2 Table of Contents EXECUTIVE SUMMARY

................................ ................................ ................................ ......... 3

I. BACKGROUND

................................ ................................ ................................ ..................... 7

II. INERT INGREDIENT PROFILE

................................ ................................ ........................... 7
III. HUMAN HEALTH ASSESSMENT

................................ ................................ ................... 8
A. Summary of Toxicity Data

................................ ................................ ................................ ... 8

B. Toxicity Endpoint Selection

................................ ................................ .............................. 16

C. Special Considerations for Infants and Children

................................ ................................ . 17

IV. EXPOSURE ASSESSMENT

................................ ................................ ................................ . 17
A. Dietary Exposure:

................................ ................................ ................................ .............. 18 i. Acute exposure

................................ ................................ ................................ ................... 19

ii. Chronic exposure

................................ ................................ ................................ ............... 19 iii. Cancer exposure

................................ ................................ ................................ ............... 19

B. Residential Exposure

................................ ................................ ................................ ......... 19

V. AGGREGATE RISK AND DETERMINATION OF SAFETY

................................ ............ 19 A. Acute Dietary Risk

................................ ................................ ................................ ............... 19 B. Chronic Dietary Risk.

................................ ................................ ................................ ........... 19 C. Aggregate Cancer Risk for U.S. Population

................................ ................................ ......... 20

D. Short

- Term Aggregate Risk

................................ ................................ ................................ . 20

E. Intermediate

- Term Aggregate Risk

................................ ................................ ...................... 20 F. Determination of Safety

................................ ................................ ................................ ........ 20

VI. OCCUPATIONAL EXPOSURE/RISK PATHWAY

................................ ........................ 20
A. Occupational Handler Risk

................................ ................................ ................................ 20

B. Occupational Post

- Application Risk

................................ ................................ .................. 21

VII. CUMULATIVE EXPSOURE

................................ ................................ ........................... 21

VIII. ENVIRONMENTAL JUSTICE STATEMENT

................................ ............................ 22

IX. ENVIRONMENTAL FATE CONSIDERATIONS

................................ .......................... 22

X. ECOTOXICITY

................................ ................................ ................................ .................... 22

XI. RISK CHARACTERIZATION

................................ ................................ ......................... 23

REFERE NCES

................................ ................................ ................................ ............................. 27
APPENDIX

................................ ................................ ................................ ................................ ... 293 EXECUTIVE SUMMARY

Dupont Tate & Lyle BioProducts Company. (198 Blair Bend Drive, Loudon, TN 37774) submitted a petition (PP 2E8091), requesting an exemption from the requirement of a tolerance pursuant to section 408(d)(1) of the Federal Food, Drug, and Cosmetic Ac t with respect to 1,3

- propanediol (CAS Reg. No. 504

- 63

- 2) as an inert ingredient for pre

- and post

- harvest (40 CFR 180.910) and antimicrobial food

- contact surface sanitizing formulations (40 CFR 40180.940). EPA published the Notice of Filing for this petit ion in the Federal Register on January 16, 2013 (78 FE 3377). No substantial comments were received in response to this notice. 1,3

- Propanediol was approved for non

- food use in 2011. The majority of the data in this risk assessment decision document has be en taken from the 2011 non

- food use decision document.

The acute oral toxicity of 1,3

- propanediol in rodents, expressed as an LD 50 ranges from 10,500 to 15,789 mg/kg bw. No acute dermal toxicity studies for 1,3

- propanediol were available in the toxicity database. The acute inhalation toxicicty of 1,3

- propanediol in rats produced a LC 50 was > 5.0 mg/L. Primary eye irritation studies of 1,3

- propanediol on rabbits showed minimal effects, slight redness of the conjunctivae

, and clearing in less than 24 hours. It is considered minimally irritating to the eyes of rabbits. Primary skin irritation studies with 1,3

- propanediol showed slight to mild erythema and edema to rabbits but clearing after 72 hrs. It is considered mildly irritating to the skin of rabbits. Dermal sensitization studies on guinea

- pigs showed that 1,3

- propanediol is not a sensitizer.

In a 14

- day inhalation toxicity study (MRID 48439008) three groups of 10 male Crl:CD (SD) IGS BR rats each were exposed by inha lation to either vapor only or a vapor/aerosol mixture of 1,3

- propanediol in air at concentrations targeted to 60, 600, or 1800 mg/m 3 (0.06, 0.60 or 1.80 mg/L) for 6 hours/day, 4 or 5 days/week for a total of 9 exposures. A procedural control group of 10 m ale rats were exposed simultaneously to air only. The analytically determined mean concentrations of 1,3

- propanediol in the exposure chambers were 41, 650 and 1800 mg/m 3 (0.041, 0.650, and 1.800 mg/L) over the duration of the study. All rats survived to th e termination of the study and were sacrificed at the end of the study duration. There were no test substance

- related clinical signs of toxicity observed during the study. No statistically significant body weight differences were observed in any group. The re were no compound

related adverse effects noted during clinical observations or pathology evaluations. The NOAEL for repeated inhalation exposure to 1,3

- propanediol in male rats was considered to be 1800 mg/m 3 or 1.8 mg/L (the highest dose tested) and no LOAEL was identified.

In a 90

- day oral toxic ity study (MRID 48439004), 1,3

- p ropanediol was administered to 10 Crl:CD ® (SD)BR rats/sex/dose by gavage at dosages of 0, 100, 300 or 1000 mg/kg/day. Reverse osmosis

- treated water was administered to controls. A ll animals survived to the scheduled necropsy. No test article

- related changes in the clinical condition of the animals were observed. Mean body weights, body weight gains, food consumption, clinical pathology parameters (hematology, serum chemistry) and o rgan weights were unaffected by test article administration. No treatment related changes were observed in eyes up on ophthalmoscopic examinations at the end of the study. Spermatogenic endpoints were unaffected in all treated males. No treatment

- related c hanges were observed at the macroscopic and microscopic examinations. Based on the data obtained, the NOAEL for systemic toxicity of 1,3

- p ropanediol4 administered orally via gavage to male and female rats for 91 or 92 consecutive days was 1000 mg/kg/day (th e highest dose tested) and no LOAEL was identified

. The mutagenic potential of 1,3

- propanediol was evaluated in a bacterial reverse mutation test, an in vitro mammalian cell gene mutation test, an in vitro chromosome aberration assay, an in vitro mammalia n cell chromosome aberration assay and a mammalian erythrocyte micronucleus test. These test were all negative except for the in vitro mammalian cell chromosome aberration assay which showed under the reported experimental conditions that 1,3

- propanediol r eproducibly induced structural chromosomal aberrations in the V79 Chinese hamster cell line. However due to negative in vivo mouse micronucleus assay, there are no concern for clastogenicity. Based on the results of these studies, 1,3

- propanediol is not considered to be mutagenic.

No carcinogenicity studies on 1,3

- propanediol were available in the toxicity database

, however based on the lack of mutagenicity concerns, lack of any systemic toxicity at the limit dose and lack of any st ructural alerts for carcinogenicity in Derek analysis, , there are no concerns for carcinogenicity for 1,3

- propanediol.

In a developmental toxicity study, 1,3

- p ropanediol was administered to 20 pregnant female Sprague

- Dawley (Hag: SD) rats/dose by gavage in 0.8% aqueous hydroxypropyl

methylcellulose gel (with cons tant dose volume of 10 mL/kg bw ) at dose levels of 0, 250, or 1000 mg/kg bw/day on gestation days (GDs) 6 through 15. Dams were sacrificed and necropsied on GD 20. There were no treatm ent

- related effects on maternal survival, clinical signs, body weight, food consumption, or gross pathology. The maternal LOAEL is not identified, and the maternal NOAEL is greater than or equal to 1000 mg/kg bw/day (the highest dose tested)

. There

were n o treatment

- related effects on live litter size, fetal deaths, early or late resorptions, or the fetal sex ratio. Mean fetal weights, fetal lengths, and placental weights of the treated groups were similar to those of controls and there were no significan t increases in the litter incidences of any individual morphological variation or retardation for either treated group. The developmental LOAEL is not identified, and the developmental NOAEL is greater than or equal to 1000 mg/kg bw/day (the highest dose tested)

. There were no immunotoxicity or neurotoxicity studies on 1,3

- propanediol available in the toxicity database. However, there was no evidence of clinical signs of neurotoxicity or immunotoxicity triggers in the available database up to the limit do se.
The proposed metabolic pathway for 1,3

- propanediol follows that for other simple alcohols, where alcohol and aldehyde dehydrogenase enzymes sequentially break down this substance to aldehydes and acids used in intermediary metabolism. 1,3

- propanediol is metabolized to 3

- hydroxypropionaldehyde, malondialdehyde or 3

- hydroxypropionic acid, malonic semi

- aldehyde, malonic acid, and ultimately, carbon dioxide and water.

EPA did not use a safety factor analysis for assessing risk because no toxicological

e ndpoints have been identified for this chemical.5 Acute and chronic dietary risk assessments were not conducted because no endpoints of concern following single or multiple exposures were identified in the available studies. 1,3

- Propanediol is not expected to be carcinogenic. Therefore, a cancer dietary exposure assessment is not necessary to assess cancer risk.

The term “residential exposure” is used in this document to refer to non

- occupational,

non

- dietary exposure (e.g., for lawn and garden pest control, indoor pest control, termiticides, and flea and tick control on pets). Due to the absence of a toxicity endpoint for 1,3

- propanediol in the database, residential exposure is not expected to be of concern. Therefore a quantitative residential exposure risk assessment was not performed.

Short

- term aggregate exposure takes into account short

- term re sidential exposure plus chronic exposure to food and water (considered to be a background exposure level). 1,3

- Propanediol is used as an inert ing redient in pesticide products that are currently registered for uses that could result in short

- term residential exposure however no adverse effects were attributable to chronic exposure to 1,3

- propanediol were seen in the toxicity database; therefore,

a s hort

- term aggregate risk assessment is not required.

Intermediate

- term aggregate exposure takes into account intermediate

- term residential exposure plus chronic exposure to food and water (considered to be a background exposure level). 1,3

- Propanediol is used as an inert ingredient in pesticide products that are currently registered for uses that could result in intermediate

- term residential exposure however no adverse effects were attributable to chronic exposure to 1,3

- propanediol were seen in the tox icity database; therefore, an intermediate

- term aggregate risk assessment is not required.

Due to the absence of dermal and inhalation toxicity, o ccupational handler and post

application risks are not of concern. Therefore occupational handler and pos t

- application risk assessments were not performed.

Based on a Biodegradability study (Berti 2007), the compound 1,3

- propanediol is readily biodegradable. Based on physico

- chemical properties, 1,3

- propanediol is water soluble and will partition to the soil . The low Kow (

- 0.71) suggests that 1,3

- propanediol is not expected to absorb by sediment or suspended solids. The study showed that 71% of the compound was converted to CO 2 after 28 days suggesting that the substance was completely mineralized without any major metabolites or degradation products. Due to its rate of biodegradation, 1,3

- propanediol is not expected to be of major environmental fate concern.

Based on 3 acute ecotoxicity studies, 1,3

- propanediol is practically non

- toxic to freshwater invert ebrates, freshwater fish and algae. Freshwater invertebrate, Daphnia magna had a 24

- hr EC 50 of 8285 mg/L and a 48

- hr EC 50 of 7417 mg/L. The freshwater fish, fathead minnow had a 96

- hr LC 50 of 9720 mg/L. Lastly the algae, Scendesmus subspicatus

, had a 72

- hr E b C 50 of 1.6g/L and a 72

- hr E r C 50 >10 g/L with a NOAEC ≤ 0.5 g/L

. Taking into consideration all available information on 1,3

- propanediol, EPA concludes that there is a reasonable certainty that no harm to any population subgroup will result from aggregate exposure to 1,3

- propanediol when considering occupation, dietary e xposure and all6 other nonoccupational sources of pesticide exposure for which there is reliable information. Therefore, the establishment of an exemption from tolerance under 40 CFR 180.910 and 180.940 for residues of 1,3

- propanediol (CAS Reg. No. 504

- 63

- 2 ) when used as a pesticide inert ingredient for pre

- and post

- harvest (40 CFR 180.910) and antimicrobial food

- contact surface sanitizing formulations (40 CFR 180.940), can be considered assessed as safe under section 408(q) of the FFDCA.7 I. BACKGROUND

Dup ont Tate & Lyle BioProducts Company . ( 198 Blair Bend Drive, Loudon, TN 37774 ) submitted a petition (PP 2E8091 ), requesting an exemption from the requirement of a tolerance pursuant to section 408(d)(1) of the Federal Food, Drug, and Cosmetic Act with respe ct to 1,3

- propanediol (CAS Reg. No. 504

- 63

- 2) as an inert ingredient for pre

- and post

- harvest (40 CFR 180.91 0) and antimicrobial food

- contact surface sanitizing formulations (40 CFR 40180.940)

. The majority of the data summarized below will be reference d from the non

- food use decision document for 1,3

- propanediol registered as an inert ingredient in pesticide formulations as a solvent, co

- solvent, diluent, or freeze point depressant. (US EPA 2011)

1,3

- propanediol is manufactured through a multi

- step fer mentation, separation and distillation process using a genetically modified non

- pathogenic and non

- toxigenic strain of Escherichia coli K

- 12. The production begins with fermentation of corn sugar by E. coli. At the end of fermentation, the biomass is deact ivated at a high temperature and removed. 1,3

- propanediol is separated from the fermentation broth by a three

- step process involving ion exchange to remove charged impurities, evaporation to remove water, and distillation to remove impurities. No solvents are used in the separation process. The final 1,3

- propanediol is a flammable, colorless and water soluble liquid.

II. INERT INGREDIENT PROFILE

A. Summary of Uses 1,3

- Propanediol is used in many applications but mainly as a monomer for the production of polyesters, polyethers and polyurethanes. It is the raw material for the production of biodegradable plastics, films, solvents, adhesives, detergents, cosmetics and med icines. (Kaur G. et al. 2012)

1,3

- Propanediol is also used as a solvent, co

- solvent, diluent, or freeze point depressant in several types of pesticide formulations, currently used for non

- food use purposes. The pesticide products may be formulated as a pr essurized liquid and aerosol, non

- pressurized liquid and trigger spray, ready

- to

- use, mop and bucket dilutable, and towelettes. It is used on the following sites: air treatment (eating establishments, hospitals, commercial, institutional, household, bathro om, transportation facilities); medical premises and equipment (including instrument pre

- soak), commercial, institutional and industrial premises and equipment; laundry equipment; hard non

- porous surface treatments (bathrooms facilities); automobiles; air conditioning filters; environmental inanimate hard surfaces; garbage containers/storage.

The proposed use is intended for pesticide formulations such as fungicides, insecticides, rodenticides, and herbicides; and, food contact surface sanitizing solution s for public eating places, dairy

- processing equipment, and food

- processing equipment and utensils.8 B. Physical Chemical Properties Some of the physical and chemical characteristics of 1,3

- propanediol , along with its structure and nomenclature, are found in Table 1.

Table 1. Physical and Chemical Properties of 1,3

- Propanediol

Parameter Value Source

Structure ChemIDplusLite

CAS # 504

- 63

- 2 ChemIDplusLite Molecular Weight (g/mol) 76.09 ChemIDplusLite

Common Names 1,3

- Propanediol, Trimethylene glycol, Propane

- 1,3

- diol ChemIDplusLite

Physical State Liquid ChemIDplusLite Melting Point (°C)

- 2.67E+01 ChemIDplusLite Boiling Point (°C) 214.4 ChemIDplusLite Density (g/cm 3 @ 20°C) 1.0597 MSDS Vapor Pressure (mmHg @ 25°C) 0.0441 ChemIDplusLite Partition Coefficient (Kow )

- 1.04E+00 ChemIDplusLite

Water Solubility (mg/L) 1.00E+06 ChemIDplusLite

Henry's Law Constant 1.74E

- 07 ChemIDplusLite

III. HUMAN HEALTH ASSESSMENT

A. Summary of Toxicity Data

Acute Oral Toxicity In an acute oral toxicity study (MRID 48422607), four rats of each sex, were administered 1,3

- propanediol at a dose level of 10.5 ml/kg (equivalent to 10,500 mg/kg). The animals were weighed, fasted overnight and the calculated dose of undiluted 1,3

- propan ediol administered by gavage using a ball

- point needle fitted to a syringe. After dosing, food and water were available ad libitum throughout a nine day observation period. The acute oral LD 50 value of rats given undiluted 1,3

- propanediol was found to be

a pproximately 10 ml/kg (10,000 mg/kg) equivalent to 10,500 mg/kg. Apart from piloerection seen in animals 24 hours after dosing there were no other signs of toxicity.

In another acute oral toxicity study (MRID 48422633), young adult albino rats (Wistar

de rived) were used. 1,3

- Porpnaediol was given undiluted by gavage to groups of five9 males and five females in single doses of 9.0, 10.8, 13.0, 15.6, or 18.7 ml per kg body weight (equivalent to 9000, 10800, 13000, 15600 or 18700 mg/kg). After treatment the

r ats received stock diet and tap water ad libitum . They were observed for signs of intoxication during a 14 day period, after which necropsies were carried out on the survivors. The LD50 was calculated according to the method of Weil (Biometrics8 (1952) 249

- 263). Within a few hours after dosing the rats showed sluggishness, sedation and ataxia but specific doses were not reported. Unconsciousness was frequently observed and preceded death. Most of the deaths occurred between 8 and 23 hours after treatment. O ne female died on the 4 th and one male on the 7 th post

- treatment day and again the dose information was not reported. After 7 days the survivors recovered gradually and looked quite healthy again at the end of the observation period. Macroscopic examinatio n of the survivors did not reveal any treatment

- related gross alterations. From the mortality figures the LD 50 of 1,3

- propanediol was calculated to be 14.9 ml per kg body weight(>15,000 mg/kg bw assuming 100% purity) with 13.7 and 16.3 as the 95% confidence limits. Therefore, the material can be classified as practically

non

- toxic.

Dermal Toxicity No studies available in the database.

Inhalation Toxicity In a acute inhalation study (MRID 48422 619), six male Crl:CD(SD)BR rats were exposed nose

- only for a single, four

- hour period to 1,3

- porpanediol aerosol at 5.0 mg/L (238 mg/kg). Test atmospheres were generated by aerosolization and concentrations of 1,3

- propanediol were measured by gravimetric analysis. Rats were weighed and observed for clinical signs of toxicity during a 14

- day recovery period. Rats were exposed to the aerosol of 1,3

- propanediol at a concentration of 5.0 mg/L (238 mg/kg). The mass median aerodynamic diameter for the aerosol te sted was 3.2μm (within respirable range )

. All rats exposed to 1,3

- propanediol survived the exposure and subsequent 14

- day recovery period. Wet fur/perineum and ocular discharge were noted in rats immediately following the exposure and were the only clinica l signs observed during the study. All rats exhibited slight to moderate weight loss one day after exposure. Although one rat had transient body

- weight loss during the remainder of the recovery period, all rats experienced an overall weight gain by the end of the 14

- day recovery period. Under the conditions of this study, the LC 50 for 1,3

- propanediol was greater than 5.0 mg/L (238 mg/kg). On an acute inhalation basis, 1,3

- propanediol is considered to be of very low toxicity

. Primary Eye Irritation In an acute eye irritation study (MRID 48422607), one male and one female albino rabbit was used. 1,3

- Propanediol (0.2 mL) was instilled into the conjunctival sac of one eye of each rabbit; the untreated eye served as a control. A visual assessment of irritancy was made 30 minutes after application and again 1, 2, 3 and 7 days after application, thence every 4 days until eye irritancy was no longer observed. In this study, the formulation was mildly irritating up to 48 hrs after instillation.10 In another acute eye irritation study (MRID 48439011), six New Zealand white albino rabbits are used for each test substance. The animals were caged individually and receive no hay or other extraneous material that might enter the eyes. The eyes of the animals were examine d before testing and only those animals without observable eye defects were used. One tenth of a millilitre of the test substance were allowed to fall on the inverted lower lid of one eye of each rabbit; the upper and lower eye lid were then carefully clos ed and subsequently held together for at least one second before releasing, to prevent loss of material. The other eye, remaining untreated, serves as a control. The eyes were not washed following instillation and the animals were released immediately. The eyes were examined at 24, 48, 72 hours and 7 days after instillation of the test material. The ocular effects of propanediol

- 1,3 consisted of slight redness of the conjunctivae in four out of six rabbits. After 48 hours these effects cleared up. In this

s tudy, the formulation was minimally irritating

Primary Skin Irritation In an acute dermal irritation study (MRID 48422607), the occluded patch test of Draize was used to assess the skin irritation potential of undiluted 1,3

- propanediol to abraded and inta ct rabbit skin (4/sex). Lint patches were applied to the abraded and intact skin and 0.5ml test material was applied to each. The patches were left in place for 24 hours. Reactions were assessed visually for the degree of erythema and edema. Seven days aft er the application of the test material a final visual assessment was made. In this study, the formulation was mildly irritating with no signs of skin irritation 3 days after the exposure period.

In another acute dermal irritation study (MRID 48439011), twelve healthy adult New Zealand White albino rabbits were used. Twenty four hours prior to applying the materials, the hair was removed from the backs of the animals. An amount of 0.5 ml of the test substance was brushed on the intact or abraded skin unde r a surgical patch measuring 1 inch x 1 inch. The patches were fixed to the application site by means of adhesive tape and the entire trunks of the rabbits were wrapped with an impervious material to maintain the test patches in position and to retard evap oration of volatile substances. Six rabbits were treated on the intact skin, the other six on the abraded skin. The abrasions were minor incisions through the stratum corneum, but not sufficiently deep to disturb the derma or to produce bleeding. After an exposure period of 24 hours the patches and the material applied were removed and the resulting skin reactions were evaluated by the method of Draize. A second reading was made 48 hours later (72 hours after application). In this study, the formulation wa s slightly irritating, which consists of very slight erythema and edema which was cleared after 72 hrs

.
Dermal Sensitization In a skin sensitization study (MRID 48422635), a total of 32 young male albino SPF guinea pigs, were randomly divided into 4 grou ps. Two control groups and two test groups comprising 8 animals each. One control and one test group was used for each of the test samples. The test animals were treated with intradermal injection of 0.1 mL of a 25% aqueous dilution for the induction perio d. A 10% aqueous dilution was used for the challenge dose. The test samples caused mild to severe skin reactions upon repeated11 intradermal injections in all animals during the induction period. There were no significant differences between test and contro l animals with respect to the degree and incidence of erythema and edema. From the results obtained it may be concluded that no sensitization occurred upon treatment with the two products tested. Based on the results of this study, 1,3

- propanediol is not considered to be a contact sensitizer.

In a separate skin sensitization study (MRID 48422607), the guinea

- pig maximization test as described by Magnusson and Kilgman, was used to assess the skin sensitization potential of 1,3

- propanediol. Intradermal induction was performed at 2.5% w/v 1,3

- propanediol in water. A topical induction was tested and undiluted. The topical challenge was 50% 1,3

- propanediol in water. Based on the results of this study, 1,3

- propanediol is not considered to be a contact sensi tizer.

The results of the available acute toxicity studies are summarized in Table 3. Acute Toxicity

Table 3. Acute Toxicity Profile of 1,3

- Propanediol

Study Type Results Toxicity Category MRIDs # /Reference Acute Oral

- rat LD 50 = 10,500 mg/kg bw (Range Finding) N/A 48422607 Acute Oral

- rat LD 50 = 15,789 mg/kg bw IV 48422633 Acute Dermal

- N/A N/A N/A Acute Inhalation

- rat NOAEL > 5.0 mg/L IV 48422619 Primary Eye Irritation

- rabbit Minimal effects, clearing in less than 24 hrs IV 48422607 Primary Eye Irritation

- rabbit Minimal effects, clearing in less than 24 hrs IV 48439011 Primary Skin Irritation

- rabbits Mild Erythema and edema, no signs after 72 hrs IV 48422607

Primary Skin Irritation

- rabbits Slight to mild Erythema, slight to no signs after 72 hrs IV 48439011

Dermal Sensitization

– guinea

pigs Product is not a sensitizer Neg. 48422607

Dermal Sensitization

– guinea

pigs Product is not a sensitizer 48422635

Subchronic Inhalation Toxicity

– Rat In a 14 day inhalation toxicity s tudy (MRID 48439008) three groups of 10 male Crl:CD (SD) IGS BR rats each were exposed by inhalation to either vapor only or a vapor/aerosol mixture of 1,3

- propanediol in air at concentrations targeted to 60, 600, or 1800 m g/m 3 (0.06, 0.60 or 1.80 mg/L) for 6 hours/day, 4 or 5 days/week for a total of 9 exposures. A procedural control group of 10 male rats were exposed simultaneously to air only. Rats were weighed prior to each exposure and were observed for clinical signs p rior to, during, and following each exposure. At the end of the exposure period, clinical pathology evaluations were conducted on 10 rats/group, and 5 rats/group were sacrificed and necropsied. At the end of the 18

- day recovery period, the 5 surviving rats /group were given clinical pathology examinations, then sacrificed and necropsied. All rats were examined for gross and microscopic changes. The analytically determined mean concentrations of 1,3

- propanediol in the exposure chambers were 41, 650 and 1800 mg/m 3 (0.041, 0.650, and 1.800 mg/L) over the duration of the study. All rats survived to12 the termination of the study and were sacrificed by design. There were no test substance

related clinical signs of toxicity observed during the study. No statisticall y significant body weight differences were observed in any group. There were no compound

- related adverse effects noted during clinical pathology or pathology evaluations. The NOAEL for repeated inhalation exposure to 1,3

- propanediol in male rats was consid ered to be 1800 mg/m 3 or 1.8 mg/L. Subchronic Oral Toxicity

– Rat In a 90

- day oral toxicity study (MRID 48439004), 1,3 Propanediol (purity not reported; Lot no. D47617, 09/06/96) was administered to 10 Crl:CD ® (SD)BR rats/sex/dose by gavage at dosages of 0, 100, 300 or 1000 mg/kg/day. Reverse osmosis

- treated water was administered to controls. All animals survived to the scheduled necropsy. No test article

related changes in the clinical condition of the animals were observed. Mean body weights, body weight gains, food consumption, clinical pathology parameters (hematology, serum chemistry) and organ weights were unaffected by test article administration. No treatment related effects were observed on eyes at ophthalmoscopic examinations conducted at the end o f the study. Spermatogenic endpoints were unaffected in all treated males. No treatment

- related changes were observed at the macroscopic and microscopic examinations. Based on the data obtained, the no

- observed

adverse

- effect level (NOAEL) for systemic tox icity of 1,3

- Propanediol administered orally via gavage to male and female rats for 91 or 92 consecutive days was 1000 mg/kg/day.

Chronic Oral Toxicity

- No chronic studies were available in the database.

Developmental and Reproductive Toxicity

- Rats 1 ,3

- Propanediol, Polymer Grade (99.8% a.i) was administered to 20 pregnant female Sprague

- Dawley (Hag: SD) rats/dose by gavage in 0.8% aqueous hydroxypropyl

methylcellulose gel (with constant dose volume of 10 mL/kg bw or 10,000 mg/kg) at dose levels of 0, 250, or 1000 mg/kg bw/day on gestation days (GDs) 6 through 15. Dams were sacrificed and necropsied on GD 20. All fetuses were weighed, sexed, measured, and examined externally; approximately one

- half were subjected to visceral examination, and the remai ning one

- half were subjected to skeletal examination. All placentae were weighed individually. There were no treatment

- related effects on maternal survival, clinical signs, body weight, food consumption, or gross pathology. The maternal LOAEL is not iden tified, and the maternal NOAEL is greater than or equal to 1000 mg/kg bw/day. There were no treatment

- related effects on live litter size, fetal deaths, early or late resorptions, or the fetal sex ratio. Mean fetal weights, fetal lengths, and placental we ights of the treated groups were similar to those of controls. Malformations were only observed in one fetus from a control litter, and there were no significant increases in the litter incidences of any individual morphological variation or retardation f or either treated group. The developmental LOAEL is not identified, and the developmental NOAEL is greater than or equal to 1000 mg/kg bw/day.

Immunotoxicity No i mmunotoxicity studies were available in the database.13 Neurotoxicity No neurotoxicity studies were available in the database.

Mutagenicity and Genotoxicity In a reverse gene mutation assay in bacteria (MRID 48439014), strains TA98, TA100, TA102, TA1535 and TA1537 of S. typhimurium were exposed to 1,3

- propanediol (≥99.8% a.i., lot number EK 33/92

- 1) dissolved in double distilled water in two independent assays using triplicate plating. A cytotoxicity assay in strains TA98 and TA100 tested concentrations of 0, 3.3, 10, 33.3, 100, 333.3, 1000, 2500, or 5000 μg/plate with and without S9

- mix. The first mutagenicity assay used the plate incorporation method at concentrations of 0, 33.3, 100, 333.3, 1000, 2500, or 5000 μg/plate with and without S9

- mix. The second mutagenicity assay used the pre

- incubation method at the same concentrations with an d without S9

- mix. The test material 1,3

- propanediol was tested at concentrations up to the limit concentration for the assay, and there was no evidence that the assays were affected by cytotoxicity or insolubility. The number of revertants per plate was no t increased over the concurrent solvent control value at any test material concentration, with or without S9

- mix, in any test strain. The solvent and positive controls induced the appropriate responses in the corresponding strains. There was no evidence of induced mutant colonies over background.

In an in vitro mammalian cell chromosome aberration assay (MRID 48422613), Chinese hamster V79 cells were exposed to 1, 3

- propanediol (Haskell Number H

- 24783, 99.9% purity) in culture medium with and without activation. The concentrations tested were 0, 625, 1250, 2500, and 5000 μg/mL. Without activation (

- S9 mix), the exposures were either for 4 hours, followed by a recovery time of 16 hours before cell harvest or an exposure time of 20 hours followed immedia tely by cell harvest. With activation (+S9 mix), the exposures were for 4 hours, followed by a recovery time of 16 hours before cell harvest. The S9

- fraction was obtained from Aroclor 1254

- induced male Sprague

- Dawley rat liver.

In a cytotoxicity pre

- test experiment, no toxicity effects (as measured by cell killing) were noted either with or without activation up to the limit concentration for the assay of 5000 μg/mL. This established the doses to be used in the cytogenetic tests (0, 625, 1250, 2500, and 50 00 μg/mL). The cytogenetic tests showed that there were no significant increases in the percentages of metaphase cells with structural chromosomal damage or polyploid cells over the solvent control values, either without or with activation. Within the eva luated concentration ranges, both with and without activation, the mitotic indices were not significantly reduced.

In an in vitro mammalian cell chromosome aberration assay (MRID 48439012), Chinese hamster V79 cells were exposed to 1,3

- propanediol (99.8% purity, Batch # EK 33/92

- 1) in culture medium in two separate experiments. In experiment I, without activation, the concentrations tested were 0, 250, 1000, and 2500 μg/mL and the exposures were for 18 hours, followed by cell harvest (18

- hour mutation fixa tion period); with activation (S9 mix), the concentrations tested were 0, 500, 2500, and 5000 μg/mL and the exposures14 were for 4 hours, with a 14

- hour recovery period before harvest (18

- hour mutation fixation period). In Experiment II, without activation, the concentrations tested were 0, 375, 1250, and 2500 μg/mL (18

- hour fixation interval) and 0 and 1250 μg/mL (28

- hour fixation interval). In experiment II, with activation, the concentrations tested were 0, 2500, 3750, and 5000 μg/mL (18

- hour fixation inte rval) and 0 and 5000 μg/mL (28

- hour fixation interval). In experiment II, the treatments lasted 4 h with S9 mix and for the entire fixation interval without S9 mix.

In the same study, a cytotoxicity pre

- test experiment showed no toxicity effects were
note d either with or without activation up to the limit concentration for the assay of 5000 μg/mL. However, in the cytogenetic experiments in the absence of activation, evaluations were only possible up to a concentration of 2500 μg/mL (18

- hour mutation fixati on period) and 1250 μg/mL (28

- hour mutation fixation period) because of low cell and metaphase numbers as well as poor metaphase quality at higher doses. With activation, test groups were scorable up to 5000 μg/mL. Within the evaluated concentration ranges

, both with and without activation, the mitotic indices were not significantly reduced. In both experiments I and II, there were statistically significant and biologically relevant increases in the chromosome aberration frequencies after treatment with 250 0 μg/mL (highest dose attainable) of the test material without activation. With activation, there were no increases in chromosome aberration frequencies in either experiment, up to the maximum dose of 5000 μg/mL. In both experiments there were no increases in the frequencies of polyploid metaphases at any dose level, either with or without activation. The positive controls used in both experiments gave appropriate responses.

In a mammalian cell gene mutation assay at the hypoxanthine

- guanine phosphoribosyl transferase (HGPRT) locus (MRID 48439013 ), Chinese hamster V79 cells cultured in vitro were exposed to 1, 3

- propanediol (≥ 99.8 % a.i., Batch No. EK 33/92

- 1 ) dissolved in culture medium at concentrations of 0, 250, 1000, 2500, or 5000 μ g/mL in the absence and presence of mammalian metabolic activation for 4 hours. The test chemical, 1, 3

- propanediol, was tested up to the limit concentration for the assay. There were no indications of insolubility. The cytotoxicity pretest provided no evidence of cytotoxicit y, either with or without metabolic activation. However, in both independent mutagenicity experiments I and II, in the absence of metabolic activation the cloning efficiencies showed significant decreases at 1000, 2500 and 5000 μg/mL. The cell density at t he first subculturing was only slightly reduced at 2500 μg/mL , being 77.2 % and 75.1% of the control values in experiments I and II, respectively. At the highest test concentration of 5000 μg/mL, there was a marked reduction of the cell density at first su bculturing, to 37.8 % and 14.4 % in Experiments I and II, respectively. The only slight suggestions of any increases in the mutation rate by the test material were not considered biologically significant because (1) the corresponding solvent controls had r elatively low mutation rates in these experiments, (2) the mutation rates of the treated cells were well within the historical control range ( 0

- 45 mutants/10 6 cells), and (3) there were no hints of any increases in response to increasing concentrations. Th e positive controls did induce the appropriate response. There was no evidence of induced mutant colonies over background.15 In a Hsd/Win: NMRI mouse bone marrow micronucleus test (MRID 48439005), 14 mice/sex were administered 2150 mg/kg of 1,3

- propanediol (Batch No. EK 33/92

- 1, 99.8% pure) dissolved in water via gavage. Half the animals were sacrificed 24 hours after treatment and half were sacrificed 48 hours after treatment, with the bone marrow cells being harvested immediately upon sacrifice. In all exp eriments, slides from five animals per sex and group were examined, with 1000 polychromatic erythrocytes (PCEs) being examined for micronuclei per mouse. The ratio of PCEs to normochromatic erythrocytes (NCEs) was always based on 1000 erythrocytes (PCEs + NCEs) scored per slide for every mouse. In the experiment, 1,3

- propanediol was tested only at 2150 mg/kg because a preliminary toxicity assay showed that this was the maximum practicable dose and it exceeded the guideline requirements for a limit dose of 2 000 mg/kg. There was no reduction in the PCE/NCE ratio at either sampling

- time (24 or 48 hours) in this experiment. There was also no statistically significant test

- article

- related increase in micronucleated polychromatic erythrocytes in either male or fem ale animals when compared with corresponding negative control group animals at the 24

- and 48

- hour sampling times. The same was true for the evaluation of the data of both sexes combined at the 24

- hour sampling time. However, at the 48

- hour sampling time a slight, statistically significant increase (p = 0.029) in micronucleated polychromatic erythrocytes was present. To determine whether this increase indicated a potential mutagenic activity of the test material, according to the test guideline, a second te st (repeat experiment) was performed to examine the reproducibility of the statistically significant response at the 48

- hour sampling time in males and females combined, and to assess a possible dose relation in the increase of micronucleated polychromatic erythrocytes. In the repeat experiment, after a single oral administration of the test material at 1000, 1470, or 2150 mg/kg, there was again no reduction in the PCE/NCE ratio at any test dose when compared with the corresponding negative control group. T here was no statistically significant test article

- related increase in micronucleated polychromatic erythrocytes in either male or female animals analyzed separately, or in males and females combined, when compared with corresponding negative control group animals at the 48

- hour sampling time after treatment. There was no dose

- related increase in the number of micronucleated polychromatic erythrocytes in either sex. The statistically significant positive response in males and females combined for the 48

- hou r sampling time in the experiment was therefore not verified during the repeated test using two additional dose levels and was, accordingly, considered to be biologically insignificant. The vehicle (saline) controls had acceptable micronuclei frequencies. The positive control mice (males and females treated with cyclophosphamide) showed statistically significant increases in the frequency of micronuclei, indicating that the assay was working properly. Under the experimental conditions reported, 1,3

- propaned iol was considered to not be mutagenic in mice as measured by damage to chromosomes or the mitotic apparatus.

Carcinogenicity No carcinogenicity studies were available in the database. However based on lack of mutagenicity concern, lack of any systemic toxicity up to limit dose in the available studies, and lack of any structural alerts for carcinogenicity in Derek analysis, EPA concluded that 1,3

- propanediol is not expected to pose a cancer risk.16 Metabolism and Pharmacokinetics The proposed metabolic pathway for 1,3

- propanediol follows that for other simple alcohols, where alcohol and aldehyde dehydrogenase enzymes sequentially break down this substance to acids used in intermediary metabolism. 1,3

- propanediol is metabolized to 3

- hydroxypropionaldehyde, malondialdehyde or 3

- hydroxypropionic acid, malonic semi

- aldehyde, malonic acid, and ultimately carbon dioxide and water.

Table 4 . Toxicology Profile for 1 ,3

- Propanediol Guideline No./

Study Type Doses Levels MRID No. (year)/References Results

2

- week Inhalation Toxicity study (rats) 0, 41, 650, 1800 mg/m 3 (0, 0.041, 0.650, 1.800 mg/L) MRID48439008 Scott (1998) LOAEL = was not established NOAEL = 1800 mg/m 3 or 1.800 mg/L

90

- Day Oral Toxicity Study ( rats ) M ale : 0, 100, 300, 1000 mg/kg bw/day F emale : 0, 100, 300, 1000 mg/kg bw/day MRID: 48439004 Kirkpatrick (1999) LOAEL = was not established. NOAEL = 1,000 mg/kg bw/day

Developmental Toxicity (rats) 0, 250, 1000 mg/kg bw/day MRID: 48439006 Leuschner (1992) Maternal LOAEL was not established. Maternal NOAEL = 1,000 mg/kg/day Developmental LOAEL was not established. Developmental NOAEL = 1,000 mg/kg/day Bacterial Reverse Mutation Test 0, 3.3, 10, 33.3, 100, 333.3, 1000, 2500, 5000 μg/plate MRID: 48439014 Wollny (1994) No evidence of induced mutant colonies over background.

In vitro mammalian Cell Gene Mutation Test 0, 250, 1000, 2500, 5000 μg/mL MRID: 48439013 Wollny (1994) No evidence of induced mutant colonies over background.

In Vitro Chromosome Aberration Assay 0, 625, 1250, 2500, 5000 μg/mL MRID: 48422613 Gudi (2001) No evidence of induction of structural and numerical chromosome aberrations.

in vitro mammalian cell chromosome aberration ass ay Variable for each test with a maximum of 5000 μg/mL. MRID: 48439012 Wolfgang (1994) Under the experimental conditions reported, the test article 1,3

- propanediol reproducibly induced structural chromosomal aberrations in the V79 Chinese hamster cell line. Mammalian Erythrocyte Micronucleus Test 2150 mg/kg bw MRID: 48439005 Krauser (1995) 1,3

- propanediol, did not induce micronuclei in bone marrow erythrocytes of mice (males and/or females) given a single oral dose of the test material up to a maximum dose of 2150 mg/kg, and then assayed at 24 and 48 hours post

treatment.

B. Toxicity Endpoint Selection No toxicological endpoints have been identified for 1,3

- propanediol due to no adverse observable effects seen in toxicity studies with doses up to 1,000 mg/kg/day

.17 C . Special Considerations for Infants and Children EPA did not use a safety factor analysis for assessing risk because no systemic toxicity or developmental toxicity was seen in the developmental toxicity study in rats. No systemic toxicity w as seen in the 90

- day toxicity study in rats via gavage at doses up to 1

, 000 mg/kg/day.

IV

. EXPOSURE ASSESSMENT

In conducting a dietary exposure assessment using the Dietary Exposure Evaluation Model DEEM

- FCID TM , Version 3.16 , EPA used food consumption information from the U.S. Department of Agriculture’s National Health and Nutrition Examination Survey, What we eat in America, (NHANES/WWEIA). This dietary survey was conducted from 2003 to 2008 . As to residue levels in food, n o residue data were submitted for 1,3

- propanediol. In the absence of specific residue data, EPA has developed an approach which uses surrogate information to derive upper bound exposure estimates for the subject inert ingredient. Upper bound exposure est imates are based on the highest tolerance for a given commodity from a list of high

- use insecticides, herbicides, and fungicides. A complete description of the general approach taken to assess inert ingredient risks in the absence of residue data is conta ined in the memorandum entitled “Alkyl Amines Polyalkoxylates (Cluster 4): Acute and Chronic Aggregate (Food and Drinking Water) Dietary Exposure and Risk Assessments for the Inerts.” (D361707, S. Piper, 2/25/09) and can be found at http://www.regulations.gov in docket ID number EPA

- HQ

- OPP

- 2008

- 0738.

In the dietary exposure assessment, the Agency assumed that the residue level of the inert ingredient would be no higher than the highest tolerance for a given commodit y. Implicit in this assumption is that there would be similar rates of degradation (if any) between the active and inert ingredient and that the concentration of inert ingredient in the scenarios leading to these highest of tolerances would be no higher t han the concentration of the active ingredient.

The Agency believes the assumptions used to estimate dietary exposures lead to an extremely conservative assessment of dietary risk due to a series of compounded conservatisms. First, assuming that the level of residue for an inert ingredient is equal to the level of residue for the active ingredient will overstate exposure. The concentration of active ingredients in agricultural products is generally at least 50 percent of the product and often can be much higher. Further, pesticide products rarely have a single inert ingredient; rather there is generally a combination of different inert ingredients used which additionally reduces the concentration of any single inert ingredient in the pesticide produc t in relation to that of the active ingredient.

Second, the conservatism of this methodology is compounded by EPA’s decision to assume that, for each commodity, the active ingredient which will serve as a guide to the18 potential level of inert ingredient residues is the active ingredient with the highest tolerance level. This assumption overstates residue values because it would be highly unlikely, given the high number of inert ingredients, that a single inert ingredient or class of ingredients would be present at the level of the active ingredient in the highest tolerance for every commodity. Finally, a third compounding conservatism is EPA’s assumption that all foods contain the inert ingredient at the highest tolerance level. In other words, EPA ass umed 100 percent of all foods are treated with the inert ingredient at the rate and manner necessary to produce the highest residue legally possible for an active ingredient. In summary, EPA chose a very conservative method for estimating what level of in ert residue could be on food, and then use this methodology to choose the highest possible residue that could be found on food and assumed that all food contained this residue. No consideration was given to potential degradation between harvest and

consum ption even though monitoring data shows that tolerance level residues are typically one to two orders of magnitude higher than actual residues in food when distributed in commerce.

Accordingly, although sufficient information to quantify actual residue l evels in food is not available, the compounding of these conservative assumptions will lead to a significant exaggeration of actual exposures. EPA does not believe that this approach underestimates exposure in the absence of residue data.

A. Dietary Exposur e:

In evaluating dietary exposure to 1,3

- propanediol, EPA considered exposure under the proposed exemption from the requirement of a tolerance (40 CFR 180.940(a)) and as an inert ingredient used in pesticide formulations applied to growing crops (40 CFR 180.910). EPA assessed dietary exposures from 1,3

- propanediol as follows:

In the absence of actual dietary exposure data resulting from this proposed use the EPA has utilized a conservative, health

- protective method of estimating dietary intake that is based upon conservative assumptions related to the amount of residues that can be transferred to foods as a result of the proposed use of 1,3

- propanediol in food contact sanitizing pesticide products. This same methodology has been utilized by EPA in estim ating dietary exposures to antimicrobial pesticides used in food

- handling settings. The Agency believes the assumptions used to estimate chronic dietary exposures lead to an extremely conservative assessment of dietary risk due to a series of compounded

co nservatisms as described in the unit. First, when a surface is treated with a disinfectant, a quantity of the disinfectant remains on the surface (Residual Solution). In the absence of any other data, EPA has used an estimated worst

- case concentration of 1mg of solution
per squar e centimeter (cm 2 ) of treated surface area for this quantity. Second, the conservatism of this methodology is compounded by EPA’s decision to assume a worst case scenario that all food that an individual consumes will come into contact with 4,000

cm 2 of sa nitized non

- porous food

- contact surfaces. This contact area represents all the surface area from silverware, china, and glass used by a person who regularly eats three meals per day at an institutional or public facility. The surface area of counter tops t hat comes in contact with food is expected to be smaller than the surface area for food19 utensils. As a conservative estimate, EPA assumed that 2,000 cm 2 of treated counter top surface area, comes into contact with an individual’ s food per day. Third, EPA a ssumes that 100% of the material presented on food contact surfaces will migrate to food.

i. Acute exposure . No adverse effects attributable to a single exposure of 1,3

- propanediol were seen in the toxicity databases. Therefore, acute dietary risk asse ssment for 1,3

- propanediol is not required.

ii. Chronic exposure

. No adverse effects attributable to a chronic exposure of 1,3

- propanediol were seen in the toxicity databases. Therefore, chronic dietary risk assessment for 1,3

- propanediol is not require d.

iii. Cancer exposure

. 1,3

- Propanediol is not expected to be carcinogenic. Therefore, a cancer dietary exposure assessment is not necessary to assess cancer risk.

B. Residential Exposure

The term “residential exposure” is used in this document to refer to non

- occupational,

non

- dietary exposure (e.g., for lawn and garden pest control, indoor pest control, termiticides, and flea and tick control on pets). Due to the absence of a toxicity end point for 1,3

- propanediol in the database, residential exposure is not expected to be of concern. Therefore a quantitative residential exposure risk assessment was not performed.

V. A GGREGATE RISK AND DETERMINATION OF SAFETY

EPA determines whether acut e and chronic pesticide exposures are safe by comparing aggregate exposure estimates to the aPAD and cPAD. The aPAD and cPAD represent the highest safe exposures, taking into account all appropriate safety factors (SFs). EPA calculates the aPAD and cPAD by dividing the POD by all applicable UFs. For linear cancer risks, EPA calculates the probability of additional cancer cases given the estimated aggregate exposure. Short

- , intermediate

- , and chronic

- term risks are evaluated by comparing the estimated a ggregate food, water, and residential exposure to the POD

. T he MOE is the product of all applicable UFs and should not be exceeded.

A . Acute Dietary R isk

. An acute aggregate risk assessment takes into account exposure estimates from acute dietary consumption of food and drinking water using the exposure assumptions discussed in section IV for acute exposure and the us e limitations in pesticide formulations. However there was no hazard attributable to a single exposure

seen in the toxicity database for 1,3

- propanediol ; therefore an acute aggregate risk assessment is not required.

B . Chronic Dietary R isk. A chronic aggregate risk assessment takes into account exposure estimates from chronic dietary consumption of food and drinking water using the exposure assumptions discussed in section IV for chronic exposure and the us e20 limitations in pesticide formulations. However there was no hazard attributable to chronic exposures in the toxicity database for 1,3

- propanediol, therefore an chronic
aggre gate risk assessment is not required.

C

. Aggregate Cancer Risk for U.S. P opulation

. The Agency has not identified any concerns for carcinogenicity relating to 1,3

- propanediol ; therefore, a cancer dietary exposure assessment was not performed and an aggreg ate risk assessment is not a

concern.

D

. Short

- T erm Aggregate R isk

. Short

- term aggregate exposure takes into account short

- term residential exposure plus chronic exposure to food and water (considered to be a background exposure level). 1,3

- Propanediol is used as an inert ingredient in pesticide products that are currently registered for uses that could result in short

- term residential
exposure however no adverse effects were attributable to chronic exposure to 1,3

- propanediol were seen in the toxicity database; therefore, a short

- term aggregate risk assessment is not required.

E

. Intermediate

- T erm Aggregate R isk

. Intermediate

- term aggregate exposure takes into account intermediate

- term residential exposure plus chronic exposure to food and water (con sidered to be a background exposure level). 1,3

- Propanediol is used as an inert ingredient in pesticide products that are currently registered for uses that could result in intermediate

- term residential exposure however no adverse effects were attributable to chronic exposure to 1,3

- propanediol were seen in the toxicity database; therefore, a n intermediate

- term aggregate risk assessment is not required.

F . Determi nation of S afety . EPA concludes that there is a reasonable certainty that no harm will result to the general population or to infants and children from aggregate exposure to residues of 1,3

- propanediol

.

VI. O CCUPATIONAL EXPOSURE/RISK PATHWAY

The representative occupational scenarios selected by the Agency for assessment are evaluated based on likely maximum application rates for products which may contain the inert ingredient for the short

- term exposure assessment, and average application rates for products likely to contain the inert ingredient for the intermediate

- and long

- term exposure dura tions. Active ingredient application rates are corrected for the maximum amount of inert ingredient likely to be in the final formulations to determine exposure and risk from exposure to the inert ingredient by fungicide, insecticide or herbicide.

RD traditionally considers a level of concern (LOC) for these risk assessments to be an MOE of 100 based on the standard 10X inter and 10X intra species extrapolation safety factors and additional uncertainty in the database.

A. Occupational Handler Risk21 Expo sure Scenarios Due to the absence of dermal and inhalation toxicity end points

, o ccupational handler risks are not of concern. Therefore an occupational handler risk assessment was not performed.

B. Occup ational Post

- A pplication Risk

Exposure Scenarios RD uses the term post

- application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred
to as re

- entry exposure). Such exposures may occur when workers enter previousl y treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting. Post

- application exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical’s degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post

- application exposure. In halation exposures are not typically calculated for occupational post

- application scenarios because inhalation exposures generally account for a negligible percentage of the overall body burden for most pesticide chemicals.

Due to the absence of dermal and inhalation toxicity endpoints , occupational post

application risks are not of concern. Therefore an occupational post

- a pplication risk assessment was not performed

.

VI I

. C UMULATIVE EXPSOURE

Cumulative effects from substances with a common mechanism of toxicity . Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider “available information” concerning the cumulative effects of a particular pesticide's residues and “other substances that have a common mechanism of toxicity.”

EPA has not found 1,3

- propanediol to share a common mechanism of toxicity wi th any other substances, and that 1,3

- propanediol do es not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has assumed that 1,3

- propanediol do es not have a common mechanism of toxicity with other substances. For information regarding EPA's efforts to determine which chemicals have a

common m echanism of toxicity and to evaluate the cumulative effects of such chemicals, see EPA's website at http://www.epa.gov/pesticides/cumulative

.22 VIII

. E NVIRONMENTAL JUSTICE STATEMENT

Potential areas of environmental justice concerns, to the extent possibl e, 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.eh.doe.gov/oepa/guidance/justice/eo12898.pdf

. 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, R D estimates risks to population subgroups from pesticide exposures that are 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 co nsumption patterns are compiled by the USDA under 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 pest icide 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 expe rtise 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

I X. E NVIRONMENTAL FATE CONSIDERATIONS

Based on a Biodegradab ility study (Berti 2007) (MRID 48422603) , the compound 1,3

- propanediol is readily biodegradable. Based on physico

- chemical properties, 1,3

- propanediol is water soluble and will partition to the soil. The low Kow (

- 0.71) suggests that 1,3

- propanediol is
not expected to absorb by sediment or suspended solids. The study showed that 71% of the compound was converted to CO 2 after 28 days suggesting that the substance was completely mineralized without any major metabolites or degradation products. Due to its rat e of biodegradation, 1,3

- propanediol is not expected to be of major environmental fate concern.

X. E COTOXICITY

In an acute invertebrate toxicity study (Kuhn R. et al. 1989), Daphnia magna , 6

- 24 hours old, were placed in each test and control vessel, i.e. 20 animals per concentration step. After a test period of 24 hours and again after 48 hours, the number of animals in the control and test solution that could still swim w as counted. Both pH and oxygen content were monitored in the experiment to assur e they were wi thin acceptable ranges. The 24

- hour EC 50 was de termined to be 8285 mg/L and 48

- hour EC 50 was determined to be 7417 mg/L. This concentration is above limit dose and therefore 1,3

- propanediol is considered practically non

- toxic on an acute basis to aquatic invertebrates. (MRID 48422622)23 In an acute fish toxicity study (Samel, A. 2000), fathead minnows were tested in a static system at five nominal concentrations, 750, 1250, 2500, 5000 and 10,000 mg/L 1,3

- propanediol, as well as a dilution w ater control. Each test chamber (15L) held 10 fish. A recirculating water bath was used to maintain a mean temperature of 22°C over the 96

- hour test. Dissolved oxygen, pH and temperature were measured in all chambers/replicate chambers of control and test substance concentrations. No mortality or sublethal effects were seen in any of the test concentrations or in the water control fish. The 96

- hour LC 50 was determined to be greater than 9720 mg/L, the mean measured concentration. This concentration is above the limit dose required for testing and therefore 1,3

- propanediol is considered practically non

- toxic on an acute basis to freshwater fish. ( MRID 48422628 )

In an algal toxicity study (Kamp, N. 1996), Scendesmus subspicatus was used to test growth rate th r ough biomass production after 72 hour incubation in different dilutions of 1,3

- propanediol. Algae in a solution without any test substance served as control. A stock solution with 12.5 g test substance dissolved in deionized water was prepared along with the f ollow test concentrations: 0.5, 1.0, 2.0, 4.0, 8.0 and 10g per liter. The test and control solutions were incubated for a period of 72 hours at 25 °C and at an illumination rate of ~8000 lux. The E b C 50 (inhibition of biomass after 72 hours) is 1.6 g t est substance per liter of deionized water and the E r C 50 (inhibition of growth rate after 72 hours) is > 10 g test substance per liter of deionized water. The NOEC was ≤ 0.5 g test substance per liter of deionized water. Based on these values, 1,3

- propaned iol is considered practically non

- toxic to algae. ( MRID 48439002 )

X I. R ISK CHARACTERIZATION

Dupont Tate & Lyle BioProducts Company. (198 Blair Bend Drive, Loudon, TN 37774) submitted a petition (PP 2E8091), requesting an exemption from the requirement o f a tolerance pursuant to section 408(d)(1) of the Federal Food, Drug, and Cosmetic Act with respect to 1,3

- propanediol (CAS Reg. No. 504

- 63

- 2) as an inert ingredient for pre

- and post

- harvest (40 CFR 180.910) and antimicrobial food

- contact surface sanitiz ing formulations (40 CFR 40180.940). EPA published the Notice of Filing for this petition in the Federal Register on January 16, 2013 (78 FE 3377). No substantial comments were received in response to this notice. 1,3

- Propanediol was approved for non

- food use in 2011. The majority of the data in this risk assessment decision document has been taken from the 2011 non

- food use decision document.

The acute oral toxicity of 1,3

- propanediol in rodents, expressed as an LD 50 ranges from 10,500 to 15,789 mg/kg bw. No acute dermal toxicity studies for 1,3

- propanediol were available in the toxicity database. The acute inhalation toxicicty of 1,3

- propanediol in rats produced a LC 50 was > 5.0 mg/L. Primary eye irritation studies of 1,3

- propanediol on rabbits showed minimal effects, slight redness of the conjunctivae

, and clearing in less than 24 hours. It is considered minimally irritating to the eyes of rabbits. Primary skin irritation st udies with 1,3

- propanediol showed slight to mild erythema and edema to rabbits but clearing after 72 hrs. It is considered mildly irritating to the skin of rabbits. Dermal sensitization studies on guinea

- pigs showed that 1,3

- propanediol is not a sensitize r.24 In a 14

- day inhalation toxicity study (MRID 48439008) three groups of 10 male Crl:CD (SD) IGS BR rats each were exposed by inhalation to either vapor only or a vapor/aerosol mixture of 1,3

- propanediol in air at concentrations targeted to 60, 600, or 18 00 mg/m 3 (0.06, 0.60 or 1.80 mg/L) for 6 hours/day, 4 or 5 days/week for a total of 9 exposures. A procedural control group of 10 male rats were exposed simultaneously to air only. The analytically determined mean concentrations of 1,3

- propanediol in the e xposure chambers were 41, 650 and 1800 mg/m 3 (0.041, 0.650, and 1.800 mg/L) over the duration of the study. All rats survived to the termination of the study and were sacrificed at the end of the study duration. There were no test substance

- related clinica l signs of toxicity observed during the study. No statistically significant body weight differences were observed in any group. There were no compound

related adverse effects noted during clinical observations or pathology evaluations. The NOAEL for repeat ed inhalation exposure to 1,3

- propanediol in male rats was considered to be 1800 mg/m 3 or 1.8 mg/L (the highest dose tested) and no LOAEL was identified.

In a 90

- day oral toxic ity study (MRID 48439004), 1,3

- p ropanediol was administered to 10 Crl:CD ® (SD)BR rats/sex/dose by gavage at dosages of 0, 100, 300 or 1000 mg/kg/day. Reverse osmosis

- treated water was administered to controls. All animals survived to the scheduled necropsy. No test article

- related changes in the clinical condition of the animals were observed. Mean body weights, body weight gains, food consumption, clinical pathology parameters (hematology, serum chemistry) and organ weights were unaffected by test article administration. No treatment related changes were observed in eyes up on ophthal moscopic examinations at the end of the study. Spermatogenic endpoints were unaffected in all treated males. No treatment

- related changes were observed at the macroscopic and microscopic examinations. Based on the data obtained, the NOAEL for systemic toxi city of 1,3

- p ropanediol administered orally via gavage to male and female rats for 91 or 92 consecutive days was 1000 mg/kg/day (the highest dose tested) and no LOAEL was identified

. The mutagenic potential of 1,3

- propanediol was evaluated in a bacterial reverse mutation test, an in vitro mammalian cell gene mutation test, an in vitro chromosome aberration assay, an in vitro mammalian cell chromosome aberration assay and a mammalian erythrocyte micronucleus test. These test were all negative except for the in vitro mammalian cell chromosome aberration assay which showed under the reported experimental conditions that 1,3

- propanediol reproducibly induced structural chromosomal aberrations in the V79 Chinese hamster cell line. However due to negative in vivo mouse micronucleus assay, there are no concern for clastogenicity. Based on the results of these studies, 1,3

- propanediol is not considered to be mutagenic.

No carcinogenicity studies on 1,3

- propanediol were available in the toxicity database

, however based on the lack of mutagenicity concerns, lack of any systemic toxicity at the limit dose and lack of any structural alerts for carcinogenicity in Derek analysis, , there are no concerns for carcinogenicity for 1,3

- propanediol.

In a developmental toxici ty study, 1,3

- p ropanediol was administered to 20 pregnant female Sprague

- Dawley (Hag: SD) rats/dose by gavage in 0.8% aqueous hydroxypropyl

methylcellulose gel (with cons tant dose volume of 10 mL/kg bw ) at dose levels of 0, 250, or 1000 mg/kg bw/day on ges tation days (GDs) 6 through 15. Dams were sacrificed and necropsied25 on GD 20. There were no treatment

- related effects on maternal survival, clinical signs, body weight, food consumption, or gross pathology. The maternal LOAEL is not identified, and the maternal NOAEL is greater than or equal to 1000 mg/kg bw/day (the highest dose tested)

. There
were no treatment

- related effects on live litter size, fetal deaths, early or late resorptions, or the fetal sex ratio. Mean fetal weights, fetal lengths, and pl acental weights of the treated groups were similar to those of controls and there were no significant increases in the litter incidences of any individual morphological variation or retardation for either treated group. The developmental LOAEL is not iden tified, and the developmental NOAEL is greater than or equal to 1000 mg/kg bw/day (the highest dose tested)

. There were no immunotoxicity or neurotoxicity studies on 1,3

- propanediol available in the toxicity database. However, there was no evidence of cli nical signs of neurotoxicity or immunotoxicity triggers in the available database up to the limit dose.

The proposed metabolic pathway for 1,3

- propanediol follows that for other simple alcohols, where alcohol and aldehyde dehydrogenase enzymes sequentially break down this substance to aldehydes and acids used in intermediary metabolism. 1,3

- propanediol is metabolized to 3

- hydroxypropionaldehyde, malondialdehyde or 3

- hydroxypropionic acid, malonic semi

- aldehyde, malonic acid, and ultimately, car bon dioxide and water.

EPA did not use a safety factor analysis for assessing risk because no toxicological endpoints have been identified for this chemical.

Acute and chronic dietary risk assessments were not conducted because no endpoints of

concern following single or multiple exposures were identified in the available studies. 1,3

- Propanediol is not expected to be carcinogenic. Therefore, a cancer dietary exposure assessment is not necessary to assess cancer risk.

The term “residential exposure” is used in this document to refer to non

- occupational,

non

- dietary exposure (e.g., for lawn and garden pest control, indoor pest control, termiticides, and flea and tick control on pets). Due to the absence of a toxicity end point for 1,3

- propanediol in the database, residential exposure is not expected to be of concern. Therefore a quantitative residential exposure risk assessment was not performed.

Short

- term aggregate exposure takes into account short

- term re sidential e xposure plus chronic exposure to food and water (considered to be a background exposure level). 1,3

- Propanediol is used as an inert ingredient in pesticide products that are currently registered for uses that could result in short

- term residential exposure however no adverse effects were attributable to chronic exposure to 1,3

- propanediol were seen in the toxicity database; therefore, a short

- term aggregate risk assessment is not required.

Intermediate

- term aggregate exposure takes into account intermed iate

- term residential exposure plus chronic exposure to food and water (considered to be a background exposure level). 1,3

- Propanediol is used as an inert ingredient in pesticide products that are currently registered for uses that could result in intermed iate

- term residential exposure however no adverse26 effects were attributable to chronic exposure to 1,3

- propanediol were seen in the toxicity database; therefore, an intermediate

- term aggregate risk assessment is not required.

Due to the absence of derm al and inhalation toxicity, o ccupational handler and post

application risks are not of concern. Therefore occupational handler and post

- application risk assessments were not performed.

Based on a Biodegradability study (Berti 2007), the compound 1,3

- prop anediol is readily biodegradable. Based on physico

- chemical properties, 1,3

- propanediol is water soluble and will partition to the soil. The low Kow (

- 0.71) suggests that 1,3

- propanediol is not expected to absorb by sediment or suspended solids. The study showed that 71% of the compound was converted to CO 2 after 28 days suggesting that the substance was completely mineralized without any major metabolites or degradation products. Due to its rate of biodegradation, 1,3

- propanediol is not expected to be of m ajor environmental fate concern.

Based on 3 acute ecotoxicity studies, 1,3

- propanediol is practically non

- toxic to freshwater invertebrates, freshwater fish and algae. Freshwater invertebrate, Daphnia magna had a 24

- hr EC 50 of 8285 mg/L and a 48

- hr EC 50 of 7417 mg/L. The freshwater fish, fathead minnow had a 96

- hr LC 50 of 9720 mg/L. Lastly the algae, Scendesmus subspicatus

, had a 72

- hr E b C 50 of 1.6g/L and a 72

- hr E r C 50 >10 g/L with a NOAEC ≤ 0.5 g/L

. Taking into consideration all available information on 1,3

- propanediol, EPA concludes that there is a reasonable certainty that no harm to any population subgroup will result from aggregate exposure to 1,3

- propanediol when considering occupation, dietary exposure and all other nonoccupational sources of pes ticide exposure for which there is reliable information. Therefore, the establishment of an exemption from tolerance under 40 CFR 180.910 and 180.940 for residues of 1,3

- propanediol (CAS Reg. No. 504

- 63

- 2) when used as a pesticide inert ingredient for pre

- and post

- harvest (40 CFR 180.910) and antimicrobial food

- contact surface sanitizing formulations (40 CFR 180.940), can be considered assessed as safe under section 408(q) of the FFDCA.27 REFERENCES

Berti, W.R., Wolstenholme, B.W. (2007). 1,3

- Propanediol: Assessment of Ready Biodegradability by the Co2 Evolution Test. Testing laboratory: Environmental and Microbiological Sciences & Engineering. Report No.: EMSER 10

- 06. Owner company: E.I. du Pont de Nemours and Company. MRID 48422603. Unpublsh ed.

Coombs, A.D., Clark, D.G. (1997). Acute toxicity, skin and eye irritation and skin sensitizing potential of trimethylene glycol. Testing laboratory: Experimental Toxicology Division of Shell Toxicology Laboratory Tunstall. Report no.: TLGR.0026.77. Ow ner company: Shell Chemical Co. MRID 48422607. Unpublished.

Gingell, R., Kirkpatrick, J.B., Steup, D.R. (2000). Subchronic Toxicity Study of 1,3

- Propanediol Administered Orally to Rats. International Journal of Toxicology , 19:27

- 32. MRID 48422612.

Gudi, R., Brown, C. (2001). H

- 24783 In Vitro Mammalian Chromosome Aberration Test. Testing laboratory: BioReliance. Report no.: DuPont

- 5683. Owner company: E.I. DuPont de Nemours and Company. MRID 48422613. Unpublished.

Kamp, N. (1996a). Study on the Toxicity t owards Algae of 1,3

- Propanediol according to OECD

Test Guideline 201, Edition dated June 7 th , 1984. Testing laboratory: Institut Fresenius. Report no.: Degussa 95

- 0127

- DGO. Owner company: E.I. DuPont de Nemours and Company. MRID 48439002. Unpublished.

Ka ur. G., Srivastava, A.K., Chand, S. (2012) Advances in biotechnological production of 1,3

- propanediol. Biochemical Engineering Journal Vol 64. Pg. 106

- 118.

Kegelman, T.A. (1997). Inhalation Approximate Lethal Concentration (ALC) of H

- 22121 in Rats. Testi ng laboratory: Haskell Laboratory for Toxicology and Industrial Medicine. Report no.: HL

- 1997

- 00095. Owner company: E.I. DuPont de Nemours and Company. MRID 48422619. Unpublished

Kirkpatrick, J.B. (1999). A 90

- Day Oral (Gavage) Study of 1,3

- Propanediol in Rats. Testing laboratory: WIL Research Laboratories, Inc. Report no.: WIL

- 93128. Owner company: Shell Chemical Company. MRID 4849004. Unpublished.

Kranser, K. (1995). 1,3

- Propanediol, Mouse Micronucleus Test (Single Oral Administration). Testing laborato ry: ASTA Medica AG, Institute of Toxicology. Report no.: Degussa 94

- 0170

- DGM. Owner company: E.I. DuPont de Nemours and Company. MRID 48439005. Unpublished.

Kuhn, R., Pattard, M., Pernak, K.

- D., Winter, A. (1989). Results of the Harmful Effects of Selected Water Pollutants (Anilines, Phenols, Aliphatic Compounds) to Daphnia magna

. Water Research , 23(4):495

- 499. MRID 48422622.28 Leuschner, F. (1992). Examination of the Influence of 1,3

- Propanediol, polymer Grade on t he Pregnant Rat and the Fetus by Oral Administration. Testing laboratory: Laboratory of Pharmacology and Toxicology. Report no.: Degussa 92

- 0063

- DGB. Owner company E.I. DuPont de Nemours and Company. MRID 48439006. Unpublished.

Mertens, J.J. W.M. (1997). A 14

- Day Oral (Gavage) Range

- Finding Study of 1,3

- Propanediol in Rats. Testing laboratory: WIL Research Laboratories, Inc. Report no.: WIL

- 93127. Owner company: Shell Cheimcal Co. MRIS 48439007. Unpublished.

Samel, A. (2000). H

- 24503: Static, Acute, 96

- Ho ur LC50 to the Fathead minnow, Pimphales promelas . Testing laboratory: Haskell Laboratory for Toxicology and Industrial Medicine. Report no.: DuPont

- 4185. Owner company E.I. DuPont de Nemours and Company. MRID 48422628. Unpublished.

Scott, R.S. (1998). H

- 23131: Two

- Week Inhalation Toxicity Study in Male Rats. Testing laboratory: Haskell Laboratory for Toxicology and Industrial Medicine. Report no.: DuPont

1167. Owner company: E.I. DuPont de Nemours and Company. MRID 48439008. Unpublished.

Spanjers, M.Th ., Til, H.P. (1979). Determination of the Acute Oral Toxicity of Propane

- 1,3

- Diol in Rats. Testing laboratory: Degussa, Frankfurt, W. Germany. Report no.: Degussa 79

- 0077

- DKT. Owner company: E.I. DuPont de Nemours and Company. MRID 48422633. Unpublished.

Til, H.P., Keizer, A.M.M. (1979). Sensitization potential of Propanediol

- 1,3 and its distillation residue in guinea pigs. Testing laboratory: Centraal instituut voor voedingsonderzoek. Report no.: Degussa 79

- 0078

- DKT. Owner company: E.I. DuPont de Nemours and Company. MRID 48422635. Unpublished

Van Beek, L. (1979). Primary skin and eye irritation tests with propanediol

- 1,3 in albino rabbits. Testing laboratory: Degussa Industrielle Toxikologie. Report no.: Degussa

- 79

- 0093

- DKT. Owner company: E.I. DuPont d e Nemours and Company. MRID 48439011. Unpublished.

Volkner, W. (1994). Chromosome aberration assay in Chinese hamster v79 cells in vitro with 1,3

- propanediol Testing laboratory: CCR (Cytotest Cell Research GMBH & Co.). Report no.: Degussa 94

- 0059

- DGM. Own er company: E.I. DuPont de Nemours and Company. MRID 48439012. Unpublished.

Wollny, E. (1994a). Gene mutation assay in Chinese hamster V79 cells in vitro (V79/HPRT) with 1,3

- Propanediol. Testing laboratory: CCR (Cytotest Cell Research GMBH & Co.). Report no.: Degussa 94

- 0060

- DGM. Owner company: E.I. DuPont de Nemours and Company. MRID 4849013. Unpublished.

Wollny, E. (1994b). Salmonella typhimurium reverse mutation assay with 1,3

- propanediol. Testing laboratory: CCR (Cytotest Cell Research GMBH & Co.). Re port no.: Degussa 94

- 0058

- DGM. Owner company: E.I. DuPont de Nemours and Company. MRID 48439014. Unpublished.APPENDIX



## Derek Nexus Report
Author rkent Report date 20 February 2013 12:24:09 Prediction date 20 February 2013 12:22:30 Program version Derek Nexus: 3.0.1, Nexus: 1.5.0 Compound name Structure Species bacterium, mammal Endpoints alpha

- 2

- mu

- Globulin nephropathy, Anaphylaxis, Bladder urothelial hyperplasia, Carcinogenicity, Cardiotoxicity, Cerebral oedema, Chloracne, Cholinesterase inhibition, Chromosome damage in vitro, Chromosome damage in vivo, Cumulative effect on white cell cou nt and immunology, Cyanide

- type effects, Developmental toxicity, Genotoxicity in vitro, Genotoxicity in vivo, Hepatotoxicity, HERG channel inhibition in vitro, High acute toxicity, Irritation (of the eye), Irritation (of the gastrointestinal tract), Irrita tion (of the respiratory tract), Irritation (of the skin), Lachrymation, Methaemoglobinaemia, Mutagenicity in vitro, Mutagenicity in vivo, Nephrotoxicity, Neurotoxicity, Occupational asthma, Ocular toxicity, Oestrogenicity, Peroxisome proliferation, Phosph olipidosis, Photo

- induced chromosome damage in vitro, Photoallergenicity, Photocarcinogenicity, Photogenotoxicity in vitro, Photogenotoxicity in vivo, Photomutagenicity in vitro, Phototoxicity, Pulmonary toxicity, Rapid prototypes: adrenal gland toxicity, Rapid prototypes: bladder disorders, Rapid prototypes: blood in urine, Rapid prototypes: bone marrow toxicity, Rapid prototypes: bradycardia, Rapid prototypes: cardiotoxicity, Rapid prototypes: chromosome damage in vitro, Rapid prototypes: hepatotoxicity, Rapid prototypes: kidney disorders, Rapid prototypes: mitochondrial dysfunction, Rapid prototypes: nephrotoxicity, Rapid prototypes: splenotoxicity, Rapid prototypes: testicular toxicity, Rapid prototypes: thyroid toxicity, Respiratory sensitisation, Skin sensitisation, Teratogenicity, Testicular toxicity, Thyroid toxicity, Uncoupler of oxidative phosphorylation Superendpoints Carcinogenicity (SUPER), Chromosome damage (SUPER), Genotoxicity (SUPER), Hepatotoxicity (SUPER), HERG channel inhibition (SUPER), Irritation (SUPER), Miscellaneous endpoints (SUPER), Mutagenicity (SUPER), Ocular toxicity (SUPER), Rapid prototypes: adrenal gland toxicity (SUPER), Rapid prototypes: bladder disorders (SUPER), Rapid prototypes: blood in urine (SUPER), Rapid prototypes: bone marrow toxicity (SUPER), Rapid prototypes: bradycardia (SUPER), Rapid prototypes: cardiotoxicity (SUPER), Rapid prototype s: chromosome damage in vitro (SUPER), Rapid prototypes: hepatotoxicity (SUPER), Rapid prototypes: kidney disorders (SUPER), Rapid prototypes: mitochondrial dysfunction (SUPER), Rapid prototypes: nephrotoxicity (SUPER), Rapid prototypes: splenotoxicity (SU PER), Rapid prototypes: testicular toxicity (SUPER), Rapid prototypes: thyroid toxicity (SUPER), Reproductive toxicity (SUPER), Respiratory sensitisation (SUPER), Skin sensitisation (SUPER), Thyroid toxicity (SUPER)30 Constraints Perceive tautomers true Perceive mixtures true Perceive alerts without rules false Average molecular mass 76.09 (Lhasa Limited, version 1.0) Exact molecular mass 76.0524 (Lhasa Limited, version 1.0) Log Kp

- 3.92 (Potts & Guy, version 1.0 (LogP: BioByte Corp., version 5.3; Average Molecular Mass: Lhasa Limited, version 1.0)) Log P

- 1.04 (BioByte Corp., version 5.3)


### Submitted compound



### Predictions

**Derek KB 2012 1.0** KnowledgeBase name Derek KB 2012 1.0 KnowledgeBase version 1.0 KnowledgeBase last modified 29 November 2012 11:56:30 KnowledgeBase location C:/Program Files/Lhasa Limited/Lhasa Knowledge Suite

- Nexus 1.5/KnowledgeBases/org.lhasalimited.pluto.knowledge.derek_1.0.7 KnowledgeBase certified by Lhasa Limited, Leeds, Yorkshire, UK31 

### Alerts found RapidPrototype059 1,3

- Dihydroxypropane or derivative. Rapid prototypes: nephrotoxicity in mammal


### Reasoning summary Rapid prototypes: nephrotoxicity in mammal is EQUIVOCAL


### Reasoning summary and alerts found Rapid prototypes: nephrotoxicity in mammal is EQUIVOCAL RapidPrototype059 1,3

- Dihydroxypropane or derivative


### Alert overview: RapidPrototype059 1,3

- Dihydroxypropane or derivative

Comments This alert describes the nephrotoxicity of 1,3

- dihydroxypropane and its derivatives. This is a rapid prototype alert derived using a proprietary data set of 731 chemicals, classified on the basis of the presence or absence of histopathologic lesions in the kidney in oral rat repea t dose studies mostly of 28

- days duration. Eight chemicals in this data set activated this rapid prototype alert and five of these were nephrotoxic.



### Locations

Reasoning details
Rapid prototypes: nephrotoxicity is EQUIVOCAL

The parameters that have influenced your prediction are: substructures in the input structure, which have a potential for rapid prototypes: nephrotoxicity, your selected species which is mammal.

Rule 266: If [species mammal] is [certain] then [Species dependent variable 8] is [equivocal] species mammal is CERTAIN32 Rule 995: If [Rapid prototypes: nephrotoxicity alert] is [certain] then [Rapid prototypes: nephrotoxicity] is [Species dependent variable 8] Rapid prototypes: nephrotoxicity alert is CERTAIN Species dependent variable 8 is EQUIVOCAL



### Rule 266 If [species mammal] is [certain] then [Species dependent variable 8] is [equivocal]

Comments: In mammals the variable "Species dependent variable 8" is equivocal.

References:



### Rule 995 If [Rapid prototypes: nephrotoxicity alert] is [certain] then [Rapid prototypes: nephrotoxicity] is [Species dependent variable 8]

Comments: If a chemical contains a rapid prototype alert for nephrotoxicity then it is conside red equivocal that the chemical will cause nephrotoxicity in mammals and impossible in bacteria. The variation in rule outcome with species is achieved via use of the variable "Species dependent variable 8".

References: 

### Reasoning **glossary:** Certain There is proof that the proposition is true. Probable There is at least one strong argument that the proposition is true and there are no arguments against it. Plausible The weight of evidence supports the proposition. Equivocal There is an equal weight of evidence for and against the proposition. Doubted The weight of evidence opposes the proposition. Improbable There is at least one strong argument that the proposition is false and there are no arguments that it is true. Impossible There is proof that the proposition is false. Open There is no evidence that supports or opposes the proposition. Contradicted There is proof that the proposition is both true and false.