The RTU-L label directs that 1 day or mo re before treatment, soil covering buried galls should be removed. Any galls la rger than a baseball should be largely removed by cutting. The EP is painted onto the galls, the cut surfaces (if applicable), and 1⁄2-inch of the surroundi ng healthy bark assuring thorough coverage. Retreatment is pe rmitted in 4-6 months if live galls are found. If over half of the trunk is galled, any more t han half may be treated in 4-6 months. The EP is only to be applied to inedible plant parts. Fruit and nuts are not to be used

for food or feed.

Technical m-cresol exhibits low to moderate acute oral toxicity (Category II in rat and III in mouse and rabbit) and acute dermal to xicity (Category II in rat and III in rabbit). However, the technical is corrosi ve and causes severe irritation of the skin and eyes (Sax and Lewis, 1989). The acute inhalation toxicity study was waived in the past because the only hum an exposure route considered likely during painting of the 0.466% RTU-L onto galls is dermal. The EP caused a very low level of dermal irritation (Toxicity Category IV) although it was a dermal sensitizer (MRID 00138520 and 00138521).

In a 28-day toxicity study, mice were f ed m-cresol at 0, 300, 1000, 3000, 10,000, or 30,000 ppm. The threshold NOAEL wa s 300 ppm (53 mg/kg/day in males and 66 mg/kg/day in females) at which increased relative liver weights and thin appearance occurred in females. The LOAEL of 1000 ppm ( approximately 200 mg/kg/day) was based upon signs of neurot oxicity. Increased relative kidney weight was observed in males dosed at 3000 ppm. At 10,000 ppm, the following effects occurred: hunched posture and rough coat in both sexes; in females, labored respiration, lethargy, and sunken eyes; and several deaths. Some of the more serious effects observed at 30,000 ppm were: mammary gland, ovarian, and uterine atrophy; increased brain weight s in males; lethargy and tremors; increased relative kidney weights; and so me deaths. In rats fed the same treatment concentrations, m-cresol was comparatively less toxic as the NOAEL was 3000 ppm (252 mg/kg/day) based on increased relative liver weights at the LOAEL of 10,000 ppm (870 mg/kg/ day) (Dietz, 1992, NIH/NTP).

In 90-day rat and mouse feeding studies co nducted by Dietz in 1992 (NIH/NTP),

animals were dosed with a mixture of m- cresol and p-cresol (60:40). This and other studies demonstrated a similar toxicity of all three isomers (o-, m-, and pcresol). The mouse doses were roughly 0, 130, 250, 500, 1000, and 2000 mg/kg/day. The mouse NOAEL would be 250 mg/kg/day based on hyperplasia of the nasal respiratory epithelium occurring at the LOAEL of 500 mg/kg/day. The rat doses were approximately 0, 160, 330, 650, 1300, and 2600 mg/kg/day. The LOAEL was the lowest dose tested (1 60 mg/kg/day) at which dose-related hyperplasia of the nasal re spiratory epithelium was observed. A NOAEL was not determined in this rat study.

A 21-day dermal toxicity study was c onducted using rabbits (MRID 00138520). The RTU-L (m-cresol and 2,4-xylenol at 0.46% ai) was applied to abraded or intact skin at 1 or 2 ml/kg/day and com pared to the RTU-L blank (product without the ai’s). After 21 days of dermal ex posure, severe dermal damage to both

2abraded and intact skin resulted whether t he RTU-L or the formulation blank was applied. Hyperplasia of regional lym ph nodes and myeloid hyperplasia of the

bone marrow also occurred

. Note that dermal irritation did not result (Toxicity Category IV) from the short exposure to the RTU-L in the acute dermal toxicity study (MRID 00138520). As a result of the severe skin irritation in the 21-day dermal toxicity study testing the EP, a der mal toxicity study testing the TGAI was

waived in the 1994 RED because it showed the EP was corrosive to skin.

In a rat developmental toxicity study, m-cresol was administered by gavage to pregnant females on gestation days 6-15 at 0, 30, 175, or 450 mg/kg/day. The only observation at the middle dose was perio ral wetness. At the LOAEL of 450 mg/kg/day, effects included reduced body we ight gain, decreased gestational weight, increased relative liver weight, hypoactivity, audible respiration, ataxia, twitches, tremors, prone positioning, perioral wetne ss, and urogenital wetness. The NOAEL for maternal toxicity was 175 mg/kg/day. As developmental toxicity was not observed at any dose, the NOAEL was at least 450 mg/kg/day for mcresol (Bushy Run, 1988).

In a two-generation reproduction toxicity study, m-cresol was administered by gavage to rats at 0, 30, 175, or 450 mg/k g/day. The LOAEL for the F1 parents was 30 mg/kg/day at which weight suppre ssion occurred; therefore, the NOAEL would be <30 mg/kg/day. Perioral we tness occurred at 175 mg/kg/day. The offspring NOAEL was 175 mg/kg/day based on reduced mean pup weight and body weight gain at the LOAEL of 450 mg/kg/day (Bushy Run, 1989).

NTP (Izard, et al., 1992) conducted a m ouse reproduction toxicity study dosing with a 60:40 mix of m-cresol/p-cresol at 0, 0.25, 1.0, and 1.5% in the food for 14 weeks. The NOAEL for parental (F0) reproductive effects was 1.0% (~1400 mg/kg/day) and the LOAEL was 1.5% (~ 1600 mg/kg/day). The most common

effects at the F0 LOAEL were reduced liv e pup weight, number of live pups/litter, increased liver and kidney weights, and decreased epididymal and seminal vesicle weights. In the F1 generation, the NOAEL for reproductive effects was 0.25% (~460 mg/kg/day) and the LOAEL was 1.0% (~1800 mg/kg/day). The

most common effects at the F1 LOAEL were decreased body (both sexes) and male reproductive organ weights, and in creased liver and kidney weights and ovary weights in females.

m-Cresol did not induce gene mutations in Salmonella spp. (Ames assay) or in mouse lymphoma tests either with or wit hout activation. It had no effect on unscheduled DNA synthesis in rat hepatocytes or on chromosomal aberration in

mouse bone marrow. In Ch inese hamster ovary cells , there were suggestive data that m-cresol induced chromosomal aberrations but only upon activation. Results suggestive of transformation of BALB/C-3T3 cells occurred only without

activation.

m-Cresol has no food uses registered under FI FRA or uses subject to regulation by the Food and Drug Administration (FDA ). On 6/11/99, m-cresol was delisted as being “not approved for inert ingredient use, food or nonfood,” in a pesticide

3product (FR Vol. 64, No. 11, p. 31575). No tolerance or tolerance exemption has

been established under FFDCA for m-cres ol. Human dietary exposure to residues of m-cresol is not expected. T herefore, a dietary (f ood) risk assessment will not be necessary.

Use of m-cresol in the greenhouse is not ex pected to result in contamination of drinking water. Use in the field also is not expected to result in contamination of drinking water due to the use pattern and low volume of use. Thus, human dietary exposure to residues of m-cresol in drinking water is not expected. Therefore, a dietary (d rinking water) risk assessment is not required.

As the RTU-L label does not restrict us e of the product to ce rtified professional applicators and as the volume of the product container is 1⁄2 gallon, it is apparent that the EP may be purchased and used by re sidential applicators. Therefore, an assessment of residential applicator expos ure and risk is appropriate. However,

the assessment conducted in association with the 1994 RED is considered to remain protective of potential residentia l applicator exposure s. Therefore, no residential risk assessments are expe cted to be needed for the m-cresol Registration Review.

The only source of exposure contributi ng to aggregate risk to m-cresol is the residential adult applicator source. As noted above, the 1 994 RED assessment is protective of aggregate exposure as well.

Occupational exposure of applicators is pos sible during paint br ush treatment of crown galls with the EP in frui t or nut orchards or orna mental plantings. Again, the occupational applicator assessment conducted in association with the 1994 RED remains protective of potential ri sks. Therefore, no occupational risk assessments are expected to be needed for the m-cresol Registration Review. Label instructions and the requirement that handlers wear certain personal protective equipment (PPE) ar e sufficient to protect work ers from the localized, irritation effects of exposure to m-cresol.

The primary source of information for th is assessment was the September, 1994 RED. No new toxicity data for m-cr esol have been submitted to the Agency since the RED was issued. The purpos e of this scoping document is to

determine whether sufficient data are ava ilable to support registration review,

whether new human health assessment s are needed to support registration review, and to report why the Agency f eels it may be appropriate to conduct new risk assessments under the registration review process.

Section 1. Chemical Identity

Table 1.1 Chemical Identity

Common Name m-cresol

Chemical Name 1-hydroxy-3 -methylbenzene; 3-methylphenol Empirical Formula C 7 H 8 O

4Molecular Weight 108.14

PC Code 022102 CAS Registry Number 108-39-4 Registration Review Case No. 4027

Chemical Structure:

m-Cresol is a clear to yellowish liquid at room temperature wit h a phenolic odor.

It melts at 11.5 °C and boils at 202.2 °C. It is fairly so luble in water (2.5%) and miscible in ethanol, chloroform, and diethyl ether. The dissociation constant is

9.8 x 10 -11 at 25 °C. The vapor pressure is 0.18 mmHg at 25 °C. m-Cresol has an octanol/water partition coefficient, pK o/w , of 1.98. The specific gravity at 20 °C is 1.034 g/ml.

Section 2. Toxicology

The toxicity database for m-cresol is adequate to permit the Agency to conduct a hazard characterization for this Registrati on Review. No additional toxicity data are expected to be needed at this time bas ed on the m-cresol volume of use and registered use pattern.

Acute Toxicity

Technical m-cresol exhibits low to moderate acute oral toxicity (Category II in rat and III in mouse and rabbit) and acute dermal to xicity (Category II in rat and III in rabbit). However, the technical is corrosi ve and causes severe irritation of the skin and eyes of rabbit (Sax and Lewis, 1989). The acute inhalation toxicity study was waived in the past because the only human exposure route considered likely during paint ing of the 0.466% RTU-L ont o galls is dermal. The RTU-L caused a very low level of derma l irritation (Toxicity Category IV) in rabbits although it was a dermal sensitizer (MRID 00138520 and 00138521).

Subchronic Toxicity

In a 28-day toxicity study, mice were f ed m-cresol at 0, 300, 1000, 3000, 10,000, or 30,000 ppm. The threshold NOAEL wa s 300 ppm (53 mg/kg/day in males and 66 mg/kg/day in females) at which increased relative liver weights and thin appearance occurred in females. The LOAEL of 1000 ppm ( approximately 200 mg/kg/day) was based upon signs of neurot oxicity. Increased relative kidney weight was observed in males dosed at 3000 ppm. At 10,000 ppm, the following effects occurred: hunched posture and rough coat in both sexes; in females, labored respiration, lethargy, and sunken eyes; and several deaths. Some of the more serious effects observed at 30,000 ppm were: mammary gland, ovarian,

5and uterine atrophy; increased brain weight s in males; lethargy and tremors; increased relative kidney weights; and so me deaths. In rats fed the same treatment concentrations, m-cresol was comparatively less toxic as the NOAEL was 3000 ppm (252 mg/kg/day) based on increased relative liver weights at the LOAEL of 10,000 ppm (870 mg/kg/ day) (Dietz, 1992, NIH/NTP).

In 90-day rat and mouse feeding studies co nducted by Dietz in 1992 (NIH/NTP),

animals were dosed with a mixture of m- cresol and p-cresol (60:40). This and other studies demonstrated a similar toxicity of all three isomers (o-, m-, and pcresol). The mouse doses were roughly 0, 130, 250, 500, 1000, and 2000 mg/kg/day. The mouse NOAEL would be 250 mg/kg/day based on hyperplasia of the nasal respiratory epithelium occurri ng at the LOAEL of 500 mg/kg/day. The rat doses were approximately 0, 160, 330, 650, 1300, and 2600 mg/kg/day. The LOAEL was the lowest dose tested (1 60 mg/kg/day) at which dose-related hyperplasia of the nasal re spiratory epithelium was observed. A NOAEL was not determined in this rat study.

A 21-day dermal toxicity study was c onducted using rabbits (MRID 00138520). The RTU-L (m-cresol and 2,4-xylenol at 0.46% ai) was applied to abraded or intact skin at 1 or 2 ml/kg/day and com pared to 2 ml/kg/day of the RTU-L blank (product without the ai’s). After 21 days of dermal exposure, severe dermal damage to both abraded and intact skin re sulted whether the RTU-L or the formulation blank was applied. Hyperplas ia of regional lymph nodes and myeloid hyperplasia of the bone marrow also occurred

. Note that dermal irritation did not result (Toxicity Category IV ) from the short exposure to the RTU-L in the acute dermal toxicity study (MRID 00138520). As a re sult of the severe skin irritation in the 21-day dermal toxicity study testing t he EP, a dermal toxicity study testing the

TGAI was waived in the 1994 RED because it showed the EP was corrosive to skin. The acute and 21-day dermal toxicity studies, when taken together, indicate that the petroleum distillates in the RTU-L as diluent/solvent are largely or wholly responsible for the skin damage.

Chronic/Carcinogenicity

The registered uses of m-cresol are not expe cted to result in dietary exposure or long-term occupational or resi dential exposure. Therefor e, neither a chronic nor a cancer study is considered necessary. Accordingly, risk assessments are not expected to be needed for dietary exposur e or for long-term occupational or residential exposures regardless of exposure route.

Reproductive and Developmental Toxicity

In a rat developmental toxicity study, m-cresol was administered by gavage to pregnant females on gestation days 6-15 at 0, 30, 175, or 450 mg/kg/day. The only observation at the middle dose was perio ral wetness. At the LOAEL of 450 mg/kg/day, effects included reduced body weight gain, decreased gestational weight, increased relative liver weight, hypoactivity, audible respiration, ataxia, twitches, tremors, prone pos itioning, perioral wetness, and urogenital wetness.

6The NOAEL for maternal toxicity was 175 mg/kg/day. As developmental toxicity was not observed at any dose, the NO AEL was at least 450 mg/kg/day for mcresol.

In a two-generation reproduction toxicity study, m-cresol was administered by gavage to rats at 0, 30, 175, or 450 mg/k g/day. The LOAEL for the F1 parents was 30 mg/kg/day at which weight suppre ssion occurred; therefore, the NOAEL would be <30 mg/kg/day. Perioral we tness occurred at 175 mg/kg/day. The offspring NOAEL was 175 mg/kg/day based on reduced mean pup weight and body weight gain at the LOAEL of 450 mg/kg/day (Bushy Run, 1989).

NTP (Izard, et al., 1992) conducted a m ouse reproduction toxicity study dosing with a 60:40 mix of m-cresol/p-cresol at 0, 0.25, 1.0, and 1.5% in the food for 14 weeks. The NOAEL for parental (F0) reproductive effects was 1.0% (~1400 mg/kg/day) and the LOAEL was 1.5% (~ 1600 mg/kg/day). The most common

effects at the F0 LOAEL were reduced liv e pup weight, number of live pups/litter, increased liver and kidney weights, and decreased epididymal and seminal vesicle weights. In the F1 generation, the NOAEL for reproductive effects was 0.25% (~460 mg/kg/day) and the LOAEL was 1.0% (~1800 mg/kg/day). The

most common effects at t he F1 LOAEL were decreased body (both sexes) and male reproductive organ weights, and incr eased liver and kidney weights and ovary weights in females.

Mutagenicity

m-Cresol did not induce gene mutations in Salmonella spp. (Ames assay) or in mouse lymphoma tests either with or without activation. It had no effect on unscheduled DNA synthesis in rat hepatocytes or on chromosomal aberration in

mouse bone marrow. In Ch inese hamster ovary cells , there were suggestive

data that m-cresol induced chromosoma l aberrations but only upon activation. Results suggestive of transformation of BALB/C-3T3 cells occurred only without

activation.

Section 3. Dietary Exposure

Food Exposure

m-Cresol has no food uses registered under FIFRA or uses subject to regulation by the Food and Drug Administration (FDA ). On 6/11/99, m-cresol was delisted as being “not approved for inert ingredient use, food or nonfood,” in a pesticide product (FR Vol. 64, No. 11, p. 31575). No tolerance or tolerance exemption has

been established under FFDCA for m-cres ol. Human dietary exposure to residues of m-cresol is not expected due to the low concentration of m-cresol in the RTU-L, the low treatment rate, the base-of-trunk/directed treatment, and the label restriction against using fruit or nuts for food or f eed. Therefore, a dietary (food) risk assessment will not be necessary.

7Drinking Water Exposure

Use of m-cresol in the greenhouse is not ex pected to result in contamination of drinking water. Use in the field also is not expected to result in contamination of drinking water due to the use pattern and low volume of use. Thus, human dietary exposure to residues of m-cresol in drinking water is not expected. Therefore, a dietary (d rinking water) risk assessment is not required.

Section 4. Residential Exposure

As the RTU-L label does not restrict us e of the product to ce rtified professional applicators and as the volume of the produc t container is 1⁄2 gallon, it is apparent that the EP may be purchased and used by re sidential applicators. Therefore, an assessment of residential applicator expos ure and risk is appropriate. However, the assessment conducted in association with the 1994 RED remains protective of potential residential applic ator exposures. Therefore, no residential risk assessments are expected to be needed for the m-cresol Registration Review.

Section 5. Aggregate Risk

The only source of exposure contributi ng to aggregate risk to m-cresol is the residential adult applicator source. As noted above, the 1994 RED assessment is protective of aggregate exposure as well.

Section 6. Occupational Exposure

Occupational exposure of applicators is pos sible during paint br ush treatment of crown galls with the EP in fr uit or nut orchards or or namental plantings. Again, the occupational applicator assessment conducted in association with the 1994 RED remains protective of potential ri sks. Therefore, no occupational risk assessments are expected to be needed for the m-cresol Registration Review. Label instructions and the requirement that handlers wear certain personal protective equipment (PPE) ar e sufficient to protect work ers from the localized, irritation effects of exposure to the EP.

Section 7. Human Incident Reports

No m-cresol-specific incidents have been reported in the OPP incident database. Low-molecular-weight phenols such as m-cresol have been reported as being contact sensitizers (Bruze, M. and Zime rson, E. 1997. Cross-reaction patterns in patients with contact allergy to simple methylol phenols. Contact Dermatitis. Aug. 37(2):82-6. This r eport is supported by a dermal sensitization study in

which the RTU-L was found to be a sensitizer.

8Section 8. Cumulative Risk

EPA does not have, at this time, availabl e data to determine whether m-cresol has a common mechanism of toxicity with other substances or how to include this pesticide in a cumulative risk a ssessment. For the purposes of this Registration Review, EPA has assumed that m-cresol does not have a common mechanism of toxicity with other substances.

Section 9. Endocrine Disruption

As required under FFDCA section 408( p), EPA has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (including pesticide active and other ingr edients) 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 Admi nistrator may designate.” The EDSP employs a two-tiered approach to making t he statutorily requi red 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 det ermine 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.

Between October 2009 and February 2010, EPA i ssued test orders/data call-ins for the first group of 67 chem icals, which contains 58 pesticide active ingredients and 9 inert ingredients. This list of chemicals was selected based on the potential for human exposure through pat hways such as food and water, residential activity, and certain post-applicat ion agricultural scenarios. This list should not be construed as a list of known or likely endocrine disruptors.

m-Cresol is not among the group of 58 pesti cide active ingredi ents on the initial

list to be screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide chemicals. Accord ingly, EPA anticipates issuing future

EDSP test orders/data call-ins for a ll pesticide active ingredients.

For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, the test guidelines and t he Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/.

Section 10. Over all Conclusions

The Agency has screened the hazard and ex posure databases for m-cresol and does not anticipate that additional toxi city or exposure data will be needed for

910 registration review. In addition, the Agency does not expect that additional

human health risk assessment s will be needed to comp lete the m-cresol Registration Review.