _L1 

Monique M. Perron, Sc.D., Toxicologist ~ T ..£,1./V'--

Risk Assessment Branch I (RAB 1) 

Health Effects Division (HED, 7509P) 

THROUGH: Thurston G. Morton, Acting Branch Chief 

George F. Kramer, Ph.D., Senior Chemist ~_,,,--

RAB I /HED (7509P) 

TO: Matthew Manupella, Chemical Review Manager 

Cathryn Britton, Team Leader 

Kevin Costello, Branch Chief 

Pesticide Re-Evaluation Division (PRD/7508P) 

Attached is HED's human health risk assessment scoping document for alpha-chlorohydrin (3-

chloro-1 ,2-propanediol) to support Registration Review. As part of Registration Review, PRO 

of the Office of Pesticide Programs (OPP) has requested that HED evaluate the hazard and 

exposure data and conduct occupational and residential exposure assessments, as needed, to 

estimate the risk to human health that will result from the currently registered uses of pesticides. 

This memorandum serves as HED's scoping document AND draft human health risk assessment 

of the dietary, occupational and residential exposure, and aggregate risk from the registered uses 

of a lpha-chlorohydrin. 

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Alpha-Chlorohydrin Human Health Risk 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 

Table of Contents 

Executive Summary .......................................................................................................................................... 3 

HED Recon1111endations ................................................................ ................................................................... 3 

Data Deficiencies .. ....... .... .... ................ ............ .... .... .... ....... ... ........... ... ............................ 3 

Tolerance Considerations ................................................................................................. 3 

Label Recommendations .............................. .... ................... .................................. ........... 3 

Introduction ...................................................................................................................................................... 4 

Che1nical Identity ............................................................................................................. 4 

Physical/Chemical Characteristics .......................................... ......................................... 4 

Pesticide Use Pattern ........................ ... ..... .... .... ........... ....... .... ............................ ... ........... 4 

Consideration of Environmental Justice ........................................................... ... ............ 5 

Hazard Characterization and Dose-Response Assessment ............................................................................... 5 

Toxicology Analysis .......... .... .... .... ........ .... ............ ................................ ........... ... ............ 5 

Consideration of Toxicity to Children ...................................................... ....................... 6 

Dietary Exposure and Risk Assessment ........................................................................................................... 6 

Residential (Non-Occupational) Exposure and Risk Assessment... .................................................................. 6 

Aggregate Exposure/Risk Characterization ...................................................................................................... 6 

Cumulative Exposure/Risk Characterization .................................................................................................... 6 

Spray Drift ........................................................................................................................................................ 7 

Public Health and Pesticide Epidemiology Data .............................................................................................. 7 

Occupational Exposure/Risk Characterization ................................................................................................. 7 

References ........................................................................................................................................................ 7 

Appendix A. Toxicology Protile and Executive Summaries ........................................................................................ 8 

A. I Toxicology Data Requirements .............................................................................. ...... ... . 8 

A.2. Toxicity Profiles .............................................................................................................. 9 

. ... . ... ... . . ~ .. ... . .. .. 

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A lpha-Chlorohydrin Human Health Risk Assessment 0428647 

1.0 Executive Summary 

HED has prepared a qualitative human-health risk assessment to support registration review for 

the use of alpha-chlorohydrin (3-chloro- 1,2-propanediol; 3-MCPD; U-5897). When writing this 

risk assessment, HED primarily considered the following two documents: (i) AlphaChlorohydrin: Human Health Risk Assessment for Proposed Use as a Rodenticide (R. Mitkus, 17 

August 2006; 0326010) and (ii) HED's Hazard and Science Policy Council (HASPOC) 

recommendations (U. Habiba, 29-September-20 15, TXR#0057207). 

Alpha-chlorohydrin was first registered in 1983 and was cancelled in 1991 due to maintenance 

fee non-payment; it was then newly registered in 2006. The only registered use for alphachlorohydrin is as a tamper-proof bait station/bait application delivery system for elimination of 

Norway rats. One product (Epibloc® Rodenticide, produced by Gametrics, Ltd.) is currently 

registered containing alpha-chlorohydri n, which is for retail sale to and use only by certified 

applicators or persons under their direct supervision and only for those uses covered by the 

Certified Applicator's certification. Alpha-chlorohydrin is approved for use in and around the 

indoors of commercial/industrial facilities and sanitary sewers, the label states not to use the 

product in any faci lity where children may be present, and there are no outdoor uses permitted. 

As a restricted-use pesticide (RUP), there are no proposed or current registrations that allow for 

residentia l use. Because negligible exposure is expected from the currently-registered product, a 

quantitative human hea lth risk assessment has not been previously conducted. 

No data deficiencies were identified for the toxicology, residue chemistry, or occupational/ 

residential exposure databases. Dietary exposure is not expected and occupational/residential 

exposures are anticipated to be negligible from the currently registered uses of a lphachlorohydrin. Based on the negligible exposure potential of the currently registered uses of 

alpha-chlorohydri n, no toxicological points of departure (PO Os) have been established. As a 

result, quantitative risk assessments are not necessary to conclude with reasonable certainty that 

exposures to the currently registered uses of alpha-chlorohydrin do not pose a significant human 

health risk. • 

2.0 HED Recommendations 

HED has no objection for continued registration of the current alpha-chlorohydrin pesticide 

product. 

2.1 Data Deficiencies 

• None. 

2.2 Tolerance Considerations 

Alpha-chlorohydrin is not a food-use chemical. There are currently no U.S. tolerances 

established for alpha-chlorohydrin. 

2.3 Label Recommendations 

HED has no label recommendations at this time. 

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Alpha-Chlorohydrin Human Health Risk Assessment 0 428647 

3.0 Introduction 

Alpha-chlorohydrin is a rodenticide registered to control Norway rats. The active ingredient (ai) 

exists as a racemic mixture of R- and S-alpha-chlorohydrin causing reversible infertility in male 

animals at relatively low doses. The structure, chemical name, and other identifiers are found in 

the chemical identity table (Table 3.1.1 ). 

3.1 Chemical Identity 

Table 3.1. 1. Nome ncla ture o f a-Chlo ro h yd rin. 

Cit 

Chemical structure HO,~CI 

Common name a-chlorolw<lrin 

Company experimental name U-5897 

IUPAC Name (RS)-3-chloropropylcnc glycol 

CAS name 3-chloro-1.2-orooanediol 

CAS registry number 96-24-2 

End-use product (EP) Epibloc® Rodenticidc ( I% alpha-chlorohydrin) 

3.2 Physical/Chemical Characteristics 

Alpha-chlorohydrin's vapor pressure is not included due to inconsistencies in values between the 

Food and Drug Administration (FDA) database and the Pesticide Properties Database. 

Table 3.2.1. Phvsicochem ica l Properties of a-Chlo rohydrin. 

Parameter Value Reference 

Melting point -40°C 

Density 1.322 g/cm3 at 20°C The Pesticide properties Database: Water solubility I 000 g/L at 20°C 

Octanol/water partition coefficient. http://sitcm.herts.ac.uk/aeru/iupac/indcx.htm 

Log Pow -0.85 at 20°C and pH 7 

3.3 Pesticide Use Pattern 

Alpha-chlorohydrin is currently registered under one label as Epibloc® Rodenticide (1 % alphachlorohydrin per 5-gram edible bait/sachet; EPA Reg. No. 42882-E) to control Norway rats. 

Each bait-containing sachet (placepack) is placed by an applicator inside tamper-resistant bait 

stations in and around commercial/industrial faci lities, and sanitary sewers. As a RUP, the 

product label specifies that sale and use is to and by, respectively, certified applicators or persons 

under their direct supervision only, and that bait-containing sachets "must be placed in tamperproof bait boxes or in locations not accessible to children, pets, domestic animals, or wildlife." 

With negligible exposure and considering that industrial rodenticidc applications are not a 

covered use under the Worker Protection Standards (WPS), no personal-protective equipment 

(PPE) is required for alpha-chlorohydrin. 

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Alpha-Chlorohydrin Human Health Risk Assessment 0 428647 

3.4 Consideration of Environmenta l J ustice 

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

(http://www.epa. uov/compl iance/environmentalj ustice/resources/policy/exec order 12898.pd D. 

As a part of every pesticide risk assessment, OPP considers a large variety of consumer 

subgroups according to well-established procedures. In line with OPP policy, HED estimates 

risks to population subgroups from pesticide exposures that arc based on patterns of that 

subgroup's food and water consumption, and activities in and around the home that involve 

pesticide use in a residential setting. Extensive data on food consumption patterns are compiled 

by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used 

in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed 

and categorized by subgroups based on age, season of the year, ethnic group, and region of the 

country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups 

and exposure assessments are performed when conditions or circumstances warrant. Whenever 

appropriate, non-dietary exposures based on home use of pesticide products and associated risks 

for adult applicators and for toddlers, youths, and adults entering or playing on treated areas 

post-application are evaluated. Further considerations are currently in development as OPP has 

committed resources and expertise to the development of specialized software and models that 

consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary 

patterns among specific subgroups. 

4.0 Hazard Characterization and Dose-Response Assessment 

4.1 Toxicology Analysis 

No guideline studies are available in the alpha-chlorohydrin database; however, numerous 

literature studies were used to evaluate its hazard potential. Guideline studies are required for 

non-food use pesticides in accordance with the current 40 CFR Part 158 Toxicology Data 

Requirements; however, the HASPOC concluded based on a weight-of-evidence approach that 

these studies are not required at this time due to the limited exposure pattern of alphachlorohydrin and the qualitative nature of the risk assessment (U. Habiba, 29-September-20 15, 

TXR#0057207). If the use patterns were to change, or new policies/procedures are put into 

place, then the need for these studies may be revisited. The TOXLINE (National Library of 

Medicine) database literature search did not identify any new toxicological information not 

already considered. 

Alpha-chlorohydrin exists as a racemic mixture of R- and S-alpha-chlorohydrin. It is moderately 

toxic following acute oral exposure and has a low order of acute toxicity via the dermal route. 

Alpha-chlorohydrin is not a dermal irritant, although it has been shown to be a severe eye 

irritant. 

At low doses in subchronic rodent studies, alpha-chlorohydrin causes decreased sperm motility 

and/or decreased fertility. At higher doses (approximately one order of magnitude), testicular 

lesions develop leading to permanent infertility. Multi-organ toxicity is also observed at higher 

doses of alpha-chlorohydrin following subchronic exposure, and these include nephrotoxicity, 

neurotoxicity, and immunotoxicity. Following chronic exposure to alpha-chlorohydrin, 

nephrotoxicity (chronic progressive nephropathy, kidney tubule hyperplasia) is observed, and 

several types of benign tumors deve lop. Tumor formation is believed to occur through a nonPage 5of15 
Alpha-Chlorohydrin Human Health Risk Assessment 0428647 

genotoxic mode of action. No developmental toxicity studies exist in the database, although 

many reproductive toxicity studies exist for adult animals, a fact which is consistent with the 

testing of alpha-chlorohydrin as a chemosterilant in adult male rodents, displaying the critical 

effects on the male reproductive system following exposure to alpha-chlorohydrin. 

4.2 Consideration of Toxicity to Children 

Food Quality Protection Act (FQPA) considerations do not apply to alpha-chlorohydrin for the 

currently registered (non-food) use patterns described in this risk assessment. In addition, no 

toxicological PODs were selected for alpha-chlorohydrin and thus, an additional safety factor to 

protect children is not needed. 

5.0 Dietary Exposure and Risk Assessment 

Based on the registered rodenticide use, residue data are not required and none have been 

submitted. In addition, based on the registered use, HED does not anticipate dietary (food and 

water) exposure. A quantitative drinking water assessment was not conducted by the 

Environmental Fate and Effects Division (EFED); therefore, drinking water exposure estimates 

were not provided. 

6.0 Residential (Non-Occupational) Exposure and Risk Assessment 

Residential handler and post-application exposures from alpha-chlorohydrin are expected to be 

negligible as the registered product is a RUP and not approved for use in residential 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 housing. Therefore, quantitative residential handler and post-application exposure 

assessments are not necessary to conclude with reasonable certainty that residential exposures to 

the currently registered uses of alpha-chlorohydrin do not pose a significant human health risk. 

7.0 Aggregate Exposure/Risk Characterization 

As quantitative dietary and residential exposure assessments are not required for alphachlorohydrin and no toxicological PODs have been established, a quantitative aggregate 

assessment is not required either to conclude with reasonable certainty that aggregate exposures 

to the currently registered uses of alpha-chlorohydrin do not pose a significant human health risk. 

8.0 Cumulative Exposure/Risk Characterization 

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to alpha-chlorohydrin and any other substances; and alpha-chlorohydrin does not appear to 

produce a toxic metabolite produced by other substances. For the purposes of this action, 

therefore, EPA has assumed that alpha-chlorohydrin does not have a common mechanism of 

toxicity with other substances. For information regarding EPA 's efforts to determine which 

chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such 

chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning 

common mechanism determinations and procedures for cumulating effects from substances 

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 Spray Drift 

The alpha-chlorohydrin end use product Epibloc® Rodenticide is formulated as a bait-containing 

sachet and is unlikely to result in spray drift due to its application method in tamper-proof bait 

boxes. 

10.0 Public Health and Pesticide Epidemiology Data 

A summary report listing incidents for alpha-chlorohydrin 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 the U.S. from 1998 to 2015. The evaluation of incident 

data for alpha-chlorohydrin indicates 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 alpha-chlorohydrin. The 2015 review of the incident data does not 

warrant further investigations at this time. 

11.0 Occupational Exposure/Risk Characterization 

As mentioned in Section 3.3, alpha-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. Occupational handler and post-application exposures are 

not anticipated since the products are packaged in an enclosed system. Alpha-chlorohydrin is 

approved for use in and around the indoors of commercial/industrial facilities and sanitary 

sewers, the label states not to use the product in any facility where children may be present, there 

are no outdoor uses permitted. 

Additionally, no toxicological POOs have been established for alpha-chlorohydrin. Therefore, 

quantitative occupational handler and post-application exposure assessments are not necessary to 

conclude with reasonable certainty that occupational exposures to the currently registered uses of 

alpha-chlorohydrin do not pose a significant human health risk. 

12.0 References 

Memo, R. Mitkus et al., 17 August 2006, D326010 

Memo, S. Recore et 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 

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Alpha-Chlorohydrin Human Health Risk Assessment D428647 

Appendix A. Toxicology Profile and Executive Summaries. 

A.1 Toxicology Data Requirements 

Study requirements ( 40 CFR 158.340) for use of alpha-chlorohydrin. Use of the new guideline 

numbers does not imply that the new (1998) guideline protocols were used. 

Table A.I.I. Toxicoloev Data Requirements. 

Study 

Technical 

Required Satisfied 

870.1100 Acute Oral Toxicity ...................................................... No1 -- 870.1200 Acute Dermal Toxicity .................................................. No1 -- 870.1300 Acute Inhalation Toxicity ............................................. No1 -- 870.2400 Acute Eye Irritation ............................................. .......... No1 -- 870.2500 Acute Dermal Irritation ................................................. No1 -- 870.2600 Skin Sensitization .......................................................... No1 -- 870.3 100 90-Day Oral Toxicity in Rodents .................................. No -- 870.3 150 90-Day Oral Toxicity in Nonrodents ............................ No -- 870.3200 21 /28-Day Dermal Toxicity .......................................... No -- 870.3250 90-Day Dermal Toxicity ............................................... No' -- 870.3465 90-Day Inhalation Toxicity ........................................... No -- 870.3700a Prenatal Developmental Toxicity (rodent) .................... No' -- 870.3700b Prenatal Developmental Toxicity (nonrodent) .............. No1 -- 870.3800 Reproduction and Fertility Effects ................................ No1 -- 870.4 100a Chronic Toxicity (rodent) .............................................. No -- 870.4 IOOb Chronic Toxicity (nonrodent) ....................................... No -- 870.4200a Carcinogenicity (rat) ..................................................... No -- 870.4200b Carcinogenicity (mouse) ............................................... No -- 870.4300 Combined Chronic Toxicity/Carcinogenicity ............... No -- 870.5100 Mutagenicity- Bacterial Reverse Mutation Test.. ........ No' -- 870.5300 Mutagenicity- Mammalian Cell Gene Mutation Test ... No' -- 870.5385 Mutagenicity- ln vivo cytogenetics .............................. No' -- 870.5395 Mutagenicity- ln vivo cytogenetics ............................. No1 -- 870.6200a Acute Neurotoxicity Screening Battery (rat) ................. No' -- 870.6200b Subchronic Neurotoxicity Screening Battery (rat) ........ No1 -- 870.6300 Developmental Neurotoxicity ....................................... No -- 870.7485 Metabolism and Pharmacokinetics ................................ No -- 870.7600 Dermal Penetration ....................................................... No -- 870.7800 lmmunotox icity ............................................................. No1 -- I. HASPOC concluded lhese s1ud1cs are not reqmred al llllS tune (U. Hab1ba, 29-Septcmbcr-2015, TXR#0057207). 

Page 8 of 15 
Alpha-Chlorohydrin Human Health Risk Assessment 0428647 

A.2. Toxicity Profiles 

Ta ble A.2. 1. Acute Tox icity Profile -Aloha-Chlorohydrin. 

Guideline No./Study Type• Results Toxicity Category MRID/Refcrcnce No. 

870.1100/ Acute oral toxicity LDso = 159 mg/kg (M/F) II Glenn and Burr (1968) (mouse) 

870.1100/ Acute oral toxicity LDso = 13 I mg/kg (M/F) II Glenn and Burr ( 1968) (rat) 

870.1200/Acute dennal LDso ~ 2000 mg/kg (M/F); slight 

toxicity (rabbit) dermal irritation at 24 hrs. clearing by 111 Meyer ( 1980) 

day 6 

870.2500/Primary dermal Not a demrnl irritant IV Meyer ( 1980) irritation (rabbit) 

870.2400/Primary eye Corrosive; severe eye irritant I Glenn and Burr ( 1968) irritation (rabbit) 

870.2400/Primary eye 

Minimally irritating to 

irritation (rabbit) washed/unwashed eyes at 48/24 hrs. Ill Meyer ( 1980) 

resp., clearing by 72 hrs. 

a No submined acute toxicity study was acceptable according to current ( 1998) OPPTS guideline requirements (see 

e.g., Memo, B. Hanson, I 0/26/2004, DP# 308393). 

Ta ble A.2.2. Subch ronic and Chronic Toxicity and Ccnotox icity Profile - Alpha-Chlorohydrin. 

Study Type• Doses Results MRID/Reference No. 

NOAEL not observed. 

LOA EL = 52 mg/kg/day 

based on foci of 

7-day oral toxicity (dog; demyelination, 

capsule) 0, 52, 83, or 13 1 mg/kg/day vacuolization, and Glenn and Burr ( 1969) 

degenerative neurons and 

glial cells in thalamus and 

hippocampus and 

decreased body weight. 

NOAEL not observed. 

LOA EL = 720/365/522 

mg/kg/day based on 

pneumonitis, foca l 

pulmonary hemorrhage, 

alveolar edema, slight 

bronchitis and hepatic 

congestion (dogs); 

0 or 4 mg/L (4 hrs/day) (equivalent pulmonary focal 

5-day inhalation toxicity (rat, to 0 or 720/365/522 mg/kg/day for hemorrhage and Glenn and Moe ( 1969) rabbit, dog) rat/rabbit/dog, respectively') congestion, cloudy 

swelling of the 

hepatocytes, testicu lar 

hypogenesis, and focal 

polioencephalomalacia 

(inflammation and 

softening of the grey 

maner of the brain) 

(rabbits); and testicular 

hypogenesis, renal tubular 

1 Estimated in the absence of a physiologically based toxicokinetic (PBTK) model as follows: [(Concentration in 

mg/L) x I 00% absorption x (45 L/hr/kg for a rat; 22.8 L/hr/kg for a rabbit; and 32.6 L/hr/kg for a dog) x 4 hrs]. 

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A lpha-Chlorohydrin Human Health Risk Assessment 0428647 

Table A.2.2. Subchronic a nd Chronic Toxicity and Genotoxicity Profile - Alpha-Chlorohydrin. 

Study Type • Doses Results MRID/Referencc No. 

casts, renal cystic tubular 

dilatation, and pulmonary 

congestion (rats). 

NOA EL = 25 mg/kg/day. 

LOAEL = 30 mg/kg/day 

based on death caused by 

severe bone marrow 

560-day oral toxicity 0, I 0, 25, 30, 50, 150, or 200 depression (neutropenia, Ray and Ceru ( 1968); 

(monkey; dietary) mg/kg/day thrombocytopenia, and Kirton et al. ( 1970) 

anemia) and secondary 

hemorrhagic pneumonia, 

enteritis, pleuritis, and 

peritonitis. 

55-day oral toxicity 0 or 25 mg/kg/day NOA EL= 25 mg/kg/day. Ray et al. ( 1967) (monkey; gavage) LOAEL not observed. 

NOAEL not observed. 

LOA EL = 35 mg/kg/day 

30-day oral toxicity (dog; 0 or 35 mg/kg/day based on decreased Glenn et al. ( 1969) dietary) prostate and testis weight 

and decreased body 

weight. 

NOAEL not observed. 

LOAEL = 30 mg/kg/day 

based on increased relative 

kidney weight (F) on day 

2; increased scrum ALT 

4-week oral toxicity (rat; 

(F), decreased Hb and Marchesini and Stalder 0, 30, or 60 mg/kg/day MCV (M&F), and 

gavage) increased relative kidney (1983) 

and liver weights on day 

25; and mild tubule 

dilatation of testes and 

decreased body-weight . gain at tem1ination . 

NOA EL not observed. 

LOAEL = 9/ 11 mg/kg/day 

(M/F) based on increased 

90-day oral toxicity (rat; 0, 9/ I I, 27 /3 1, or 43/46 mg/kg/day relative kidney weight, Marchesini and Stalder decreased serum drinking water) (M/ F) creatinine, and increased ( 1989) 

number ofexfoli ated 

epididymal spermatozoids 

(M only)•. 

NOA EL = 20 mg/kg/day. 

Carcinogenicity (mouse; 0 or 2 mg/mouse (equivalent to 20 LOAEL not observed. Van Duuren et al. 

dermal) mg/kg/day; 3X/week) for 83 weeks No skin papillomas or (1974) 

carcinomas observed. 

NOAEL not observed. 

0, 30, or 60 mg/kg/day (2X/week); 

LOAEL = 30 mg/kg/day 

Chronic Oral based on severe testicular 

Toxicity/Carcinogenicity 

doses increased to 0, 35, or 70 degeneration and atrophy. 

Weisburger et al. 

(rat; gavage) mg/kg/day (after I 0 weeks) up to ( 198 1) 

week 72 Marginally positive trend 

(P=0.044) only for 

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Alpha-Chlorohydrin Human Health Risk Assessment 0428647 

Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile - Alpha-Chlorohydrin. 

Study Type • Doses Results MRID/Refer ence 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 010, 1.1 / 1.4, 5.2/7.0, or 28135 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 

hyperplasia in males; and 

increased incidences of 

kidney tubule hyperplasia 

in females*. 

NOAEL not observed. 

LOA EL= 25 mg/kg/day 

based on decreased sperm 

Non-guideline - Male motility after 3 days Kreider and Dutt reproductive function and 0 or 25 mg/kg/day (25 days) (reversible), increased# (1970) perfom1ance (sheep; capsule) abnormal spem1 

(irreversible), and 

decreased fertil ity 

(reversible). 

NOAEL not observed. 

Non-guideline - 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 lity and concentration ( 1972) 

after 3 days (reversible) 

and infertility (reversible). 

Non-guideline - Male 

reproductive function and 0 or 15 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-guideline - 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) 

Epididymal lesions also 

observed at 35 mg/kg/day 

afler single dose. 

Non-guide line - 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 (equivalent to 0, 2.9, 4.3 , 5.7, 8.6, LOA EL = 4.3 mg/kg/day Ericsson and Baker 

and performance (rat; 14, 29, 43, or 86 mg/kg/day; I, 2, or based on infertility (8 (1970) 

gavage) 8 days) days). 

NOAEL = I mg/kg/day. 

Non-guideline - Male and 0, 0.2, 1, 1.25, 2.5, 5, I 0, or 25 LOA EL = 1.25 mg/kg/day 

female reproductive function mg/rat (2 weeks-4 months) based on decreased (30%) Vickery et al. ( 1974) 

and performance (rat; oral) fertility and percentage of 

fertilized eggs. 

Page 11 of 15 
Alpha-Chlorohydrin Human Health Risk Assessment 0428647 

Table A.2.2. Subchronic and Chronic Toxicity and Gcnotoxicitv Profile - Alpha-Chlorohvdrin. 

Study Type• Doses Results MRID/Rcfcrence 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) 

drinking water) mg/kg/day ( 10 days) based on epid idyma l 

lesions. 

NOAEL not observed. 

LOAEL = 140 mg/kg/day 

Non-guideline - Male 

• 

based on sloughing of 

reproductive function (rat; 0 or 140 mg/kg epididymal epithelium Hoffer et al. ( 1973) 

gavage) after 2 hrs., followed by 

obstruction of epididymal 

tract. 

NOAEL = 2 mg/kg/day. 

Non-guideline - Male and LOAEL = 3 mg/kg/day 

fema le reproductive 0, 0. 1, 0.5, 1, 2, 3,4, 5, or I 0 mg/kg* based on increased Parish ( 1989) 

perfonnance (rat; gavage) incidence of preimplantation loss. 

NOAEL not observed. 

Non-guideline - Male and LOA EL = 5 mg/kg/day 

based on decreased sperm Woods and Garside female reproductive 0, 5, I 0, or 20 mg/kg (5 or 14 days) motility, altered sperm (1996) performance (rat; gavage) motion, and decreased 

pregnancy rate (0%). 

NOAEL not observed. 

Non-guideline - Male and LOAEL = 5 mg/kg/day Kawaguchi er al. fema le reproductive 0, 5, or 20 mg/kg (3 or 18 days) based on altered sperm (2004) perfonnance (rat; gavage) motion and decreased 

pregnancy rate. 

Non-guideline - 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 mg/kg/day Kwack et 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/kg/day 

based on reduced 

Non-guideline - Male percentage of motile 

reproductive function (rat; 0, 5, I 0, or 20 mg/kg (8 days) sperm, curvilinear Toth et al. (1992) 

drinking water) velocity, straight-line 

velocity, lateral head 

displacement, and 

linearity. 

NOAEL = I mg/kg/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 et al. ( 1994) 

performance (rat; gavage) sperm and decreased 

fertility. 

NOAEL = 1 mg/kg/day. 

LOA EL= 3 mg/kg/day 

Non-guideline - Male and based on decreased 

female reproductive function 0, I, 3, or 10 mg/kg (9 days) fertilization and pregnancy Ban et al. ( 1999) and performance (rat; rates, # spem1 reaching 

gavage) oviducts of females, sperm 

velocity, and lateral head 

displacement. 

Non-guideline - Male and 0, 2, or 8 mg/kg (14 days) NOAEL not observed. Yamada et al. ( 1995) female reproductive function 

Page 12of15 
Alpha-Chlorohydrin Human Health Risk Assessment 0428647 

Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profil e - Alpha-Chlorohydrin. 

Study Type• Doses Results MRID/Reference No. 

and performance (rat; LOA EL = 2 mg/kg/day 

gavage) based on decreased sperm 

activity when incubated 

for 2 hrs. 

NOAEL = 50 mg/kg/day. 

LOA EL = I 00 mg/kg/day 

based on decreased 

Non-guideline - absolute and relative 

0, 25, 50, or I 00 mg/kg ( 14 days) thymus weight (in the Lee et al. (2004, 2005) lmmunotoxicity (rat; gavage) absence of decreased body 

weight), # cells in spleen 

and thymus, and antibody 

forming response. 

In vivo dominant lethal 125 mg/kg i.p. or 20 mg/kg/day mutation (JCR/Ha Swiss Negative* Epstein et al. ( 1972) 

mice) (oral; 5 days) 

In vivo dominant lethal 0, 5, or I 0 mg/kg/day (oral; 5 days) Negative* Jones et al. ( 1969) mutation (male mice) 

In vivo dominant lethal 0, 5, I 0, or 20 mg/kg/day (oral; 5 Negative* Jones and Jackson 

mutation (male Wistar rats) days) (1976) 

In vivo micronucleus test 40- 120 mg/kg Negative* Jaccaud and 

(bone marrow, OF1 mice) Aeschbacher ( 1989) 

Negative* 

In vivo micronucleus test 0, 15, 30, or 60 mg/kg/day (oral; 2 Piloerection and bone (bone marrow, male Han days) marrow cytotoxicity Marshall (2000) 

Wistar rats) observed after 2 days at 60 

mg/kg/day. 

In vivo unscheduled DNA 

synthesis (male 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/plate) Positive with and without Silhankova et al. 

(S. cyQhimurium TA 1535) metabolic activation * (1982) 

In vitro reverse mutation Negative with and without Silhankova et al. (S. cyphimurium TAl537, 2-200 μmol/plate (0.2-22 mg/plate) 

TAl538, TA98) metabolic activation * (1982) 

In vitro reverse mutation I 0-1000 nol/pl ate (I. 1-1 I 0 Positive with and without Stolzenberg and Hine (S. cyphimurium TA I 00, 

TAl535) mg/plate) metabolic activation*. ( 1979; 1980) 

Negative with metabolic 

In vitro reverse mutation I 00- IOOO μmo I/plate (I 1-1 10 activation. Stolzenberg and Hine 

(S. typhimurium TA98) mg/plate) Equivocal without (1979) 

metabolic activation*. 

In vitro reverse mutation Positive with and without (S. tyQhimurium TA I 00, 0.1-10 mg/plate metabolic activation*. Zeiger et al. ( 1988) 

TA 1535) 

Negative with metabolic 

ln vitro reverse mutation activation. 

(S. cyphimurium T A97) 0. 1-10 mg/plate Zeiger et al. ( 1988) 

Not tested without 

metabolic activation*. 

Page 13of 15 
Alpha-Ch lorohydrin Human Health Risk Assessment 0428647 

Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile - Alpha-Chlorohydrin. 

St udy Type • Doses Results MRID/Reference No. 

Negative with metabolic 

In vitro reverse mutation activation. 

(S. typhimurium T A98) 0.1 -10 mg/plate Zeiger et al. ( 1988) 

Positive without metabolic 

activation•. 

Negative with metabolic 

In vitro reverse mutation activation. Majeska and Matheson Not reported (S. typhimurium TA I 00) Not tested without (1983) 

metabolic activation* . 

In vitro reverse mutation 0.01-1.25 mg/plate Positive with and without Ohkubo et al. ( 1995) (S. typhimurium TA I 00) metabolic activation*. 

Negative with metabolic 

In vitro reverse mutation activation. 

(S. typhimurium TA677, 0.01-1.25 mg/plate Ohkubo et al. ( 1995) 

TA98) Positive without metabolic 

activation•. 

In vitro mutation (E. coli 2-200 μmo l/plate (0.2-22 mg/plate) Negative with and without Silhankova et al. 

WP2, TM930, TM I 080) metabolic activation*. ( 1982) 

In vitro mutation (E. coli 2-200 μmol/plate (0.2-22 mg/plate) Negative with and without Ohkubo et al. ( 1995) WP2, TM930, TM I 080) metabolic activation•. 

Negative with metabolic 

In vitro forward mutation activation. 

(Schizosaccharomyces I 00-300 mmol/L ( 11-33 mg/ml) Rossi et al. ( 1983) 

plombe) Positive without metabolic 

activation•. 

Positive with metabolic 

In vitro gene mutation activation. 

(Mouse lymphoma ce lls, Tk 2-9 mg/ml Henderson et al. ( 1987) 

locus) Negative without 

metabolic activation*. 

In vitro mutation (HeLa Not reported Negative with and without Painter and Howard 

cells) metabolic activation•. (1982) 

In vitro mutation (Mouse 0.1-2 mg/ml Positive* Piasecki et al. ( 1990) fibroblasts, M2 clone) 

In vitro sister chromatid Positive with and without 

exchange (Chinese hamster 0.7-2.8 mg/ml May ( 1991) 

V79 cells) metabolic activation*. 

In vitro gene mutation Weak positive at toxic 

(Chinese hamster V79 cells, 0.3-70 mmol/L (0.033-7.7 mg/ml) concentration of 50 GOrlitz ( 199 1) 

hprt locus) mmol/L (5.5 m?/ml)*. 

Page 14of15 
Alpha-Chlorohydrin Human Health Risk Assessment 0428647 

Table A.2.2. Subchronic and Chronic Toxicitv and Genotoxicitv Profile - Alpha-Chlorohvdrin. 

Study Type • Doses Results MRID/Reference No. 

After 24 hrs, 9% o.-

ch lorohydrin excreted 

unchanged in urine; 30% 

exhaled as C02 (although 

much of dose unaccounted 

for); P-chlorolactate 

comprised 23% of 

urinary metabolites. Jones et al. ( 1978)*; 0 or I 00 mg/kg (i.p.) Evidence for tissue- Miller and Krake Metabolism 0, I 0 (rats, rabbits) or 17 (monkeys) specific localization of is ( 1968); Krake and 

mg/kg (oral) equivocal. Parent is Miller (1969) detoxified by conjugation 

with glutathione and then 

by acetylation to form the 

corresponding mercapturic 

acid; compound also 

undergoes oxidation to Pchlorolactic 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 Series No. 48, 401-432. 

Table A.2.3. Parenteral Toxicity Profile - Alpha-Chlorohydrin. 

Study Type • Doses Results MRID/Reference No. 

Acute/4-day toxicity NOAEL not observed. 

(subcutaneous injection; 0 or 35 mg/kg/day LOAEL = 35 mg/kg/day G Jenn et al. ( 1969) based on decreased dog) prostate and testis weights. 

NOAEL not observed. 

30-day toxicity LOAEL = 35 mg/kg/day 

based on decreased Glenn and Sokolowski (subcutaneous injection; 0 or 35 mg/kg/day prostate and testis weights (1969) dog) and decreased body 

weie.ht. 

Male and female NOA EL= 0.5 mg/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 

perfonnance 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/kg/day. Glenn and Sokolowski performance 0 or 35 mg/kg/day (I or 4 days) LOAEL not observed 4-5 (1969) (subcutaneous injection; 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) (intraperitoneal; mouse) tremors and severe lesions 

in the central nervous 

system. 

Page 15of15