UNITED STATES ENVIRONMENTAL PROTECTION AGE CY WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY AND**POLLUTIO~** PREVENTiON

February 18, 2011

MEMORANDUM

SUBJECT: 

### Summary of Human Health Effects Data for the p-Chloro-m-cresol

and Sodium p-Chloro-m-cresolate Registration Review Decision

Document.

PC Coders): 064205, 064206 DP Bareode(sYNo(s): D383015 Registration No(s): PCMC 33967-8,33967-9,33967-12,49403-19

Decision No.: 440820 NaPCMC 39967-21,39967-22,39967-25,39967-26,39967-27,

39967-46

Petition No(s).: NA 

### Regulatory Action: Human Health Registration


### Review

Risk Assess Type: Multiple Chemicals Case No(s).: 3046,5011

CAS No(s): 59-50-7, 15733-22-9

TXRNo.:NA p-Chloro-m-Cresol, Sodium p-Chloro-m-Cresolate

MRID Nors).: NA 40 CFR: None

FROM:

TO:

THRU: Nathan Mottl, Biologist

Team Two
Risk Assessment and Science Support Branch (RASSB)


### Antimicrobials Division (751 OP)

Seiichi Murasaki, Chemical Review Manager 

### Regulatory Management Branch II

Antimicrobials Division (7510P)



### Lance Wannell, Team Leader Regulatory Management Branch 

## n
Antimicrobials Division (751 OP)



### Nader Elkassabany. Branch Chief

Risk Assessment and Science Support Branch (RASSB)


### Antimicrobials Division (751 OP)

Page 1 of20EXECUTIVE SUMMARY

The Antimicrobials Division (AD) Registrati on Review Team has evaluated the status of the human health assessments for p-ch loro-m-cresol (case 3046, PC Code 064206) and sodium p-chloro-m-cresolate (case 5011, PC Code 064205) for the purpose of registration review. p-Chloro-m-cresol (PCMC) was first re gistered as a pesticide in the U.S in 1968 and sodium p-chloro-m-cresolate (Na PCMC) was first registered in 2000.

PCMC is formulated in two manufacturi ng use products (MUPs) as a >99.9% active ingredient (a.i.) and as a dilu table concentrate (e.g., 29.6% a.i. ) that is also mixed with ophenyl phenol at 12.5% a.i. Na PCMC is manu factured as a formulating intermediate (71 % ai) and as ready-to-use sol uble concentrates in five end- use products (31.9 to 71% ai). In addition, two of the Na PCMC end-use prod ucts contain other act ive ingredients such as o-phenyl phenol, octhilinone, and sodium pyrithione.

A reregistration eligibility decision (R ED) document for PCMC was conducted in 1997. Since Na PCMC was registered in 2000, it was not included in the Registration Eligibility Decision (RED) document or the or iginal PCMC case. A RED is not required for chemicals registered after November 1, 1984. The PCMC RED indicated that PCMC

is a microbicide used to cont rol slime-forming bacteria, yeas ts and fungi as an industrial preservative in oil recovery drilling muds/packer fluids, a dhesives, coatings, emulsions, leather processing liquors and leather products , metal working fluids, and paints. PCMC has a use classification as a material preserva tive and currently does not have a pesticide tolerance or exemption from the requirement of a tolerance. PCMC is cleared by the Food and Drug Administration (FDA) as an indirect food additive and formulated into adhesives (21 CFR 175.105), and paper and paperboard components (176.180, 176.200, 176.210). In addition, it has a food contact no tification (FCN) as a preservative in lubricants at levels not to exceed 1 percent (FCN 560). It should be noted that PCMC has been recently registered for industrial, hospi tal, household, institutional, and hard surface disinfection. During registra tion review, the Agency may have to determine if any tolerances or exemptions from the require ment of a tolerance are needed for the

disinfectant use.

Na PCMC has the same uses as PCMC and also has similar application rates. Past risk assessments submitted for registration ha ve utilized much of the same toxicity, chemistry and exposure data used for PCMC . During registration the Agency concluded
that much of the data for PCMC could be bridged to Na PCMC, since Na PCMC is rapidly protonated in water to form PCMC. EPA did not identify any FDA clearances for the Na PCMC active ingredient even though the uses were practically identical to PCMC.

The Agency did not identify a dietary risk assessment for PCMC/Na PCMC that assesses indirect food additive uses, and base d on review of the current labeled uses, anticipates developing dietary assess ments for the following use patterns:

• Adhesives,

• Cements,

• Coatings,

• Food contact paper,

Page 2 of 20• Lubricant oils,

• Detergents, and

• Cleaning solutions.

The purpose of this review is to examin e and characterize the existing hazard and exposure databases for PCMC and to determine whether new data and risk assessments are expected to be needed. Based on this review of the Agency data, existing risk assessments, reviews and the existing use patt ern , the Agency expects that data and
additional risk assessments will be needed to assess occupational, residential, dietary, and drinking water exposures. In addition, the Agency anticipates that a dditional toxicity and exposure studies may be needed to assess the hazards of PCMC.

Page 3 of 20Section 1. Chemical Identity

Tables 1 and 2 identify the chemical identi fication of the two activ e ingredients covered in this registration review.

Table 1. Chemical Identity

Common

Name p-Chloro-m-cresol

Synomyms 4-Chloro-3-cresol, 4-Chloro-3- methylphenol, Parachlorometacresol

PC Code 064206 CAS registry

number 59-50-7

Registration
Review Case

No. 3046

Structure

According to the RED, PCMC is a white crystalline solid that is moderately soluble in water (4 gm/L), and very soluble in or ganic solvents (500 gm/L ethanol). PCMC is lipophilic with a log Kow of 3. The melting point of the solid is 63-65oC and the boiling point is 239oC. The molecular weight is 142.6. The solution in water acts as an organic weak acid with a pH of 5.6 and a dissociation constant of 9.4. The vapor pressure is 0.25 mm Hg at 25oC.

Table 2. Chemical Identity

Common

Name Sodium p-Chloro-m-cresolate

Synomyms p-Chloro-m-cresol, sodium salt; Parachlorometacresolate, sodium salt; Sodium Parachlorometacresolate; Sodium 4-chloro-3-cresolate; Sodium 4-chloro-3-methylphenolate; Sodium p-chloro-mmethylphenate;

PC Code 064205 CAS registry

number 15733-22-9

Page 4 of 20Registration
Review Case

No. 5011

Structure

Section 2. Toxicology

The Agency has reviewed the existing toxi city assessments and toxicity data for PCMC and Na PCMC. The Agency reviewed the historical toxicological database supporting the reregistration of PCMC and Na PCMC. Based on the use pattern, the Agency expects that additional toxicity data will be needed.

It appears that the Agency decided to re ly on the same toxicity information taken from the Registration Eligibility Decision (R ED) for p-Chloro-m-cre sol to support the registration of sodium p-chloro-m -cresolate (Na PC MC) (D331570, D331571, D331573, D331575). The Agency identified only one acute oral toxicity study th at is unique for Na

PCMC.

Acute Toxicity

PCMC

For registration review, the Agency will re ly on the existing acute toxicity database developed during reregistration. Accord ing to Agency documentation (D011751),
PCMC has an acute oral t oxicity category of III based on an oral LD50 of 3,636 mg/kg for female rats and 5,129 mg/kg for male rats . An acute dermal toxicity category of IV was based on a dermal LD50 of >5,000 mg /kg from a dermal rat study. PCMC was
identified as corrosive to the eye and skin on rabbits (acute toxicity category I). However, it was not a dermal sensitizer in guinea pi gs. The rat inhalation study was waived since
PCMC is corrosive on skin.

Na PCMC

According to Agency documentation (D280484), the registrant submitted an acute toxicity test for Na PCMC. The data indicate d that Na PCMC had an acute oral toxicity category of III based on an oral LD50 of >2000 mg/kg for male rats and 1,272 mg/kg for female rats. This study was reviewed as accep table. Since there is no technical product, the acute data requirements are brid ged to the technical product PCMC.

Mutagenicity

The Agency does not anticipate the need for additional mutagenicity data based on review of the existing mutageni city data submitted during re registration of PCMC. In the

Page 5 of 20database of mutagenicity studies, no eviden ce of gene mutation was identified in two acceptable in vitro bacterial reverse gene mutation (Ames) assays (MRID 00078838 and MRID 42199901). No forward gene mutations we re seen in an in vitro study Chinese hamster ovary (HGRPT) study with and w ithout metabolic activation (MRID 41548601). No chromosome aberrations were seen in an acceptable in vivo mammalian cytogenetics bone marrow micronucleus assay in mice (MRID 41598101 and MRID 42005201). PCMC was tested in rat primary hepatocy tes in an unscheduled DNA synthesis study (UDS) assay and did not cause DNA damage or inducible repair unde r the conditions of the study (MRID 41598101 and MRID 42163201).

Subchronic Toxicity

Oral

One subchronic feeding study in 20/sex male and female Wistar rats at dose levels of 0, 150, 500 or 1500 ppm for 13 weeks (0, 12, 41, or 120 mg/kg/day for males and 0, 17, 54, or 167 mg/kg/day for females) was found in the existing literatur e. Clinical signs, body weights, food consumption, clinical bioche mistry, urinalysis, or gan weights, gross pathology and microscopic pathology were m easured. At 500 and 1500 ppm, a decrease in body weight gain was observed in males but not females (5-6% less than controls). No
other effects were observed. The decreases in body weight gain are not of toxicological significance. The NOEL is gr eater than 1500 ppm which wa s the highest dose tested (MRID 00124844).

Dermal

A 21-day dermal study using a TGAI of 99.9% PCMC was tested in a 21-day dermal study in New Zealand White rabbits (10/sex/dose group) at the following dose levels: 0, 10, 40 or 160 mg/kg/day. The animals were dosed 5 days/week for a total of 15 applications. It appears that the test material was applie d without a vehicle. Dermal
irritation was observed in all treated groups, which ranged from slight erythema and very slight edema (10 mg/kg/day) to severe er ythema and slight ed ema (160 mg/kg/day).
Other dermal effects included skin thicke ning, scaling, blanching, raw areas, necrosis, brown scab-like areas, and sloughing. Fissuring occurred in one mid-dose female and in two high dose males. The NOAEL for dermal irr itation is less than 10 mg/kg/day lowest dose tested. No systemic effects were observe d at either 10 mg/kg/da y or 40 mg/kg/day. At 160 mg/kg/day, a compound related enhancing effect on nonsupporative pericholangitis (both sexes) and bile duct proliferation (females) in the liver were observed. The systemic NOEL is 40 mg/kg/da y and the LOEL is 160 mg/kg/day based on enhanced liver pathology in both sexes (MRID 00062905).

Inhalation

No inhalation toxicity tests are available.

Developmental Toxicity

Page 6 of 20EPA reviewed a rat developmental study on PCMC (D179265) in which PCMC
was administered to Wistar rats at dose levels of 0, 30, 100, and 300 mg/kg/day during days 6-15 of gestation. At 300 mg/kg, 6 dams died and treatment-relate d clinical signs of toxicity included audible br eathing sounds, gasping breathi ng, reduced motility and high stepping gait, lying on side, somnolence, a bdominal position, spas tic convulsions, rough coat, sunken flanks and bloody muzzle. At 100 mg/kg, labored breathing was observed in two rats, and decrease in body weight ga in. The NOAEL for maternal toxicity is 30 mg/kg/day and the LOAEL is 100 mg/kg/day based on clinical signs of toxicity and decreases in body weight gain (100 mg/kg/da y and above) and death, decreases in food consumption and increases in total re sorptions (300 mg/kg/day). The NOAEL for developmental toxicity is 100 mg/kg/day and the LOAEL is 300 mg/kg/day based on a significant decrease in the mean fetal weight per litter at 300 mg/kg/day when compared to the control group and a slight increas e in the number of microphthalmias or anophthalmias at this dose level (MRID 42292901).

Chronic Toxicity/Carcinogenicity

Technical PCMC (99.9 to 99.97 % a.i.) was tested in a chronic/carcinogenicity feeding study for male and female Wistar rats . Fifty rats per sex we re tested per dose
level at 24 months with an addi tional ten per sex scheduled to be sacrificed at 53 weeks. The following dose levels were administered: 0, 400, 2000, or 10,000 ppm (0, 21, 103.1, or 558.9 mg/kg/day for males and 0, 27.7, 134.3, or 743.5 mg/kg/day for females). The systemic NOAEL is less than 400 ppm and the systemic LOAEL is 400 ppm based on poor general condition, decreased body weight and food efficiency, increased water intake, decreased urinary protein, changes in organ weights and histopathology of the kidney, brain (400 ppm and above), testes and epididymides (2000 ppm and above) (MRID 42784801).

In this study, pituitary tumors were found in females, and male rats had a significant increasing trend in te sticular interstitial cell tumo rs (p <0.05). The incidences of these tumors, however, were within the historical control range. Therefore, the

increased incidence of tumors seen in this study was not related to treatment with PCMC. Based on the results of the study, the Agency c oncluded that PCMC is not classifiable as a human carcinogen and is assigned to Group D.

Reproductive Toxicity

Since the Agency expects that there will be chronic effects as a result of the uses (e.g., metalworking fluid use), the Agency anti cipates the need for a rodent reproduction and fertility effects study. This study examines the reproductive and neurotoxicity effects in the maternal rat and developing offspring. It may also provide a toxicity endpoint applicable for human health risk assessment to women (15-49 years of age), infants and

children.

Summary of Toxicity Data

The Agency reviewed the existing toxi city database, the acute toxicity and mutagenicity, subchronic (oral and dermal), de velopmental, chronic, and carcinogenicity

Page 7 of 20studies. Based on the review, the Agency expects the need to conduct risk assessments based on inhalation exposures (e.g., aerosols re sulting from applica tion of paint using airless sprayer and aerosol exposure to me tal working fluids) and reproductive effects (e.g. chronic exposure to metalworking fluid. Thus, the Agency anti cipates that a 90-day inhalation and reproductive eff ect studies will be needed for registration review. In addition chronic exposure to metal working fl uids would also trigger the need for a rodent reproduction and fertility study.

In addition, the Agency also anticipates the need for at least a non-rodent (e.g., rabbit) developmental study to identify the susceptibi lity of different sp ecies. It is a wellrecognized scientific fact that species responses to developm ental insult can vary widely as a result of pharmacokinetic or pharm acodynamic differences. The dose at which maternal or prenatal developmental toxicity is observed may not be the same across species, and the severity of the response in dams or fetuses may also differ.

Section 3. Dietary Assessment

Although categorized as a non-food use, AD an ticipates that there may be indirect dietary exposure to PCMC and Na PCMC. Si nce PCMC and Na PCMC are both used in adhesives, paper and paperboar d, and lubricants as a preserva tive against bacteria, mold, and fungi, it is possible that th ese chemicals could indirectly migrate into food exposed to the treated paper and adhesives. PCMC is cleared by the Food and Drug Administration (FDA) as an indirect food additive and formulated into adhesives (21 CFR 175.105), and paper and paperboard components (1 76.180, 176.200, 176.210). In addition, it has a food contact notification (FCN) to preserve lubri cant at levels not to exceed 1 percent (FCN 560). This use has not yet been codified under FDA guidelines (as per 21 CFR). It should be noted that Agency did not iden tify an FDA clearance for Na PCMC.

EPA did not identify a dietary risk assessment for the indirect food additive uses for PCMC in the RED. As a result, EPA anticip ates the need to conduct dietary exposure and risk assessments for the following use patterns:

• Adhesives,

• Cements,

• Coatings,

• Food contact paper, and

• Lubricant oils.

In addition, PCMC and Na PCMC are used in detergents and cleaning solutions used for industrial, hospital, household, institutional, and hard surface disinfection. The Agency will need to assess potential acute and chronic indirect ingestion exposure estimates resulting from the use of disinfectan ts on kitchen surfaces in the home and also an assessment for detergents.

All registered use sites for PCMC /Na PC MC are indoors. Although expected to be infrequent, dietary exposures via drinking water may occur in the event a discharge of
contaminated waste water occurs from a fac ility manufacturing preservatives for paints, metal working fluids, adhesive, cements, coatin gs, etc. The contaminated water may then

Page 8 of 20pass through wastewater treatmen t facilities and into drinking water. However, there are
no environmental fate data to determin e whether PCMC/Na PCMC can pass through
wastewater treatment facilities into dri nking water or migrate into residential groundwater wells as a result of its current us e patterns. Upon receip t and review of the environmental fate data the Agency anticip ates requiring (hydrolysis, photolysis, and ready biodegradability), the need for a dr inking water exposure a ssessment for PCMC/Na PCMC will be determined. Therefore, the need for a dietary drinking water assessment will be revisited upon submission and review of the needed environmental fate data.

Section 4. Aggregate and Cumulative Exposure

In examining aggregate exposure, EPA take s into account the available and reliable information concerning exposures to pesticid e residues in food and drinking water, and non-occupational pesticide exposures. Dietar y (food and drinking water) exposures of concern are anticipated for PCMC/Na PC MC. An aggregate risk assessment for PCMC/Na PCMC is needed to assess aggreg ate exposures from diet ary sources (food and water) residential handler and post-a pplication exposures for paint.

Section 408(b)(2)(D)(v) of FFDCA require s that, when considering whether to establish, modify, or revoke a tolerance, th e Agency consider "available information” concerning the cumulative effects of a part icular pesticide's residues and "other
substances that have a common mechanism of toxicity.” EPA has not yet determined
whether PCMC/Na PCMC have common mechanisms with other compounds, consequently a cumulative assessment will not be performed at this time.

Section 5. Occupational/Residential Exposure

An occupational and/or residential exposur e assessment is required for an active ingredient if (1) cert ain toxicological criteria are triggered and (2) there is potential exposure to handlers (mixers, loaders, applicat ors, etc.) during use or to persons entering treated sites after application is comple te. There are potential occupational and residential handler and post a pplication exposures to person s entering treated sites (e.g., painting, metal working,etc.). The Agency e xpects that new risk assessments are needed.

PCMC/Na PCMC are antimicrobial pestic ides used on indoor nonfood uses as a preservative for oil recovery drilling muds/packer fluids, adhesives, coatings, emulsions, leather processing liquors and leather produc ts, metal working fluids, and paints. The label does not specify specific mixing or load ing systems; therefore, the Agency assumes that workers could be exposed during mixing /loading (both open and closed mixing and loading systems). Additionally, occupational workers could also experience dermal and inhalation exposure while appl ying preservatives using brush/roller, low pressure and airless sprayers. The exposures expected are presented in bulleted format below:

• Occupational dermal and inhalation handler exposure to PCMC and Na PCMC during the open pour /closed mi xing for materials preservation, oil recovery, leather production and textile production.

Page 9 of 20• Occupational dermal and inhalation ha ndler exposures to treated metal working fluids (MWFs), treated paints (b rush/roller, low pressure and airless sprayer), and disinfectant us es (mopping and wiping).

• Residential dermal and inhalation ha ndler exposure to during the use of treated paints (brush/roller, low pressure and airless sprayer).

• Residential postapplication incidental ingestion and dermal exposure (e.g. exposure to leather and household use of disinfectants of countertops).

• Postapplication inhalation exposur e to treated paints and MWFs.

The label specifies that personal protectiv e equipment (PPE) [e.g. chemical resistant gloves, long sleeved shirt, socks, shoes, and pants] will be used for occupational handling exposures from mixing or loading. However, since this chemical is used as preservative in paints, label restrictions fo r applicators using preservative s in paint are not applicable (e.g. cannot label paint on cans). Based on Ag ency concerns to open mixing/loading, as well as potential applicator exposures (e.g. airless sprayer) the Agen cy anticipates that new risk assessments will be needed. The Ag ency will need both inhalation and dermal exposure data to conduct these risk assessm ents. In addition, description of human activity data (GDLN 875.2300 are needed for uses including material preservatives used in paint, and metal working fluids. The Agency relies on professional judgments for many of the use parameters used (e.g., am ount handled and duration of use) in the exposure assessments. The Agency will need this data to understand to conduct postapplication inhalation exposure assessments.

The Agency will also need some data to clarify some labeled use patterns. Product use data (GDLN 875.1700 and GDLN 875.2500) will help the Agency to determine and refine the exact handler and pos t-application scenarios applicable for risk assessment. A complete description of product use would ensure that the risk assessment is inclusive of the types of exposures occurring during resi dential and occupational use. The listing of the end use consumer products would be used to define the exposure scenarios to be assessed in the risk assessment. The Agency identified some specific scenarios where the product use was not clear. For example, ther e was a leather use for PCMC, but it was
unclear if the leather was actua lly used to make clothes. There is also a disinfectant product that could be used on household hard surfaces (i.e., countertops and floors).

Based on the disinfectant product use on household countertops and floors, the Agency also anticipates that indoor re sidue data (GDLN 875.2300) is needed to accurately account for the amount of resi dues found on countertops and floors from wiping or mopping activities. This data is needed to conduct post-application assessment for the disinfectant product use.

Based on the uses as a preservative in leather products and the use as a disinfectant found on hard surfaces sprayed with disinfect ant, the Agency expects that non-dietary ingestion data (GDLN 875.3000) will be neede d. This data will help the Agency to

examine the residue transfer from leather products and contact fr om hard surfaces (e.g., counter tops and floors). Without this data, the Agency would need to assume worst case assumptions.

Section 6. Anticipated Data Needs

Page 10 of 20The Antimicrobial Division (AD) anticipa tes the need for additional human health data for PCMC. The Agency expects to ne ed the following toxicology study (utility and rationale provided in Appendix A) and expos ure data (utility and rationale provided in Appendix B).

Toxicity

• 90-day inhalation toxici ty study (GDLN 870.3465)

• Developmental toxicity study (rabbit) (GDLN 870.3700)

• Reproduction and Fertility Effects study (GDLN 870.3800)

Occupational and Residential Handler Exposure Data Needs

• Dermal Exposure (Outdoor and Indoor) (GDLN 875.1100 and 875.1200)

• Inhalation Exposure (Outdoor and Indoor) (GDLN 875.1300 and 875.1400)

• Data Reporting and Calculations (GDLN 875.1600)

• Product Use Information (GDLN 875.1700)

Occupational and Residential Post Application Exposure Data Needs

• Indoor Surface Residue Di ssipation Data (GDLN 875.2300)

• Inhalation Exposure (GDLN 875.2500)

• Product Use (GDLN 875.2700)

• Description of Human Activity (GDLN 875.2800)

• Data Reporting and Calculations (GDLN 875.2900)

• Non-Dietary Ingest ion (GDLN 875.3000)

Section 7. Tolerances

There are no pesticide tolerances or exemp tions from the requirement of tolerance for

PCMC or Na PCMC.

Section 8. Endocrine Disruption

As required 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 toxicit y, 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 or gan histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductiv e loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effect s in different taxonomic groups. As part of its reregistration decision

, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenar ios from the existing hazard database.

Page 11 of 20However, as required by FFDCA section 408( p), PCMC/Na PCMC is subject to the endocrine screening part of the Endocrine Disruptor Screenin g Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingred ients) may have an effect in humans or wildlife similar to an effect produced by a “natur ally occurring estrogen, or othe r such endocrine effects as the Administrator may designate.” The ED SP 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 substa nce 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 inte ract with E, A, or T hormonal systems will proceed to the next stage of the EDSP wher e EPA will determine which, if any, of the Tier 2 tests are necessary based on the avai lable data. Tier 2 te sting is designed to identify any adverse endocrine-related eff ects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency mu st screen all pesticide chemicals. Between October 2009 and February 2010, EPA issu ed test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. PCMC/Na PCMC is not among the group of 58 pesticide active ingredients

on the initial list to be screened under the EDSP. Accord ingly, as part of registration review, EPA will issue future EDSP orders/d ata call-ins, requiring the submission of EDSP screening assays for PCMC/Na PCMC. 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 9. Human Incident Data

There have been no human incidents reported in any of the OPP databases associated with exposure to PCMC and Na PCMC.

Section 10. Overall Conclusions

The Agency reviewed the hazard and e xposure databases for PCMC/Na PCMC and anticipates that additional studies will be needed for registrati on review. Although a RED has been completed, the Agency expects to conduct any additiona l risk assessments (occupational, residential, dietary, and drinking water) for this chemical since the RED did not cover all the existing uses for regi stration review, did not complete a dietary assessment for the indirect food uses, and th e Agency will need additional toxicity and exposure data to develop a risk assessment and characterize the hazard database.

Section 11. References

p-Chloro-m-cresol Reregistration Eligibility Decision Document (RED), January 1997. http://www.epa.gov/pesticides/reregistration/status.htm

Page 12 of 20Appendix A: Toxicity Guidel ine Study Justifications

Guideline Numbers: 870.3465 Study Titles: 90-day Inhalation Toxicity Study Rationale for Requiring the Data The Agency does not have a full picture of the potential effects which PCMC/Na PCMC

could occur as a result of e xposure via the inhalation route. The needed study which was not previously availabl e would provide insight into concerns regard ing toxicity via the inhalation route. It may also provide a toxicity endpoint appl icable to an inhalation risk assessment. The Agency previously used an oral toxicological endpoi nt from a maternal toxicity endpoint from a developmental study and assumed 100% absorption. Inhalation exposure is high for workers who apply pain t through airless sprayers and brushes. These applicators would likely to be exposed to aerosols from paint applications. In addition, an inhalation study is required to address uncertainties around the inhalation toxicity to refine the Agency’s risk asse ssment. Currently for inhalation exposures an extra 10 X uncertainty factor is added for a lack of an inhalation toxicity endpoint. The study may result in a change in how risk s are quantified and removal of a 10X uncertainty. The data would allow the Agency to conclude more defi nitively whether or not there would be any concerns for inhalation toxicity in the rat. This would provide a more complete hazard characterization of PCMC and Na PCMC in regards to the potential risks to the U. S. general population.

Practical Utility of the Data

How will data be used? An inhalation study may result in changes to the endpoints and how the risks are quantified.

How could the data impact the Agency’s future decision-making? The study would form the foundation for hazard ch aracterization and toxicity endpoints selection for risk assessment through all exposure routes (ora l, inhalation, and dermal). The data would allow the Agency to conclude more definitively whether or not there would be any concerns for inhalation toxicity in rodent species. It is possibl e that the database uncertainty factor be reduced or removed, resulting in different magnitude of the value of the endpoint used for regulation. . In many cases, toxicity observed via the inhalation route is higher than toxicity observed via oral exposure, which means that the route-to-route ex trapolation used in the RED risk assessment
could have resulted in an underestimation of risks from inhalation. It is particularly important to properly assess inhalation risks for PCMC and Na PCMC because there is high inhalation exposure for workers applying paints.

Guideline Number: 870.3700 Data Requirement: Rabbit Developmental Rationale for Requiring the Data The Agency does not have a full picture of the developmental toxicity of PCMC/Na PCMC. The needed study would provide insi ght into concerns re garding pre- and/or postnatal toxicity as needed by FQPA. It may also provide a toxicity endpoint applicable

to risk assessment.

Practical Utility of the Data

Page 13 of 201. How will the data be used? The study may result in a change in how risk s are quantified. The data would allow the Agency to conclude more definitively whet her or not there are any concerns for preand/or postnatal toxicity in the rabbit. This would provide a more complete hazard
characterization of PCMC and Na PCMC in regards to the potential risk of developmental toxicity.

2. How could the data affect the risk assessment? The study may result in a change in how risk s are quantified. It is possible that the database uncertainty factor may be reduced or removed, resulting in different magnitude of the value of the endpoint used for regula tion. The difficulty of predicting real world human exposure via oral route with limited da ta and no developmental toxicity data in rabbit or other alternative information, trigge red the need for a developmental (guideline) toxicity study in the ra bbit, in order to adequately eval uate real world human exposure to PCMC and Na PCMC, particul arly women in the 15-49 years of age and infants and

children

. Guideline Number: 870.3800 Data Requirement: Reproduction a nd Fertility Effects - rodent Rationale for Requiring the Data The needed study would provide insight into concerns regarding the potential risks of reproductive toxicity in the rat as well as potential neurotoxicity in developing offspring. It may also provide a toxicity endpoint applicable to risk assessment.

Practical Utility of the Data

1. How will the data be used? The data would allow the Agency to conclude more definitively whether or not there are any concerns for potential reproductive toxicity in the rat and it would also provide some information regarding potential neurotoxicity in developing offspring exposed to PCMC and Na PCMC. Data was not available previously. The Agency needs a chronic oral toxicological endpoint to assess MWF uses. A reproductive study is needed to determine the chronic oral toxicological endpoint.

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

The study may result in a change in how risks ar e quantified. The needed study may provide a chronic toxicity endpoint applicable to risk assessment. It is possible that the database uncertainty factor be reduced or removed, resulti ng in a different magnitude of the value of the endpoint used for regulation. It is particular ly important to properly assess chronic risks for

PCMC and Na PCMC because there is ch ronic exposure for workers who use MWFs.

Appendix B: Exposure Guideline Study Justifications

Guideline Numbers: 875.1100 and 875.1200 Study Titles: Dermal Exposure (Indoor and Outdoor) Rationale for Requiring the Data Note: Dermal 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. In almost all cases, repeating an exposure study for the same scenario outdoors and indoors is not necessary.

Page 14 of 20The potential for dermal exposure is very likel y for exposure scenarios involving metal working fluids and paints. 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 exposure data to the January 2007 Science Advi sory 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 b ased on the potential for dermal exposure from the labeled uses (e.g., occupational wo rkers using paints and leather working fluids) and evidence of toxicity. If the toxicological endpoints from PCMC /Na PCMC are used to asse ss 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 de rmal exposures from application of paints. For occupational uses, the dermal e xposure data will be used to assess the short-, and intermediateterm 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 warrant mitigation, the dermal exposure data will provide the types of mitigation necessary such as chemical resistant gloves or closed syst ems for commercial uses, or potential removal of
uses from the label.
Guideline Numbers: 875.1300 and 875.1400 Study Titles: Inhalation Exposure (Indoor and Outdoor) 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 ve ry important for exposure scenarios such application of paints or metalworking fluids where aerosols would be ge nerated. In addition, inhalation exposures from application are evident in exposure studies in th e Pesticide Handlers Exposure Database (PHED). The significance of these exposures is directly affected by the severity 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 scope for QA/QC and number of monitoring units. EPA presented the need for additional handler exposur e 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 inhalation exposure data ar e based on the potential for respiratory exposure from the labeled uses (e.g., exposure to application of paints) and evidence of toxicity. If no toxicological endpoints of concern were identified, then the inhalation exposure data would not be

needed.

Practical Utility of the Data

1. How will the data be used?

Page 15 of 20The inhalation exposure data would be used to assess the residential short-term duration of painting with a paint brush/roller and an airless sprayer. For occupational uses, the inhalation exposure data

would be used to assess the short- and intermedia te-term as well as pourin g PCMC (e.g., poured into paint as a preservative in manufacturing settings, and preservation of leather preservative solutions).

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

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

Guideline Numbers: 875.1600 Study Title: Data Reporting and Calculations Rationale for Requiring the Data For all exposure studies this da ta 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 derm al and inhalation expos ure data collected.

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

This data need is triggered if an exposure study is conducted. It w ould aid the Agency to make accurate interpretations of the studies to develop an accurate and refined risk assessment and refined mitigation.

Guideline Numbers: 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 a field study. A description of how this product is used would provide for a comprehensive realistic assessment of its potential applic ations. The description of the application techniques would be used to define the exposure scenario s 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 the risk assessment is inclusive of the types of exposures occurring duri ng residential and occupational use.

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

The need for a risk assessment as needed unde r Registration Review w ould require that the
risk assessor understands how the product is applied.

Guideline Number: 875.2300

Page 16 of 20Study Title: Indoor Sur face Residue Dissipation Rationale for Requiring the Data

Based on the use of PCMC and Na_PCMC as a hard surface disinfectant for countertops and floors, human contact to treated countertops and floors may occur. There are no data available to estimate exposure to adults and children from exposure to treated floors and countertops with
PCMC and Na PCMC. Practical Utility of the Data

1. How will the data be used?

Without data, the Agency will conduct a screeni ng 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 data will be used to refine the Agency’s risk

assessment and to confirm or refute th e 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 Agency may pursue risk mitigation measures regarding the use of formulated products containing PCMC and Na PCMC as the active ingredient in occupational and residential scenarios.
Guideline Number: 875.2500 Study Title: Inhalation Exposure Rationale for Requiring the Data

The post application inhalation expo sure may be required if it is determined that the use of these products have the potential to release PCMC and Na PCMC during the product use conditions (e.g., open systems, and vapor/mists from MWFs).

Practical Utility of the Data

1. How will the data be used? The post application inhalation ex posure data will be used to assess the residential and/or occupational inhalation risks to PCMC and Na PC MC if released based on product use. For example, the use MWFs is expected to tr igger 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 bystanders. 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 pot ential removal of uses from the label.

Guideline Number: 875.2700 Study Title: Product Use

Rationale for Requiring the Data

Page 17 of 20A description of how products containing PC MC and Na PCMC are used will provide a comprehensive, realistic assessment of its potentia l applications. Product use information for the post application data is a description of what type of consumer products are treated; it is not a field study (guideline no. 875. 2700). A description of what types of consumer products are treated, specifically what types of leather, disinfectant use and paints, will provide a comprehensive, realistic assessment of potential post application exposures. Therefore, these data are required.

Product use information assists EPA to more accu rately assess pesticide exposure to applicators by describing how the pesticide is actually used a nd applied. EPA requires this information because differences in use can translate to significant differences in exposure, and thus in risk.

The guideline for post-application product use in formation was presented to the FIFRA Science Advisory Panel (SAP) in March 1998. (The draft guideline is available at http://www.epa.gov/scipoly/sap/meetings/1998/march/contents.htm .). The guideline for applicator product use information should be substantially similar to the one for post-application.

Practical Utility of the Data

1. How will the data be used?

A complete description of product use would ensure that the risk assessment is inclusive of the types of exposures occurring during residential a nd occupational use. The listing of the end use consumer products would be used to define the exposure scenario s to be assessed in the risk assessment. For example, if the use for leather is us ed to make clothes or if the preservative is used in inks, or if the product is used on countertops then a postapplication assessment may need to be

considered.

2. How could the data impact the Agency’s future decision-making? A complete description of consumer products treat ed would ensure that the risk assessment is inclusive of the types of exposures occurring during residential use. The need for a risk assessment as needed under Registration Review would requ ire that the risk assessor understands how the product is applied.

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 . Worker application parameters are generally defined by the physical nature of the formulati on (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 assessme nt noted that many of the use parameters used (e.g., amount handled and duration of use) were based on prof essional judgments. These data are needed to fill this data gap and provide information needed to refine the risk assessment.

Practical Utility of the Data

Page 18 of 201. How will the data be used?

These data will clearly identify the specific equipmen t used to deliver PCMC and Na PCMC to the use site, which in high exposure scenarios, such a metal working fl uids and paint applications, will allow the Agency to refine its risk assessment.

2. How could the data impact th e Agency’s future decision-making?

If review and evaluation of the descriptions of human activity data indicate that only closedsystems are used for mixing/loading and applying metal working fluids, then the need for a reproductivity study is negated. Therefore, submission of acceptable human activity data demonstrating the metal working fluid scenario fo r PCMC and Na PCMC is an enclosed system will eliminate a significant cost and burden for the re gistrant (specifically, th e costs associated with generating the reproductivity and fe rtility 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.

Guideline Number: 875.2900 Data Requirement: Data Reporting and Calculations Rationale for Requiring the Data For all exposure studies, these data are needed o ccupationally 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 w ill be reviewed for the adequacy of the data.

2. How could the data impact th e Agency’s future decision-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 develop 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 Indoor Surface Residue Dissipation study (875.230 0) to determine the available residue leaching from a child mouthing treated leather clothing articles as well as hand-to-mouth behavior on counter tops treated

with PCMC disinfectant.

Practical Utility of the Data

Page 19 of 20Page 20 of 20 1. How will the data be used? This product is used as a material preservative in leather products and as a disinfectant on counter tops and floors. 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 th e Agency’s future decision-making?

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