The RTU-L label directs that 1 day or more before treatment, soil covering buried 

galls should be removed. Any galls larger 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 surrounding healthy bark assuring thorough 

coverage. Retreatment is permitted in 4-6 months if live galls are found. If over 

half of the trunk is galled, any more than 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 toxicity (Category II in rat and III in 

rabbit). However, the technical is corrosive 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 human 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 fed m-cresol at 0, 300, 1000, 3000, 10,000, 

or 30,000 ppm. The threshold NOAEL was 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 neurotoxicity. 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 weights in males; lethargy and tremors; 

increased relative kidney weights; and some 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 conducted 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 (160 mg/kg/day) at which dose-related 

hyperplasia of the nasal respiratory epithelium was observed. A NOAEL was not 

determined in this rat study. 

A 21-day dermal toxicity study was conducted 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 compared to the RTU-L blank (product without 

the ai’s). After 21 days of dermal exposure, severe dermal damage to both 

2
abraded and intact skin resulted whether the RTU-L or the formulation blank was 

applied. Hyperplasia 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 result of the severe skin irritation in the 21-day 

dermal toxicity study testing the EP, a dermal 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 perioral 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 positioning, perioral wetness, 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/kg/day. The LOAEL for the F1 parents 

was 30 mg/kg/day at which weight suppression occurred; therefore, the NOAEL 

would be <30 mg/kg/day. Perioral wetness 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 mouse 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 live 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 increased 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 without activation. It had no effect on 

unscheduled DNA synthesis in rat hepatocytes or on chromosomal aberration in 

mouse bone marrow. In Chinese 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 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 

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

been established under FFDCA for m-cresol. Human dietary exposure to 

residues of m-cresol is not expected. Therefore, a dietary (food) risk assessment 

will not be necessary. 

Use of m-cresol in the greenhouse is not expected 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 (drinking water) risk assessment is not required. 

As the RTU-L label does not restrict use of the product to certified 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 residential applicators. Therefore, an 

assessment of residential applicator exposure and risk is appropriate. However, 

the assessment conducted in association with the 1994 RED is considered to 

remain protective of potential residential applicator exposures. Therefore, no 

residential risk assessments are expected to be needed for the m-cresol 

Registration Review. 

The only source of exposure contributing 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. 

Occupational exposure of applicators is possible during paint brush treatment of 

crown galls with the EP in fruit or nut orchards or ornamental plantings. Again, 

the occupational applicator assessment conducted in association with the 1994 

RED remains protective of potential risks. 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) are sufficient to protect workers from the localized, 

irritation effects of exposure to m-cresol. 

The primary source of information for this assessment was the September, 1994 

RED. No new toxicity data for m-cresol have been submitted to the Agency 

since the RED was issued. The purpose of this scoping document 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 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 C7H8O 

4
Molecular 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 with a phenolic odor. 

It melts at 11.5 °C and boils at 202.2 °C. It is fairly soluble 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, pKo/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 Registration Review. No additional toxicity data 

are expected to be needed at this time based 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 toxicity (Category II in rat and III in 

rabbit). However, the technical is corrosive 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 painting of the 0.466% RTU-L onto galls is dermal. The 

RTU-L caused a very low level of dermal 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 fed m-cresol at 0, 300, 1000, 3000, 10,000, 

or 30,000 ppm. The threshold NOAEL was 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 neurotoxicity. 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, 

5
and uterine atrophy; increased brain weights in males; lethargy and tremors; 

increased relative kidney weights; and some 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 conducted 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 (160 mg/kg/day) at which dose-related 

hyperplasia of the nasal respiratory epithelium was observed. A NOAEL was not 

determined in this rat study. 

A 21-day dermal toxicity study was conducted 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 compared 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 resulted whether the RTU-L or the 

formulation blank was applied. Hyperplasia 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 result of the severe skin irritation in 

the 21-day dermal toxicity study testing the 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 expected to result in dietary exposure or 

long-term occupational or residential exposure. Therefore, neither a chronic nor 

a cancer study is considered necessary. Accordingly, risk assessments are not 

expected to be needed for dietary exposure 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 perioral 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 positioning, perioral wetness, and urogenital wetness. 

6
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. 

In a two-generation reproduction toxicity study, m-cresol was administered by 

gavage to rats at 0, 30, 175, or 450 mg/kg/day. The LOAEL for the F1 parents 

was 30 mg/kg/day at which weight suppression occurred; therefore, the NOAEL 

would be <30 mg/kg/day. Perioral wetness 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 mouse 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 live 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 increased 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 Chinese 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. 

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-cresol. 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 feed. Therefore, a dietary 

(food) risk assessment will not be necessary. 

7
Drinking Water Exposure

Use of m-cresol in the greenhouse is not expected 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 (drinking water) risk assessment is not required. 

Section 4. Residential Exposure

As the RTU-L label does not restrict use of the product to certified 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 residential applicators. Therefore, an 

assessment of residential applicator exposure and risk is appropriate. However, 

the assessment conducted in association with the 1994 RED remains protective 

of potential residential applicator 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 contributing 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 possible during paint brush treatment of 

crown galls with the EP in fruit or nut orchards or ornamental plantings. Again, 

the occupational applicator assessment conducted in association with the 1994 

RED remains protective of potential risks. 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) are sufficient to protect workers 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 Zimerson, E. 1997. Cross-reaction patterns 

in patients with contact allergy to simple methylol phenols. Contact Dermatitis. 

Aug. 37(2):82-6. This report is supported by a dermal sensitization study in 

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

8
Section 8. Cumulative Risk 

EPA does not have, at this time, available 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 assessment. 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 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. 

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. This list of chemicals was selected based on the 

potential for human exposure through pathways such as food and water, 

residential activity, and certain post-application 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 pesticide active ingredients on the initial 

list to be screened under the EDSP. Under FFDCA sec. 408(p) the Agency must 

screen all pesticide chemicals. Accordingly, EPA anticipates issuing future 

EDSP test orders/data call-ins for all 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 the Tier 1 screening battery, 

please visit our website: http://www.epa.gov/endo/. 

Section 10. Overall Conclusions 

The Agency has screened the hazard and exposure databases for m-cresol and 

does not anticipate that additional toxicity or exposure data will be needed for 

9
10

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

human health risk assessments will be needed to complete the m-cresol 

Registration Review.