UNITED STATES ENVIRONMENTAL PROT E CTION AGENCY

WASHINGTON

, D.C. 20460

MEMORANDUM

SUBJECT: June 22, 20 1 1 OFFICE O F C H E MI CAL SAFETY

AND POLLUT I ON PR EVEN TI ON

Summary of Human Health Effects Data for the o-Benzyl-pChlorophenol (OBPCP) Registration Review Decision Document.

PC Coders): 062201

, 062202,062203 DP Barcode(s)/No(s) : D383100, D389630

Decision No.: 440916 Registration Numbers:

Refer to Appendix C

Petition No(s).: NA Regu l atory Action: Human Health Registration

Review

Risk Assess Type: Multiple Chemicals Case No(s).: 2045

TXRNo.:NA

MRID No(s).: NA

FROM :

TO:

THR U: CAS No(s): 120-32- 1 ,35471-49

- 9

, 3184-65

- 4

40 CFR: None

Nathan Mottl

, Bio l ogist



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Risk Assessment and Science Support Branch (RASSB)

Antimicrobials Division (751 OP)

Rebecca von dem Hagen, Chemical Review Manager Regu l atory Management Branch II

Antimicrobials Division (751 OP)

Lance Wonnell. Team Leader
Regulatory Management Branch II / 7 

# V /

Antimicrobials Division (75 1 OP) 

# V# d £1**l**

Nader Elkassabany, Branch Chief

# ~ Risk Assessment and Science Support Branch (RASSB)

Antimicrobials Division (751 OP)

Page 1 of30Page 2 of 30

EXECUTIVE SUMMARY

The Antimicrobials Division (AD) Registration Review Team has evaluated the status

of the human health assessments for the o-benzyl p-chlorophenol (OBPCP) case (registration review case 40 45 ). The active ingredients in the OBPCP case include the

a ctive ingredient o-benzyl-p-chlorophenol (OBPCP) (PC Code 062201), and the potassium and sodium salts of OBPCP [p otassium o-benzyl-p-chlorophenate (PC Code 062202) and sodium o -benzyl-p-chlorophen ate (PC Code 062203)]. OBPCP and its salts are used as disinfectants, fungicides/fungistats, tuberculocides, sanitizers, virucides,

ba cteriocides/bacteriostats, algaecides, and microbicides/microbiostats (slime forming bacteria, fungi and algae). OBPCP and its salts are used in a variety of different major

a ntimicrobial use categories including: agricultural premises and equipment; commercial, institutional and industrial premises; food handling processing equipment and premises;

i ndustrial processes and water systems; medical premises and equipment; and residential

a nd public access premises.

OB PCP and its salts were initially registered as a pesticide in the United States in February 1948 as a hard non porous surface disinfectant and deodorizer for use in schools, hotels, theatres, stores and office areas. The active ingredient OBPCP has 38 registered products; potass ium 2-benzyl-4-chlorophenate salt has three registered products; and sodium 2-benzyl-4-chlorophenate ha s five registered products. OBPCP and its salts are primarily used as a hard non porous surface disinfectant and deodorizer in ag ric ultural premises and equipment, commercial, institutional and industrial premises, food handling processing equipment and premises, and residential and public access areas such as horse stables, meat and poultry processing plants, mushroom houses, greenhouses, households, and animal kennels. It is also used as a hard non porous surface disinfectant in medical areas and equipment such as non conductive floors, beds, wall and floors and to pre-clean instruments and other medical equipment prior to terminal sterilization. There are some publi c health claims for this pesticide when used as a disinfectant. Unlike the other active ing redients in the case, sodium o-benzyl p-chlorophenate is also used for industrial process and water systems (recirculating cooling water systems and air washers). OBPCP

a nd its salts are formulated as soluble concentrates, ready- to -use solutions, and impregnated materials.

In addition to the registered disinfectant uses, it should be noted that the technical product (EPA Reg No. 39967-5 formulated at 98.6% active ingredient) could also be

for mulated as a preservative in metalworking fluids, rubber goods, leather, textiles, upholstery fabrics, and carpets and for water treatment uses such as air washer water, cooling tower water, sewage systems, grease traps, drains, and human drinking waterequipment. The preservative uses listed on the technical product are not listed on any enduse p roduct labels. The current guideline studies for all the registered product uses are

pr esented in Table 1. If the registrant intends to support these uses, the Agency will need additional data (Table 6) to support the preservative uses of OBPCP and its salts. The current data requirements for the end use product uses are presented in Table 5. The Agency also cannot conduct a risk assessment for the preservative uses on the technical product label, since these uses are not on any end-use products and the technical product

doe s not include application rates.Page 3 of 30

EPA examined the hazard and exposure databases for the OBPCP case to determine whether changes in science policy or deficiencies in the databases materially affected theoverall risk picture. A Registration Eligibility Decision (RED) document for o-benzy pchlorophenol was signed on December 1995. EPA has established tolerances under 40 CFR 180.940c for use in food processing equipment and utensil with a not to exceed limit of 320 ppm. FDA currently has cleared OBPCP as an indirect additive in food contact

sa nitizing solutions (21 CFR §178.1010) that can be used for food processing equipment and utensils. According to the RED pesticide fact sheet, disinfectants registered for use in federally inspected meat, poultry, and egg processing plants, as well as food preparation, storage, and serving establishments/areas, require that food products and packaging materials are removed or carefully covered prior to application and that a potable water rinse is employed after treatment (U.S. EPA 1995). For registration review, EPA expectsthat indirect exposure to surface cleaners would trigger an initial Tier I dietary screeninglevel assessment. Therefore, EPA will conduct a Tier 1 dietary screening-level assessment for food processing equipment and utensils as well as an assessment of indirect food contact from countertops in residential homes.

No new sub-chronic, chronic toxicity data for OBPCP has been submitted to the Agency since re registration. The purpose of this screen is to determine whether sufficient data are available to support registration review, whether new human health assessments are needed to support registration review, and to report why the Agency feels it may appropriate to conduct new risk assessments under the registration review process. After reviewing the end-use labels the Agency anticipates the need for the following studies.

Table 1: Data Requirements of OBPCP

Guideline No. Study Needed Special Study* Dermal Sensitization Threshold Quantification

870.3465 90

- day Inhalation Toxicity

870.3800 Reproduction and Fertility Eff ects

870.7800 Immunotoxicity

875.1200 Dermal Exposure

– Indoor

875.1 4 00 Inhalation Exposure

- Indoor

875.1600 Data Reporting and Calculations

875.1700 Product Use Information

875.2300 Indoor Surface Residue Dissipation

875.2800 * Description of Hu man Activity

875.3000 Non

- dietary Ingestion

*Additional data needs based on preservative uses. Also, more than one exposure study may be needed for each guideline number.

Additional exposure data would be needed to support the uses for the technical product (formulated at 98.6% active ingredient). Since it could be also be formulated as a preservative in metalworking fluids, rubber goods, leather, textiles, upholstery fabrics, and carpets and for water treatment uses such as air washer water, cooling tower water, sewage systems, grease traps, drains, and human drinking water equipment. The registrantPage 4 of 30

would need additional studies. The Agency cannot conduct risk assessments since there

a re no existing application rates to assess exposure.

The potential occupational handler exposure scenarios identified by the Agency after

re view of the end-use labels include (1) open-pour loading of liquid formulations, (2)

a pplying disinfectant by hand wiping surfaces, (3) applying the disinfectant by hand by dipping tools/implements into dilute disinfectant solution, (4) applying the disinfectant by mopping surfaces, (5) applying the disinfectant with hand-held, high pressure spray equipment, (6) applying the disinfectant with hand-held, low pressure spray equipment, (7 ) applying with a trigger pump sprayer, (8) applying with an aerosol can and (9) applying the disinfectant with a wet-mist fogger.

There are potential postapplication exposures scenarios based on the review of the end-use labels. There are potential inhalation concerns to persons reentering areas that have been treated with OBPCP, especially following wet-mist fogging applications and other applications in enclosed areas. Dermal and incidental oral postapplication exposures may occur from children crawling on treated floors, or hand- to -mouth exposure from counter tops and floors.

Section 1. Chemical Identity

OBPCP is a phenolic compound in which there is a hydroxyl (-OH) and chloro (Cl)

g roup attached to one of the rings at the ortho and para positions (see figure on Table 2).

OB PCP is a white to light grey solid. It has a boiling point of 175o C and a melting point of

49 oC. OBPCP is lipophilic and is only slightly soluble in water with a density of 7 mg/L and log K

ow of 4.3. The registered products contain 0.02 -98.6 % active ingredient (ai.).

Table 2 presents the chemical identity of OBPCP.

Table 2

. Chemical Identity

Common

Name o

- B enzyl p

- chlorophenol

, p otassium o

benzyl

- p

- chlorophenate, and sodium o

benzyl p

- chlorophenate Synonyms o rtho

- B enz yl

- para

- chlorophenol,

chlorophen, 2

- benzyl 4

- chlorophenol

PC Code 062201, 062202 ,062203 CAS registry

number 120

- 32

- 1, 35471

- 49

- 9, 3184

- 65

- 4

Registration

Review Case

No. 2045

StructurePage 5 of 30

Vapor

Pressure 0.075 mm Hg at 100 o C for OBPCP

Section 2. Toxicology

The Agency has reviewed toxicity studies submitted for the three active ingredients, o-benzyl-p-chlorophenol (OBPCP), sodium o-benzyl-p-chlorophenate (N a + OBPCP) and potassium o-benzyl-p-chlorophenate (K + O BPCP). The toxicological

databases for these three active ingredients are currently comprised of published and unpublished studies either submitted to the Agency or obtained directly from the published open literature during the registration process.

For the Reregistration Eligibility Decision (RED) published in 1995, the Office of

P esticide Programs’s Health Effects Division (HED) determined that toxicity studies

c onducted with OBPCP may be used to support registration of the phenate forms (Na + OBPCP and K + OBPCP) of this chemical. This decision is based upon the rapid dissociation of the sodium and potassium salts of OBPCP to the phenol moiety in vivo

, indicating biologically equivalent activities for OBPCP, Na + OBPCP, and K + OBPCP. However, this guidance does not preclude the Agency from requiring, pursuant to FIFRA section 3(c)(2)(B), additional data it deems necessary to assess the risks or benefits of an active ingredient, at a later time.

Acute Toxicity

Table 3 summarizes the results of the acute toxicity studies conducted with the technical grade active ingredient (TGAI), OBPCP.

Table 3 : Acute Toxicity Studies for OBPCP (TGAI, 75

- 95%)
STUDY (Guideline No.) MRID No(s). RESULTS TOXICITY

CATEGORY *

Acute Oral (81

- 1) 00131367

92008008 LD 50 = males: 4462 mg/kg

LD 50 = females: 3852 mg/kg

LD 50 = combined: 4147 mg/kg III

Acute Dermal (81

- 2) 00130937

92008009 LD 50 > 2000 mg/kg III

Acute Inhalation (81

- 3) 00130938

92008010 LC 50 = males: 2.60 mg/L

LC 50 = females: 2.43 mg/L

LC 50 = combined: 2.50 mg/L IV

Primary Eye Irritation (81

- 4) 0013 1368

92008011 Severely irritating

PIS score = 79 at 72 hours I

Primary Dermal Irritation (81

- 5) 45460201 Severe Irritation/Corrosion (Self

- validated) I

Skin Sensitization (81

- 6) 45424201 Skin Sensitizer NA

* Assigned toxicity categories are based on the acute toxicity study results and reflect the most current categories as identified in the U.S. Environmental Protection Agency, Label Review Manual, updated August, 2010 ( http://www.epa.gov/oppfead1/labeling/lrm/\ ).

Dermal SensitizationPage 6 of 30

The delayed contact hypersensitivity potential of OBPCP has been evaluated in albino guinea pigs using the closed patch (Beuhler) method. In this study, erythema was observed at induction and challenge sites treated with OBPCP as well as subcutaneous hemorrhaging (induction and challenge sites), blanching (induction sites), necrotic looking skin (induction sites), desquamation (challenge sites) and fissuring (challenge sites). Based on the increased incidence, duration, and severity of reactions in the test group to the challenge application, OBPCP is considered to be a dermal sensitizer.

Although an acceptable dermal sensitization study is available for OBPCP, the Agency anticipates needing additional data to quantitatively address skin sensitization for risk

a ssessment purposes during the registration review process. Severe dermal irritation and allergic type reactions in humans have been reported in the available incident data bases following exposure to OBPCP and or its sodium and potassium salts. The symptoms included skin depigmentation, itching, pain, swelling, blister, hives, and erythema. Additionally, “Mice demonstrated statistically significant dose-dependent contact hypersensitivity responses to OBPCP with or without adjuvant pretreatment.” according to

a published literature study by Stern, 1991. Furthermore, repeated dermal exposure (direct contact) is considered the primary route of exposure for some residential use scenarios (e.g., textiles and clothing). As suggested in the FIFRA Scientific Advisory

P anel Meeting (SAP, 2004), it is important to quantitatively assess dermal sensitization when dermal exposure is the primary route of concern based on product use patterns and when there is no appropriate way to label products for residential uses, specifically, textile/clothing treatments.

Therefore, the Agency anticipates the need for a special study conducted with either OBPCP, Na + OBPCP or K + OBPCP that provides quantitative data and an assessment of dose-response for both the initiation and elicitation phases of skin sensitization. The purpose of this study is to identify a threshold level for quantification of dermal

sensitization to OBPCP or its’ salts.

Mutagenicity

Three acceptable mutagenicity studies are available in the OBPCP data base: (1) a

g ene mutation assay in Salmonella typhimurium , (2) an in vivo bone marrow micronucleus assay in mice, and (3) a chromosomal aberration study in Chinese Hamster ovary (CHO) cells. OBPCP tested negatively under the conditions of each of these studies. The mutagencity battery for OBPCP is considered complete.

OBPCP (96.9% a.i.) was tested for its potential to induce reverse mutations in

Salmone lla typhimurium strains TA1535, TA1537, TA98 and TA100 (MRID 41287501). The exogenous metabolic activation mixes were derived from either hamster or rat liver S9 homogenates (all strains were tested with each). OBPCP was tested up to levels of cytotoxicity in all tested bacterial strains, ranging from 0.3 to 33 μg/plate without metabolic activation and from 1 to 100 μg/plate with metabolic activation. OBPCP failed

to i nduce a mutagenic response, either with or without metabolic activation

In an in vivo bone marrow micronucleus assay (MRID 41572801), OBPCP (97.9%

a .i.) was tested in mice at dose levels up to and including 2000 mg/kg. The animalsPage 7 of 30

showed clear signs of toxicity, although there was only slight evidence that the test chemical reached the target organ. OBPCP was negative for clastogenic activity on bone

mar row erythrocytes under the conditions of the study.

In a Chinese Hamster ovary (CHO) assay (MRID 43322901), non-activated and S9- activated cell cultures were exposed to OBPCP (99.7% a.i.) at concentrations of 0 (c ontrol), 4, 8, 15, 30 or 60 μg/ml (-S9), or 0 (control), 1.3, 2.5, 5, 10 or 20 μg/ml (+S9).

The cells were then examined for structural chromosomal aberrations 20 hours after initiation of treatment. The highest dose tested (HDT) caused excessive toxicity (complete inhibition), but there were no increases in cytogenetic effects at any dose tested.

Sub-chronic Toxicity

OBPCP was tested in subchronic gavage studies in both rats and mice (MRID 40376301, 41248202, 41462401) . The rodents were dosed 5 days/week for 13 weeks a t the following dose levels: rats - 0 (control), 30, 60, 120, 240 or 480 mg/kg/day; mice- 0 (c ontrol), 500, 650, 800 or 1000 mg/kg/day. In rats, the NOEL was 120 mg/kg/day and the LOEL was 240 mg/kg/day based on clinical signs of toxicity, changes in clinical chemistries, decreases in thymus weights, increases in kidney weights, chronic nephropathy and thymic lymphoid depletion. In mice, a NOEL was not established because kidney lesions were present at the lowest dose tested (LDT), 500 mg/kg/day. Therefore, the toxic effects observed at the LOEL of 500 mg/kg/day in mice included increased mortality, increases in clinical signs of toxicity, increases in liver weights, decreases in kidney weights, increases in renal lesions (necrosis, casts, inflammation and regeneration of renal tubules) and necrosis of thymic lymphocytes. Both studies were classified as core supplementary because only minimal summary data tables were provided to support the text of the report. In addition, neither clinical chemistry parameters nor urinalysis parameters were measured in the mouse study. However, these studies may be upgraded if the individual animal data are provided as well as table legends for clarification of the assay results.

In a 21-day dermal toxicity study (MRID 41248201), OBPCP (5% a.i.) was tested on New Zealand rabbits at dose levels of 0 (control), 1, 5 or 25 mg/kg/day. The LOEL for systemic toxicity was not established and; therefore, the NOEL for systemic effects was 25 mg/kg/day, the highest dose tested (HDT). The NOEL for dermal effects was 1 mg/kg/day, and the LOEL for dermal effects was 5 mg/kg/day based on acanthosis, hyperkeratosis, parakeratosis, dermatitis, and scabs. There were some ulcerated areas in the 25 mg/kg/day dose group. According to EPA’s review of these data, this study satisfied the 21-day dermal guideline 82-2 requirements and was classified core guideline under Subdivision F Test Guidelines (U.S. EPA, 1989).

As a result of the potential for inhalation exposures to OBPCP or the

so dium/potassium phenate forms of OBPCP from fogging, trigger spray and aerosol applications, the Agency is requiring a 90-day inhalation toxicity study conducted with either OBPCP, Na + OBPCP, and K + OBPCP to establish short- and intermediate-term

tox icity inhalation endpoints for risk assessment purposes.Page 8 of 30

Immunotoxicity

Based upon decreased thymus weights and thymic lymphoid depletion which were noticed in the 90-day oral rat study conducted with OBPCP (MRID 40376301, 41248202, 41462401), EPA has concerns about the potential immunotoxicity of this chemical. Reported incidents of autoimmune thrombocytopenia, nose/mouth bleeding, aplastic

a nemia and leukemia in humans following exposure to OBPCP also raises concern for immunotoxicity. As a result, EPA is requiring an immunotoxicity study conducted with either OBPCP, Na + OBPCP, or K + OB PCP.

Developmental

In a rat developmental toxicity study (MRID 00143775), OBPCP (97.8% a.i.) was

a dministered via gavage to Sprague-Dawley rats at dose levels of 0 (control), 100, 300 or 900 mg/kg/day on days 6-15 of gestation. Statistically significant decreases in body weight were observed at all dose levels, decreases in mean food consumption were observed in the mid- and high-dose groups and increased water intake was observed in the hig h dose group. Therefore, the maternal NOEL was considered to be less than 100 mg/kg/day (the lowest dose tested) and the LOEL is 100 mg/kg/day based on statistically significant decreases in body weight gain. No developmental toxicities were observed in the fetuses; therefore, the developmental toxicity LOEL was not established in this study and the developmental toxicity NOEL was 900 mg/kg/day (the highest dose tested).

In the second rat developmental toxicity study (MRID 00145836, 00161231, 92007001), OBPCP (96.8% a.i.) was administered via gavage to Wistar rats at dose levels

of 0 (control), 15, 75 or 375 mg/kg/day on days 6-15 post coitum. At 375 mg/kg/day, 3 of the dams died. There was also a decrease in maternal mean body weight gains (47%), and corrected body weight gains (40%) when compared to controls, as well as an increase in the number of animals with mucoid feces. The NOEL for maternal toxicity was 75 mg/kg/day and the LOEL for maternal toxicity was 375 mg/kg/day based on decreased

bod y weight gain, increased mortality and increased mucoid feces. At 375 mg/kg/day, there was a decrease in group mean fetal weights (94% of control). Therefore, the NOEL for developmental toxicity was 75 mg/kg/day and the LOEL for developmental toxicity was 375 mg/kg/day based on a decrease in mean fetal weights.

In a rabbit developmental toxicity study (MRID 00143774, 40988201, 41003901), OBPCP (97.8% a.i.) was administered to New Zealand White rabbits via gavage at 0, 10,

30 or 100 mg/kg/day on days 6-19. No maternal toxicity was observed at any dose level. The maternal toxicity NOEL was equal to or greater than 100 mg/kg/day, the highest dose tested. However, 50% mortality was observed at 150 mg/kg/day and 100% mortality was observed at 200 and 300 mg/kg/day in the pilot study. Therefore, 100 mg/kg/day is considered adequate for testing in the main study. An increase in post-implantation loss (primarily attributed to late resorptions) was observed in the high dose group when compared with controls, which was outside the range of the historical control data. However, the litter sizes were comparable between the control and the high dose group which was indicative of a minimal effect. Therefore, the NOEL for developmental toxicity was 30 mg/kg/day and the LEL for developmental toxicity was 100 mg/kg/day

ba sed on increases in post-implantation loss and late resorptions.Page 9 of 30

Reproductive Toxicity

Currently, there is no available reproduction toxicity study for OBPCP or its sodium and potassium salts. According to the RED (1995), results of the rabbit developmental toxicity study indicated a potential concern for reproductive effects following

a dministration of OBPCP. This study showed an increase in post-implantation loss and late resorptions in the high dose group when compared to controls. In addition, the developmental toxicity study conducted in Wistar rats showed decreased fetal body weights. Furthermore, one reproductive incident has been reported in the OPP incident data system involving a pregnant woman; her baby was born 6 weeks early with too much fluid in the abdomen and as a result of this condition, died. To evaluate these reproductive concerns, a 2-generation reproduction toxicity study conducted with OBPCP is required.

Chronic Toxicity and Carcinogenicity

Administration of OBPCP (97% a.i.) in corn oil via gavage to B 6 C 3 F 1 mice (males and females: 0, 120, 240 or 480 mg/kg/day) in a two-year carcinogenicity feeding study (MRID 42279302) resulted in a significant dose-related, increased trend and statistically significant pair-wise comparisons of all dose groups with the control group for renal tubule tumors (adenomas and/or combined adenomas/carcinomas, with carcinomas contributing a substantial portion of the total incidence) at p < 0.05 in male mice. There was also a significant difference in the pair wise comparison of the 120 mg/kg/day dose group with the controls for renal tubule adenomas at p < 0.05. In this study, incidences of these (rare) renal tubule tumors in male mice exceeded historical control incidences for all doses tested. The highest dose tested (480 mg/kg/day) was considered excessive based upon increasing trends in mortality, clinical signs of toxicity, lower mean body weights, and severe microscopic lesions/histopathology in a variety of organs (kidney renal nephropathy, fibrous osteodystrophy, myocardial degeneration, and coagulative necrosis and inflammation in the liver). However, dosing was considered adequate at the mid-dose for assessing the carcinogenic potential of OBPCP in mice based upon an increasing but

a cceptable trend in mortality in both sexes with increasing dose, clinical signs of toxicity, changes in organ weights, increased incidence/severity of kidney nephropathy and increased incidences of non-neoplastic lesions in a variety of organs at a lesser extent than in the high dose group. A chronic systemic toxicity NOEL could not be established for

mice because there were treatment-related effects at the lowest dose level. The chronic systemic toxicity LOEL was 120 mg/kg/day based upon treatment-related increases in mortality in both sexes, clinical signs of toxicity in both sexes (emaciation, abnormal posture, rough hair coat and hypoactivity), decreased body weights in males, changes in

or gan weights in both sexes (decreased absolute and relative kidney and thymus weights), forestomach hyperplasia and ulcer in both sexes, glandular stomach mucosa mineralization in both sexes, fibrous bone osteodystrophy in both sexes, and renal nephropathy in both sexes.

In a two-year chronic toxicity/carcinogenicity feeding study (MRID 42279301), OBPCP (97% a.i.) was administered (males: 0, 30, 60 or 120 mg/kg/day; females: 0, 60, 120, 240 mg /kg/day) in corn oil via gavage to F344/N rats for two years. Rare, renal transitional cell carcinomas in both mid- and high dose female rats (one in each group)Page 10 of 30

were observed. There was no occurrence of these tumors in concurrent controls of either sex or in any of 1,068 historical control females. There was also one renal tubule adenoma in a high dose female and one renal tubular carcinoma in a high dose male; however, these tumor types in rats were within the range of historical controls and are not considered treatment-related. Dosing in this study was considered adequate for carcinogenicity testing in rats based upon treatment-related increases in incidences of several microscopic lesions (dose-related increase in incidence/severity of renal nephropathy, hyperplasia of the kidney tubule and transitional cells, hyperplasia of the parathyroid gland, and fibrous osteodystrophy of the cranium and femur); increases in kidney weights; increases in supporting urinalysis values (coproporphyrin, protein, and alkaline phosphatase); decreases in galactosidase activities; and increases in yellow staining of the urogenital area. The chronic systemic toxicity LOEL was 30 mg/kg/day (lowest dose tested in male rats) based upon increased incidence/severity of kidney nephropathy and increased urinary coproporphyrin. A chronic systemic toxicity NOEL

c ould not be established because of the increased incidence of kidney nephropathy in male rats observed at 30 mg/kg/day compared to controls. (MRID 42279302; this is Tier 3 data

whic h were not required by the Agency. The study was performed by NTP and submitted as 6(a)(2) data).

Cancer Classification

On September 5, 1995, the Carcinogenicity Peer Review Committee (CPRC) classified OBPCP as a Group C - possible human carcinogen and that for the purpose of

risk c haracterization, the committee recommended the RfD approach for quantitation of human risk. This determination was based upon the compound-related increases in renal tubule tumors at all doses in male B6C3F1 mice (combined adenoma/carcinoma, with carcinomas contributing a substantial portion 33-50% of the total incidence) and increases in renal transitional cell carcinomas at the mid- and high-doses in female F344/N rats (with none in any of the 1, 068 historical control females as well as concurrent control animals). Renal tubular carcinomas in the mouse and renal transitional cell tumors in the

ra t are rare. In addition to the absence of a specific mechanism(s) leading to formation of these rare renal tumors in mice and rats, there were no structural analogs of OBPCP that have been tested for carcinogenic potential and no apparent genotoxicity concern from the mutagenicity data submitted to support registration of this active ingredient as a pesticide.

Metabolism

Metabolism data are not available for the active ingredients, OBPCP, Na + OB PCP, or

K + OBPCP. For antimicrobial pesticides, metabolism studies are "required only if the Agency determines that additional information on the metabolism of the chemical(s) are necessary to clarify unusual effects observed in chronic or reproduction studies or to clarify issues concerning structure activity relationships”. For OBPCP, Na + OB PCP, or

K + OBPCP, no issues were identified that warrant the need for metabolism data at this

time.

Dermal PenetrationPage 11 of 30

A dermal absorption study (MRID 43313401) for OBPCP is available. This study was conducted with OBPCP (5% a.i. formulation) administered at 5, 50, and 500 μ g/cm 2 for 1, 4, 10 hours with a 168 hour collection period. The total quantity and percent OBPCP absorbed increased with time and dose, with most of the test substance accumulating in

the bod y during the first 10 hours. At 168 hours, essentially all administered OBPCP was excreted in the uring and feces. This study has been classified as acceptable and indicates that OBPCP reacts in such a way that is typical of a chemical which destroys the integrity

of the stratum corneum of the skin (outer layer of the epidermis). Table 4 summarizes

these results.

Table 4 : Dermal Penetration of OBPCP % Absorption of 5% Formulation From Sev eral Dose Levels at Various Time Points

Dose Time 5 μg/cm 2 50 μg/cm 2 500 μg/cm 2

1 hour 7.7% 6.19% 5.42%

4 hours 15.82% 14.69% 18.96%

10 hours 23.93% 26.31% 29.15%

168 hours a 26.10% 51.61% b 41.45%

a Animals kept longer than 10 hours were washed at 10 hours. The 168 hours, 50μg/cm 2 value was considered the most appropriate to use for risk assessment purposes

. b Therefore, the dermal absorption of OBPCP is 51.6%.

Section 3. Dietary Assessment

Dietary

OBPCP currently has a tolerance exemption under 40 CFR 180.940c for use in food

pr ocessing equipment and utensil with a not to exceed limit of 320 ppm. FDA has also

c leared o-benzyl-p -chlorophenol as an indirect additive in food contact sanitizing

solut ions (21 CFR §178.1010) that can be used for food processing equipment and

utensils. For registration review, EPA expects that indirect exposure to surface cleaners would trigger an initial Tier I dietary screening-level assessment. Therefore, EPA will

c onduct a Tier 1 dietary screening-level assessment fo r food processing equipment and

utensils as well as an assessment of indirect food contact fr om countertops in residential homes. EPA anticipates the need for residue data for countertops to assess incidental oral exposure from the resulting indirect dietary exposures. Based on D310957, the EPA estimated that a worst-case dietary exposure to be 320 ppm assuming no washing or rinsing

.

Drinking Water

Since OBPCP is used in industrial cooling water towers and air washers, the Agency expects that it could migrate to groundwater and surface water and then on to drinking water. Although likely to be infrequent, dietary exposures via drinking water may occur in the event of a down-the-drain discharge. The contaminated water could pass through wastewater treatment facilities into the drinking water or may be discharged directly to surface water which is later treated. However, at this time there are no environmental fate data to determine whether OBPCP can pass through wastewater treatment facilities into drinking water or migrate into residential groundwater wells as a result of its current use patterns. Since the product is used in commercial recirculating cooling water systems, thePage 12 of 30

Agency anticipates that the effluent wastewater could discharge directly to surface water. As a result, the Agency would anticipate the need to model environmental concentrations and develop a drinking water risk assessment.

Section 4. Aggregate and Cumulative Exposure

In examining aggregate exposure, EPA takes into account the available and reliableinformation concerning exposures to residues in food and drinking water, and nonoccupational pesticide exposures. EPA expects that the dietary and residential risks will

ne ed to be aggregated. Section 408(b)(2)(D)(v) 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 does not have, at this time, available data to determine whether OBPCP has a common mechanism of toxicity with other

subst ances or how to include this pesticide chemical in a cumulative risk assessment.

Section 5. Occupational/Residential Exposure

There is potential short- and intermediate-term exposure to occupational workers for

a pplications such spraying, mopping, and wiping from the hard surface disinfectant use to

ha rd surfaces (such as counter tops), medical and agricultural equipment, animal and agricultural premises, green houses and floors. The potential occupational handlerexposure scenarios identified by the Agency after review of the labels include (1) openpour loading of liquid formulations, (2) applying disinfectant by hand wiping surfaces, (3)

a pplying the disinfectant by hand by dipping tools/implements into dilute disinfectant solution, (4) applying the disinfectant by mopping surfaces, (5) applying the disinfectantwith hand-held, high pressure spray equipment, (6) applying the disinfectant with handheld, low pressure spray equipment, (7) applying with a trigger pump sprayer, (8) applying with an aerosol can and (9) applying the disinfectant with a wet-mist fogger. Product use data will be essential to categorize the uses and equipment necessary to refine these risk assessments. The Agency expects that both the dermal and inhalation routes will

ne ed to be assessed.

In addition to the registered disinfectant uses, it should be noted that the technical product (formulated at 98.6% active ingredient) also could be formulated as a preservative in metalworking fluids, rubber goods, leather, textiles, upholstery fabrics, and carpets and for water treatment uses such as air washer water, cooling tower water, sewage systems, grease traps, drains, and human drinking water equipment. However, application rates and

e nd-use product uses are not identified on the existing end -use labels. Data would be needed to support these use patterns and additional risk assessments would need to be

c onducted.

There are potential inhalation concerns to persons reentering areas that have been treated with OBPCP, especially following wet-mist fogging applications and other applications in enclosed areas. Dermal and incidental oral postapplication exposures may

o ccur from children crawling on treated floors, or hand- to -mouth exposure from counter tops and floors.Page 13 of 30

Section 6. Incidents

The OPP Incident Data System (IDS) has reported 122 human incidents attributable to

o -benzyl-p-chlorophenol. Most of the incidents are classified as moderate incidents.

S evere dermal irritation and allergic type reactions were reported. The symptoms

include d skin depigmentation, itching, pain, swollen, blister, hives, and erythema. Reported symptom related to inhalation exposures included nasal irritation, ulcerated nasal membranes, burning throat, blisters in throat, hoarse coughing, shortness of breath, coughing, dyspnea, chest pain, and chest tightness.

Acute systemic effects for workers includ ed nausea, dizziness , stomach ache, headache, vertigo, and soft stool. For longer exposures over 6-months, workers complained of no or low appetite, weakness, and liver damage. Severe autoimmune

thromboc ytopenia, red skin rashes, nose/mouth bleeding, aplastic anemia and leukemia

wa s also reported. One incident that raised a reproductive concern, involved a pregnant woman. The baby was born 6 weeks early with too much fluid in the abdomen. The baby

di ed as a result.

Section 7. Anticipated Data Needs

The Antimicrobial Division (AD) anticipates requiring further exposure and toxicity studies for OBPCP for registration review. Table 5 lists the data needs based on the uses

of the current registered end-use labels. Table 6 list additional data requirements based on uses on the registered technical products. Note that technical product has additional use s that a re not currently presented on the end-use labels such as formulation as a preservative in metalworking fluids, rubber goods, leather, textiles, upholstery fabrics, and carpets and for water treatment uses are listed as registered uses on the manufacturing use products but are not supported by uses and applications on end-use products.

Table 5: Exposure Data Needs Based on End Use Labels

Study Needed Guideline Rationale ( also see App endix A and B)

90

- day Inhalation Toxicity 870.3465 As a result of inhalation exposures to high pressure sprays, fogging, trigger sprays and aerosols; the Agency anticipates

that a 90

- day inhalation study will be needed to develop

short

- and intermediate

- toxicity inhalation endpoints.

Reproduction and Fertility

Effects 870.3800 As a result of significant increase in post

- implantation loss in the high dose group , a human incident

, and chronic dietary exposure a reproduct ive study is needed.

Immunotoxi city 870.7800 Based upon decreased thymus weights and thymic lymphoid depletion which were noticed in the 90

- day oral rat study conducted with OBPCP (MRID 40376301, 41248202, 41462401) , EPA has concerns about the potential immunotoxicity of this chemical

. Reported

i ncidents of autoimmune thrombocytopenia, nose/mouth bleeding, aplastic anemia and leukemia in humans following exposure to OBPCP also raises concern for immunotoxicity

. Indoor Exposure ( Fogging ) 875.1 2 00 (Dermal)

875.1 4 00 (Inhalation)

875.1600 (Data Reporting) Exposure may occur while using a wet mist fogger for agricultural premises

.Page 14 of 30

Indoor Exposure ( Trigger Spray ) 875.1 2 00 (Dermal)

875.1 4 00 (Inhalation) 875.1600 (Data Reporting) Exposure may occur while spraying with a trigger pump cleaning spray in a bathroom, kitchen or other areas of the

home or office

. Indoor Exposure ( Aerosol Spray ) 875.1 2 00 (Dermal)

875.1 4 00 (Inhalation) 875.1600 (Data Reporting) Exposure may occur while spraying with a aerosol can in a bathroom, kitchen or other area s of the home or office

.

Indoor Exposure (Sponge and Wipes) 875.1 2 00 (Dermal) 875.1400 (Inhalation) 875.1600 (Data Reporting) Exposure may occur while sponging or wiping disinfectant

on a hard surface area.

Indoor Exposure (High Pressure Sprays) 875.1 2 0 0 (Dermal)

875.1 4 00 (Inhalation) 875.1600 (Data Reporting) Exposure may occur from high pressure sprays in agricultural premises

.

Product Use 875.1700 (Handler) 875.2800 (Postapplication) Product use data will be needed to characterize any

uncertainties with regard to the application equipment.

Indoor Surface Residue Dissipation Data 875.2300 Residue data for countertops would be needed to assess dermal and incidental oral exposure and an indirect dietary

exposure assessment. Inhalation Exposure 875.25 00 The post application inhalation exposure data will be used to assess the residential and/or occupational inhalation risks to estimate reentry exposure to fogging from a thermal fogger product use. This data is needed to conduct an inhalation postappli cation assessment.

Nondietary Ingestion 875.3000 The design of the non dietary ingestion exposure study can be combined with the Indoor Surface Residue Dissipation study (875.2300) to determine the available residue leaching from hand

- to

- mouth behavior o n countertops.

Table 6 : Additional Data Needs Based on Manufacturing Use Product Use*

Study Needed Guideline Rationale

Dermal Sensitization Threshold Quantification Special Toxicity Study The Agency anticipates needing additional data to quantitative ly address skin sensitization for risk assessment purposes during the registration review process. Severe dermal irritation and allergic type reactions in animal tests. In addition, human incident s have been reported following

exposure to OBPCP and or its sodium and potassium salts

. The fabric use specifically t rigger s this special dermal sensitization study . A dose response study is needed based on the expected prolonged dermal cont act associated with

clothes made out of fabric s impregnated with OBPCP

. Indoor Exposure (Sprays ) 875.1 2 00 (Dermal)

875.1 4 00 (Inhalation) 875.1600 (Data Reporting) Exposure may occur from sprays from machinist

exposures.

Indoor Exposure ( mixing/loading ) 875.1 2 00 (Dermal)

875.1 4 00 (Inhalation) 875.1600 (Data Reporting) Exposu re may occur while pouring preservative in a manufacturing setting for metal working fluids, rubber, leather, textiles, and cooling water.

Product Use 875.1700 (Handler) 875.2800 (Postapplication) Product use data will be needed to characterize any

uncer tainties with regard to the application equipment. Product use data will be needed to characterize any uncertainties with regard to post application exposure

scenarios.

Indoor Surface Residue Dissipation Data 875.2300 Residue data for clothing would be ne eded to assess dermal and incidental oral exposure. Description of Human Activity 875.2800 These data will clearly identify the specific equipment used

to deliver OBPCP to the use site, which in high exposure scenarios, such a metal working fluids will al low thePage 15 of 30 Agency to refine its risk assessment.

Nondietary Ingestion 875.3000 The design of the non dietary ingestion exposure study can be combined with the Indoor Surface Residue Dissipation study (875.2300) to determine the available residue leaching f rom a child mouthing treated leather clothing

articles as well as hand

- to

- mouth behavior on carpets.

* Additional data would be needed to support the uses for the technical product (EPA Reg No. 39967- 5 formulated at 98.6% active ingredient). Since it could be also be formulated as a preservative in metalworking fluids, rubber goods, leather, textiles, upholstery fabrics, and carpets and for water treatment uses such as air washer water, cooling tower water, sewage systems, grease traps, drains, and human drinking water equipment. The registrant would need additional studies. The actual guideline numbers for the exposure studies are similar except for 875.2800 and the dermal sensitization study. However, the uses will trigger more than one exposure study per guideline.

Section 8. Tolerances

OB PCP currently has a tolerance exemption under 40 CFR 180.940c for use in food processing equipment and utensils with a not to exceed limit of 320 ppm. OBPCP is listed

in 40 C FR 180.940c as the synonym phenol, 4-chlo ro -2 -(phenylmethyl) (CAS Reg No. 120-32-1).

S ection 9. Endocrine Disruption

As r equired by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence

, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its

re registration decision

, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), OBPCP is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two-tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine-related effects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T effect.Page 16 of 30

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. OBPCP is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Accordingly, as part of registration review, EPA will issue future EDSP orders/data call-ins, requiring the submission of EDSP screening assays for OBPCP. For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/

.

Section 10

. References

D389630. Benxylchlorophenol (o -Benzyl-p-chlorophenol; Sodium o-Benzyl-pchlorophenate; Potassium o-Benzyl-p-chlorophenate): Revised Toxicology Data

S ummaries for the Human Health Assessment Scoping Document for Registration Review of Benzylchlorophenol and Salts (Case No. 2045). Memorandum fro m M. Centra, Pharmacologist to N.Mottl, Biologist. TXR No.: 1003210. June 22, 2011.

D310957. Quarantine Exemption for USDA/FSIS for Environ LpH to Control Prions in Slaughterhouses and Meat Processing Facilities. Memorandum from D. Smegal, MPH, Toxicologist/Risk Assessor to M. Wingfield. May 12, 2005.

U.S.EPA (1987) Review of dose-ranging and main developmental toxicity studies in the rabbit and rat (Chlorophen © ): Record nol 166294/166295: EPA ID No. 49403- 2/49403-3; Accession No. 258031: Proj. Nos. 1466/1467; Caswell # 83 (Me morandum: J. Rowe to A. Castillo and O. Laird/PM #32, TXR# 005793, March 27, 1987).

U.S.EPA (1988) Registrant rebuttal comments for 21-day dermal toxicity study with Chlorophen © ; Record no. 2178886/2178887; EPA ID no. 49403-2/49403-3; Accession No. 259118; P roj. No. 8-0640; Caswell No. 83 (Memorandum: J. Rowe to J. Kempter (PM 32), TXR# 006690, May 5, 1988).

U.S.EPA (1990) 49403-2. Chlorophen © : Review of registrant comments regarding a developmental toxicity study in the rabbit; Record No. 241099; EPA ID No. 49403- 2/49403-3; Project No. 9-1001; MRID No. 410039-01; Caswell No. 83. (Memorandum: J. Rowe to B. Pringle, PM Team #32, TXR# 008109, September 25, 1990).

U.S.EPA (1990) 49403-2. Nipacide BCP. Antimicrobial Data Call-In. Submission of Data., Tox. Chem. No. 083, Project No. 0-1778. (Memorandum: P. Hurley to J. Wilson, PM Team #32, TXR# 008212, December 28, 1990).

U.S.EPA (1991) Review two (2) mutagenicity studies with o-Benzyl Parachlorphenol (Nipacide). EPA Identifying No.: 49403 -2, EPA MRID No.s: 412875-01 & 412875- 02, EPA Record No.: 255303, HED Project No. 0-0226, Caswell No. 83.Page 17 of 30

(Memorandum: S. Dapson to J. Wilson/Kempter (PM 32), TXR# 008234, January 23, 1991).

U.S.EPA (1994) 062202, 062203. Potassium and Sodium 2 -Benzyl-4 -Chlorophenate. Analogue Data for Toxicology Data Base. PC Codes 062202 and 062203, Tox. Chem. No. 083, Project Nos. D200190, D200423, Submission Nos. S459982, S460372 (Memorandum: P. Hurley to E. Mitchel/PM Team #81, May 4, 1994).

U.S.EPA (1995) o-Benzyl-p-chlorophenol Oualitative Risk Assessment Based on B 6 C 3 F 1 Mouse 2 -Year Oral Gavage Study (Memorandum: L. Brunsman to P. Hurley, TXR# 012759, February 23, 1995).

U.S.EPA (1995) Toxicology Endpoint Selection Document, Chemical Name: o-Benzyl-pc hlorophenol, TXR# 013105, (Committee Memorandum: P. Hurley and K. Baetke April 7, 1995).

U.S.EPA (1995) ADDENDUM to o-Benzyl-p-chlorophenol. Changes in Data Evalutation Records and 1-Liners, PC Code 062201, Tox. Chem. No. 083, MRID Nos. 422793-01,

001 43775, 00145836, 00161231 (Memorandum: LP. Hurley to Caswell File, TXR# 012758, April 18, 1995).

U.S.EPA (1995) 062201. o-Benzyl-p-Chlorophenol Oualitative Risk Assessment Based

on B 6 C 3 F 1 Mouse 2- Year Oral Gavage Study (Memorandum: L. Brunsman to P. Hurley, TXR# 012758, April 11, 1995).

U.S.EPA (1995) 062201. o-Benzyl-p-chlorophenol Draft Toxicology Chapter for the RED (Me morandum: P. Hurley to K. Boyle, May 17, 1995).

U.S.EPA (1995) RfD/Peer Review Report of o-Benzyl-p-chlorophenol (Committee

Memor andu m: G. Ghali to R. Douglas, TXR# 011583, June 12, 1995).

U.S.EPA (1995) 062201. o-Benzyl Para-Chlorophenol, The HED Chapter of the Reregistration Eligibility Decision Document (RED), Case 2045, Pesticide Chemical Code 062201, 062202 (potassium salt), 062203 (sodium salt) (Memorandum: K. Boyle to J. Kearns, TXR# 011631, August 4, 1995).

U.S.EPA (1995) Carcinogenicity Peer Review of o-Benzyl-p-chloro-phenol (o-BCP) (Comm ittee Memorandum: P. Hurley to R. Douglas, TXR# 011669, September 5, 1995).

U.S.EPA (1995) Reregistration Eligibility Decision (RED) Ortho-Benzyl-P-Chlorophenol.

EPA 738-F-96 -027, December 1995.

U.S.EPA (1995) R.E.D. FACTS, Ortho-Benzyl-P-Chlorophenol. PPTS (7508W). EPA

738 -F-96-027, December 1995.Page 18 of 30

Toxicology Data Submissions

MRID CITATION

00 130937 Cummins, H.; Gardner, J. (1983) Ortho-benzyl Parachlorophenol Acute

P ercutaneous Toxicity in the Rat: LSR Report No. 83/ BTP017/237. (Unpublished study received Aug 24, 1983 under 49403-2; prepared by Life Science Research, Eng., submitted by NIPA Laboratories, Inc., Wilmington, DE; CDL:251062- C)

.

00 130938 Cummins, H.; Bannerman, M. (1983) Ortho-benzyl Parachlorophenol

(Chlorophe n): Acute Inhalation Toxicity in the Rat: LSR Report No. 83/BTP030/296. (Unpublished study received Aug 24, 1983 un- der 49403

- 2; prepared by Life Science Research, Eng., submitted by NIPA Laboratories, Inc., Wilmington, DE; CDL:251062- D)

.

001 31367 Cummins, H.; Gardner, J. (1983) Ortho-benzyl Parachlorophenol Acute

Or al Toxicity in the Rat: LSR Report No. 83/BTP016/236. (Unpublished study received Aug 24, 1983 under 49403-2; prepared by Life Science Research, Eng., submitted by NIPA Laboratories, Inc., Wilmington, DE;

CDL:251062- B)

.

0 0 1 31368 Cummins, H.; Gardner, J. (1983) Ortho-benzyl Parachlorophenol Ac ute

E ye Irritation/Corrosion Test in Rabbits: LSR Report No. 83/BTP019/239. (Unpublished study received Aug 24, 1983 un- der 49403-2; prepared by

L ife Science Research, Eng., submitted by NIPA Laboratories, Inc., Wilmington, DE; CDL:251062- E)

.

0013 1369 Cummins, H.; Gardner, J. (1983) Ortho-benzyl Parachlorophenol Acute

De rmal Irritation/Corrosivity Test in Rabbits: LSR Report No. 83/BTP018/238. (Unpublished study received Aug 24, 1983 under 49403- 2; pre pared by Life Science Research, Eng., submitted by NIPA Laboratories, Inc., Wilmington, DE; CDL:251062- G)

.

00143774 Ross, F. (1985) Chlorophen: Effects of Oral Administration upon

Pregnancy in the Rabbit: Report Nos. 85/BTP033/161,85/BTP035/ 080. Unpublished study prepared by Life Science Research. 60 p.

0 0143775 Willoughby, C. (1985) Chlorophen: Teratology Study in the Rat: Report

Nos. 85/BTP032/054, 84/BTP031/583. Unpublished study pre- pared by

L ife Science Research. 82 p.

00145836 Becker, H. (1984) Embryotoxicity (Including Teratogenicity) Study with

Preventol BP Technical in the Rat: Project No. 035212. Unpublished study prepared by Research & Consulting Company. 101 p.Page 19 of 30

00161231 Sachsse, K.; Becker, H. (1985) Letter sent to whom it may concern dated

Oct 2, 1985: RCC Project 035212: Embryotoxicity (including teratogenicity) study with Preventol BP Technical in the rat: Date of report: November 27, 1984. Prepared by Research and Consulting Co. AG. 353 p.

40376301 Birnbaum, L.; Deskin, R.; Grumbein, S.; et al. (1986) Prechronic toxicity

of o -benzyl-p-chlorophenol in rats and mice. Fundamen- tal and Applied

Tox icology 7:616-625.

40988201 Ross, F. (1985) Chlorophen: Effects of Oral Administration upon

Pregnancy in the Rabbit: Supplement to LSR Report No. 85/BTP033/ 161: LSR Report No. 85/BTP033/257. Unpublished study prepared by Life Science Research Limited. 67 p.

41003901 Ross, F. (1989) Chlorophen

-- Effects of Oral Administration Upon

Pregnancy in the Rabbit: Supplement to LSR Report No. 85/BTP003/ 257. Unpublished study prepared by Life Science Research Ltd. 19 p.

41248201 Cummins, H. (1989) Product Toxicology: Nipacide BCP (Ortho-Benzyl

Parachlorophenol): 21-Day Percutaneous Toxicity Study in the R Rabbit: Project ID NIPA-1989-4. Unpublished study prepared by Life Science Research Ltd. 195 p.

41248202 Birnbaum, L. et al. (1986) Supplement to Prechronic Toxicity of OBenzyl-P-Chlorophenol in Rats and Mice: Project ID NIPA-1989-5. Unpublished study prepared by National Toxicology Program Batte- lle

C olumbus Division. 142 p.

41287501 Mortelmans, K. (1989) National Toxicology Program Salmonella

Mutagenicity Tests: II. Results from the Testing of 270 Chemicals Including Ortho-Benzyl Parachlorphenol: Lab Project Number: NIPA/1989/6. Unpublished study prepared by SRI International 40 p.

41287502 Gulati, D. (1989) National Toxicology Program: In vitro Cytogenetic

Testing of Ortho Benzyl Parachlorphenol: (Structural Chromosomal Aberration): Lab Project Number: NIPA/1989/7. Unpublished study prepared by Litton Bionetics, Inc. 10 p.

41462401 Battelle (1990) Supplement No. 2: Prechronic Toxicity Study in Rats and

Mice (O-Benzyl-p-chlorophenol): Lab Project Number: NIPA- 1990-1. Unpublis hed study. 159 p.

41572801 Edwards, C. (1990) Nipacide BCP (Ortho-benzyl Parachlorophenol):

Assessment of Clastogenic Action on Bone Marrow Erythrocytes in the Micronucleus Test: Lab Project Number: NIPA-1990-4. Unpublished study prepared by Life Science Research Ltd. 38 p.Page 20 of 30

42279301 Hejtmancik, M.; Grumbein, S.; Athey, P.; et al. (1988) Final Report on the

Chronic Gavage Study of o-Benzyl-p-Chlorophenol (CAS No. 120-32-) in

F ischer 344 Rats to National Toxicology Program. Unpublished study prepared by Battelle. 161 p.

42279302 Hejtmancik, M.; Ryan, M.; Grumbein, S.; et al. (1988) Final Report on the

Chronic Gavage Study of o-Benzyl-p-Chlorophenol (CAS No. 120-32-1) in

B 6C3F1 Mice to National Toxicology Program. Unpublished study prepared by Battelle. 81 p.

43313401 Warren, D. (1994) Dermal Absorption of (carbon 14)-o-Benzyl-pC hlorophenol from a 5% Formulation: Lab Project Number: 94-722-XC: 7332. Unpublis hed study prepared by Miles Inc. 60 p.

45424201 Glaza, S. (2001) Dermal Sensitization Study in Guinea Pigs

-- Closed Patch

Technique with Preventol BP: Final Report: Lab Project Number: 01204836: 00C-I24-DC. Unpublished study prepared by Covance Labs.,

I nc. 63 p. {OPPTS 870.2600}.

92007001 Eigenberg, D. (1990) Mobay Chemical Corp. Phase 3 Summary of MRID

00145836 and Related MRIDs 00161231. Embryotoxicity (Including Teratogenicity) Study with Preventol BP Technical in the Rat: Project 035212 (Mobay Report EHR 4099). Prepared by RCC, Research and Consulting Co. AG. 19 p.

92008008 Dooley, T. (1990) Nipa Laboratories, Inc. Phase 3 Summary of MRID

00131367. Ortho-benzyl Parachlorophenol (Chlorophen) Acute Oral Toxicity in the Rat. Prepared by Life Science Research 7 p.

92008009 Dooley, T. (1990) Nipa Laboratories, Inc. Phase 3 Summary of MRID

00130937. Ortho-benzyl Parachlorophenol (Chlorophen) Acute Percutaneous Toxicity in the Rat. Prepared by LIFE SCIENCE RESEARCH 7 p.

92008010 Do oley, T. (1990) Nipa Laboratories, Inc. Phase 3 Summary of MRID

00130938. Ortho-benzyl Parachlorophenol (Chlorophen) Acute Inhalation Toxicity in the Rat. Prepared by LIFE SCIENCE RESEARCH 9 p.

92008011 Dooley, T. (1990) Nipa Laboratories, Inc. Phase 3 Summary of MRID

00130939 and Related MRIDs 00013168. Ortho-benzyl Parachlorophenol (Chlorophen) Acute Eye Irritation/ Corrosion Test in Rabbits. Prepared by Life Science Research 7 p.

92008012 Dooley, T. (1990) Nipa Laboratories, Inc. Phase 3 Summary of MRI D

00131369. Ortho-benzyl Parachlorophenol (Chlorophen) Acute Dermal Irritation Corrosive Test in Rabbits. Prepared by LIFE SCIENCE RESEARCH. 7 p.Page 21 of 30 APPENDIX A: TOXICITY

Guideline Numbers: Special Study Study Titles: Dermal Sensitization Threshold Quantifi cation Rationale for Requiring the Data This study is needed to quantify the threshold for dermal sensitization based on the observation of a dermal sensitization response in the guideline dermal sensitization study (MRID 45424201) where OBPCP was fou nd to be a sensitizer in guinea pigs. Severe dermal irritation and allergic type reactions in humans have also been reported in the available incident data bases following exposure to OBPCP, Na + OBPCP or K + OBPCP

. The symptoms included skin depigmentatio ns, itching, pain, swelling, blister, hives, and erythema. Additionally, “Mice demonstrated statistically significant dose

- dependent contact hypersensitivity responses to OBPCP with or without adjuvant pretreatment.” according to a published literature st udy by Stern, 1991. Therefore, the Agency is requiring a special study conducted with either OBPCP, Na + OBPC or K + OBPCP that provides quantitative data and

an assessment of dose

- response for both the initiation and elicitation phases of skin

sensitizatio n. The purpose of this study is to identify a threshold level for quantification of

dermal sensitization to OBPCP or its’ salts.

Practical Utility of the Data

1. How will the data be used? The data would be used to identify a threshold for dermal sens itization of OBPCP or its’ salts. Specifically, these quantitative data would be used to identify a level (dose) of OBPCP or its’ salts that can then be used to establish a safe threshold to protect against dermal

sensitization.

2. How could the data i mpact the Agency’s future decision

- making? Currently, it is not possible to assess the residential dermal (repeat exposures) from textiles/clothing because the guideline dermal sensitization animal study does not provide

dose

- response data to establish an elicitation threshold level for sensitization. This study may provide results that change how risks are quantified. It is possible that a dermal sensitization toxicological endpoint may be established and the Agency may determine a level of safety based o n the results of this study.

Guideline Number: 87 0

. 3465 Study Titles: 90

- day Inhalation Toxicity Study Rationale for Requiring the Data The Agency is requiring a repeat

- exposure inhalation toxicity study because occupational/residential and post

- app lication/re

- entry inhalation exposures to aerosols are expected to occur during mopping, wiping , spraying, trigger pump and particularly wet

- mist fogging uses of OBPCP, Na + OBPC or K + OBPCP . As a requir e ment under the proposed 40 CFR 158 data requirements for toxicology, a 90

- day inhalation toxicity study is required for registration review. The length of this study is adequate to assess risks from repeat inhalation exposures based upon the use patterns of products containing OBPCP, Na + OBPC

or K + OBPCP

.

Th is study is critical for pesticides with use patterns in which there is potential for repeated human exposures via inhalation. The design of an inhalation study simulates the route andPage 22 of 30

duration of human exposure to aerosols of the test material. A detail ed toxicological examination including the histopathology of the respiratory system would also be conducted in an inhalation toxicity study. The information from this study would better characterize potential toxicities from repeat inhalation exposures to OBPCP, Na + OBPC or K + OBPCP and may also provide a toxicity endpoint applicable to human health, inhalation risk

assessment.

Practical Utility of the Data

1. How will the data be used?

Although inhalation is a potential exposure route for several sc enarios involving the use of

OBPCP chemicals , there is no available repeat exposure inhalation toxicity study to demonstrate the types of adverse effects that may be manifested via this route of exposure or the dose(s) at which these respiratory

- specific a dverse effects occur. A dose and effect from

a 90

- day inhalation toxicity study are most appropriate for use as the hazard component in quantitative inhalation risk assessments. These data are critical to properly characterize and quantify the hazard and risks to occupational and residential applicators exposed to OBPCP,

Na + OBPC or K + OBPCP and may result in the identification of route specific and duration appropriate endpoints for risk assessment.

2. How could the data impact the Agency’s future decis ion

- making?

In the absence of repeat inhalation toxicity data, the Agency is unable to estimate inhalation risks to persons applying products which contain OBPCP, Na + OBPC or K + OBPCP

. If used

as the source of dose and effect for inhalation risk assessmen ts, these new inhalation toxicity data would provide an estimate of the magnitude of this potential risk as well as providing a more complete characterization of overall mammalian toxicity and a better understanding of

the effects of OBPCP or its’ salts on human health.

Guideline Number: 87 0

. 3800 Study Titles: Reproduction and Fertility Effects Rationale for Requiring the Data The difficulty of predicting real world human exposure via oral route with limited data and no reproductive toxicity data in rat or other alternative information, such as SAR, surrogate data, and/or weight of evidence to the Agency triggered the need for a reproductive (guideline) toxicity study in the rat, in order to adequately evaluate real work human exposure to OBPCP, Na + OBPCP or
K + OBPCP , particularly women (15

- 49 years of age), infants and children, based on how pesticide products containing these active ingredients are used.

Practical Utility of the Data

1. How will the data be used?

The data will allow the Agency to conclude more definitively whether or not there are any concerns for potential reproductive toxicity in the rat and it may also provide a toxicity endpoint applicable to risk assessment. Since the reproductive toxicity study will also include neurotoxi city evaluations, it will also provide some information regarding potential neurotoxicity in developing offspring exposed to OBPCP and salts.Page 23 of 30

2. How could the data impact the Agency’s future decision

- making?

A reproduction and fertility effects study ma y result in a change in how risks are quantified for
OBPCP, Na + OBPCP or K + OBPCP . The required study may provide a toxicity endpoint applicable to risk assessment. It is possible that the database uncertainty factor may be reduced or removed, resulting i n a different magnitude of the value of the endpoint used for pesticide regulation.

Guideline Number : 87 0

. 7800 Study Titles: Immunotoxicity Rationale for Requiring the Data This is a new data requirement under 40 CFR Part 158 as a part of the data re quirements for registration of a pesticide (food and non

- food uses).

The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional immunotoxicity testing and is designed to evaluate the potential of a repeated chemical exposure to produce adve rse effects (i.e., suppression) on the immune system. Immunosuppression is a deficit in the ability of the immune system to respond to a challenge of bacterial or viral infections such as tuberculosis (TB), Severe Acquired Respiratory Syndrome (SARS), or neoplasia. Because the immune system is highly complex, studies not specifically conducted to assess immunotoxic endpoints are inadequate to characterize a pesticide’s potential immunotoxicity. While data from hematology, lymphoid organ weights, and hist opathology in routine chronic or subchronic toxicity studies may offer useful information on potential immunotoxic effects, these endpoints alone are insufficient to predict immunotoxicity. Therefore, the Agency is requiring an immunotoxicity study conduc ted with either
OBPCP, Na + OBPCP or K + OBPCP

.

Practical Utility of the Data

1. How will the data be used?

Immunotoxicity studies provide critical scientific information needed to characterize potential hazard to the human population on the immune syste m from pesticide exposure. Since epidemiologic data on the effects of chemical exposures on immune parameters are limited and are inadequate to characterize a pesticide’s potential immunotoxicity in humans, animal studies are used as the most

sensitive en dpoint for risk assessment. These animal studies can be used to select endpoints and doses for use in risk assessment of all exposure scenarios and are considered a primary data source

for reliable reference dose calculation.

2. How could the data imp act the Agency’s future decision

- making?

If the immunotoxicity study conducted with OBPCP, Na + OBPCP or K + OBPCP shows that the test material poses either a greater or a diminished risk than that given in an earlier decision

document conclusion, the risk a ssessments for the test material (s) may need to be revised to reflect the magnitude of potential risk derived from the new data. If the Agency does not have this data, a

10 x database uncertainty factor may be applied for conducting a risk assessment from the available

studies

.Page 24 of 30 APPENDIX B: HUMAN EXPOSUREPage 25 of 30

Guideline Number: 875.1200 Study Titles: Dermal Exposure (Indoor) Rationale for Requiring the Data
Note: Dermal exposure data are needed for both residential and occupational use s. The selection of an outdoor versus an indoor site is based on the high end exposure scenario. In almost all cases, repeating an exposure study for the same scenario outdoors and indoors is not necessary.

The potential for dermal exposure is very like ly for exposure scenarios involving wiping and spraying hard surface disinfectants . The existing CMA data base and PHED for these scenarios are limited in scope for QA/QC and number of monitoring units. EPA presented the need for additional handler expos ure data to the January 2007 Science Advisory Panel (SAP) as well as to the April 2007 Human Studies Review Board (HSRB) and both groups agreed that additional data

are warranted.

The criteria for the dermal exposure data are based on the potential for d ermal exposure from the labeled uses (e.g., occupational and residential exposures from spraying and wiping ) and evidence of toxicity. If the toxicological endpoints from OBPCP and salts are used to assess the risks, there is an endpoint selected for the dermal route

.

Practical Utility of the Data

1. How will the data be used?

The dermal exposure data will be used to assess dermal exposures from wiping and spraying

disinfectants . For occupational uses, the dermal exposure data will be used to assess the short

- , and

intermediate

- term exposures. The dermal exposure data will be used to determine the accuracy of the dermal risks to both residence and occupational workers.

2. How could the data impact the Agency’s future decision

- making?

If risks war rant mitigation, the dermal exposure data will provide the types of mitigation necessary such as chemical resistant gloves or closed systems for commercial uses, or potential removal of

uses from the label.

Guideline Number : 875.1400 Study Titles: Inha lation Exposure (Indoor) Rationale for Requiring the Data
Note: Inhalation exposure data are needed for both residential and occupational uses. The selection of an outdoor versus an indoor site is based on the high end exposure scenario (for

inhalation the selection is typically indoors). In almost all cases, repeating an exposure study for the same scenario outdoors and indoors is not necessary.

The inhalation exposure route is very important for exposure scenarios such application of paints or

metal working fluids where aerosols would be generated. In addition, inhalation exposures from application are evident in exposure studies in the Pesticide Handlers Exposure Database (PHED). The significance of these exposures is directly affected by the sever ity of the inhalation toxicological endpoint of concern. At this point in time, no toxicological data are available to assess the inhalation risk. The existing Chemical Manufacturer Association (CMA) data base and

PHED for these scenarios are limited in s cope for QA/QC and number of monitoring units. EPA presented the need for additional handler exposure data to the January 2007 Science Advisory Panel (SAP) as well as to the April 2007 Human Studies Review Board (HSRB) and both groups agreed that addition al data are warranted.

The criteria for the inhalation exposure data are based on the potential for respiratory exposure from the labeled uses (e.g., exposure to disinfectants ) and evidence of toxicity. If no toxicological endpoints of concern were iden tified, then the inhalation exposure data would not be needed.

Practical Utility of the DataPage 26 of 30

1. How will the data be used?

The inhalation exposure data would be used to assess the residential short

- term duration of painting with a paint brush/roller a nd an airless sprayer. For occupational uses, the inhalation exposure data

would be used to assess the short

- and intermediate

- term as well as pouring OBPCP

.

2. How could the data impact the Agency’s future decision

- making?

If risks warrant mitigatio n, the inhalation exposure data will provide the types of mitigation necessary such as dust mist respirators, full face respirators or closed systems for commercial uses, or potential removal of uses from the label.

Guideline Number : 875.1600 Study Titl e: Data Reporting and Calculations Rationale for Requiring the Data For all exposure studies this data need is needed to facilitate the review of the data. The study report and all raw data/calculations would be reviewed for the adequacy of the

data.

Practical Utility of the Data

1. How will the data be used?

The data are needed to interpret the dermal and inhalation exposure data collected.

2. How could the data impact the Agency’s future decision

- making?

This data need is triggered if an exposu re study is conducted. It would aid the Agency to make accurate interpretations of the studies to develop an accurate and refined risk assessment and refined mitigation.Page 27 of 30

Guideline Number : 875.1700 Study Title: Product Use Information

Rationale for Requiring the Data Product use information is a description of how the product is actually applied; it is not afield study. A description of how this product is used would provide for a comprehensive realistic assessment of its potential application s. The description of the application techniques would be used to define the exposure scenarios to be assessed in

the risk assessment. Practical Utility of the Data

1. How will the data be used?

A complete description of product use would ensure that t he risk assessment is inclusive of the types of exposures occurring during residential and occupational use.

2. How could the data impact the Agency’s future decision

- making?

The need for a risk assessment as needed under Registration Review would requi re that the risk assessor understands how the product is applied.

Guideline Number : 875.2300 Study Title: Indoor Surface Residue Dissipation Rationale for Requiring the Data

Based on the use of OBPCP as a hard surface disinfectant for countertops, hu man contact to treated countertops may occur. There are no data available to estimate exposure to adults and children from exposure to treated countertops , floors, carpets and clothing with OBPCP

. Practical Utility of the Data

1. How will the data be u sed? Without data, the Agency will conduct a screening level assessment using a conservative surface residue value of 1 mg/cm 2 . Currently, there are no data that can be used to estimate exposure to adults or to children exposed to treated wood. These dat a will be used to refine the Agency’s risk

assessment and to confirm or refute the Agency’s screening level assessment.

2. How could the data impact the Agency’s future decision

- making? Depending on the results of the dislodgeable residue study, the Agen cy may pursue risk mitigation measures regarding the use of formulated products containing OBPCP as the active ingredient in occupational and residential scenarios.

Guideline Number: 875.2500 Study Title: Inhalation Exposure Rationale for Requiring th e Data The post application inhalation exposure may be required if it is determined that the use of these products have the potential to release OBPCP during the product use conditions (e.g., open systems, and vapor/mists from MWFs).

Practical Utility o f the Data

1. How will the data be used? The post application inhalation exposure data will be used to assess the residential and/orPage 28 of 30

Guideline Number: 875.2800 Study Title: Descriptions of Human Activity Rationale for Requiring the Data

Very limited worker activity data are available for antimicrobial pesticides, including material preservatives used in paint, and metal working fluids. Work er a pplication parameters are generally defined by the physical nature of the formulation (e.g., formula and packaging), by the equipment required to deliver the chemical to the use site, and by the application rate required to achieve an

efficacious dose. The risk assessment noted that many of the use parameters used (e.g., amount handled and duration of use) were based on professional judgments. These data are needed to fill this data gap and provide information needed to refine the risk assessment.

Pra ctical Utility of the Data

1 . How will the data be used?

These data will clearly identify the specific equipment used to deliver OBPCP to the use site, which in high exposure scenarios, such a metal working fluids and paint applications, will allow th e Agency to refine its risk assessment.

2 . How could the data impact the Agency’s future decision

- making?

If review and evaluation of the descriptions of human activity data indicate that only closed

- systems are used for mixing/loading and applying met al working fluids, then the need for a reproductivity study is negated. Therefore, s ubmission of acceptable human activity data demonstrating the metal working fluid scenario for OBPCP is an enclosed system will eliminate a significant cost and burden

for the registrant (specifically, the costs associated with generating the reproductivity and fertility study data). For the other use scenarios, descriptions of human activity data will allow the Agency to refine its risk assessment and make decisions using fewer assumptions and more reliable data. occupational inhalation risks to estimate reentry exposure to fogging from a thermal fogger product use. This data is n eeded to conduct an inhalation postapplication assessment

2. How could the data impact the Agency’s future decision

- making? The inhalation exposure data will be used to determine the accuracy of the post application inhalation risks to occupational bysta nders. If risks warrant mitigation, the inhalation exposure data will provide the types of mitigation necessary such as respiratory protection from respirators or closed systems for commercial uses to potential removal of

uses from the label.Page 29 of 30

Guideline Number: 875. 29 00 Data Requirement: Data Reporting and Calculations
Rationale for Requiring the Data For all exposure studies, these data are needed occupationally and in the residential setting to
facilitate the review of the data.
Practical Utility of the Data

1. How will the data be used? The study report and all raw data/calculations will be reviewed for the adequacy of the data.

2 . How could the data impact the Agency’s future decisi on

- making? The data are needed to define and interpret the inhalation and dermal exposure data collected. This data need is triggered any time an exposure study is conducted. It would aid the Agency to make accurate interpretations of the studies to devel op an accurate and refined risk assessment and refined mitigation.

Guideline Number: 875.3000 Data Requirement: Non

- Dietary Ingestion Rationale for Requiring the Data The design of the non dietary ingestion exposure study can be combined with the Ind oor Surface Residue Dissipation study (875.2300) to determine the available residue leaching

from hand

- to

- mouth behavior on counter tops treated with OBPCP disinfectant.

Practical Utility of the Data

1. How will the data be used? This product is used as a disinfectant on counter tops. The available residues from hard surfaces will be used to determine the magnitude of children’s incidental exposure from

these uses.

2. How could the data impact the Agency’s future decision

- makin g?

The data are needed to refine the risk estimates if risks of concern are identified assuming 100% residue transfer from contact from hard surfaces (e.g., counter tops). If risks of concern are not identified when 100% residue transfer is assumed, the data are

not needed.Page 30 of 30 APPENDIX C : REGISTRATIONS

I- PC Code 062201, 2-Benzyl-4-chlorophenol

Current Active Products for AI:

211-62 1043 -118 5741-22 39967-81

303- 223 1677 -128 6836-252 39967-83

303- 225 2212 -17 6836-253 46851-1

675- 19 2296 -102 33176-6 46 851-5

675- 43 2296 -105 34810-8 46851-10

777- 94 3862 -177 34810-21 61282-53

954- 13 3862 -178 34810-31 62296-1

1043- 19 3862 -179 39967-5 66171-1

1043- 26 3862 -180 39967-6 66171-2

70385-7

70627-6

II - PC Code 062202, Potassium 2-benzyl-4-chlorophenate

Current Active Products for AI:

211 -25 4313-41 74655 -24

III - PC Code 062203, 2-Benzyl-4-chlorophenol, sodium salt

Current Active Products for AI:

211 -36 1769-374 3862 -11

Sign-off Date : 06/22/11

DP B arcode No s. : D 383100 an d D389630