NOTE TO: Loraine Passe 

FROM: Becky Jones 

SUBJECT: Risk Assessment Summary for S05-0003 

Background

S05-0003 was submitted by Kuraray America, Inc. for 3-

methoxy-3-methyl-1-butanol acetate as an import for use as a 

solvent of polyurethane plastic coating (50%), solvent used in 

paint thinner (37.5%), organic solvent of polyurethane resin 

(6.5%), solvent used in cleaning agent (3%), and solvent for 

screen printing ink (3%). The import volume was estimated to be 

200,000 kg/year. 

The same company originally submitted this chemical as 

 which went through a standard review that supported a 

concern for a potential risk associated with occupational dermal 

exposure and inhalation and dermal exposure to consumers based 

on the results of a range-finding developmental toxicity study 

submitted by the company for the hydrolysis product of the PMN 

substance (3-methoxy-3-methyl-1-butanol). A potential risk was 

also identified for occupational dermal exposure for systemic 

effects based on a LOEL from a 28-day inhalation study for the 

hydrolysis product. This case was withdrawn. 

A limited standard review for S05-0003 was conducted which 

resulted in a change in some of the exposure estimates from the 

initial report based on information from the submitter that the 

percentage of the new chemical substance in the final product is 

7%. The health reviews res very similar findings as 

compared to the review for No new information was 

available from the submitte PMN compound or its 

hydrolysis product. The reviews for developmental toxicity and 

reproductive effects introduced some information for tert-butyl 

methyl ether and tert-amyl methyl ether. These two compounds 

are not considered to be close analogs to the PMN compound but 

the results of the studies are included in the risk assessment 

to provide a more complete assessment. 

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Structure

Toxicity Data from 

PMN compound 

acute oral study in rats - LD50 = 4.6 g/kg 

negative in the Ames assay 

Hydrolysis product of PMN compound (3-methoxy-3-methyl-1-

butanol) 

negative in the Ames assay 

acute oral study in rats - LD50 = 4.4 g/kg 

acute dermal study in rats - LD50 > 2 g/kg 

negative for dermal sensitization in guinea pigs 

not a dermal irritant 

moderate eye irritant 

not a photoirritant or photosensitizer in guinea pigs 

negative in human skin patch test 

28-day dermal irritation study n rabbits - slight irritant 

at 100% concentration, not an irritant at 50% concentration 

oral developmental toxicity range-finding study in rats - 

maternal toxicity at 2000 mg/kg; developmental toxicity at 

1000 mg/kg; NOEL = 500 mg/kg 

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28-day inhalation study in rats (100, 300, 500 ppm) - some 

liver and kidney effects at all dose levels 

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Conclusions

The MOEs for inhalation exposure for all of the use 

scenarios indicate a low potential for risk associated with 

inhalation exposure. The lowest MOE is based on the high end 

estimate of 20 mg/day from vapor generated during processing 

(the typical exposure estimate is 0.33 mg/day). This gives a 

MOE of 400 for the high end value and 25,000 for the typical 

value using the LOEL of 118.5 mg/kg from the 28-day oral study 

on the hydrolysis product of the PMN compound. Other scenarios 

that give a MOE less than 1000 for this endpoint are: 

inhalation of mist from use of wood furniture coating (MOE = 

850, inhalation exposure estimate = 10 mg/day) and inhalation of 

vapor during automotive OEM high end exposure estimate of 18 

mg/day (MOE = 460) with a typical exposure estimate of 0.31 

mg/day (MOE = 27,000). All of the other inhalation exposure 

estimates result in MOEs that are much higher than 1000. MOEs 

based on the NOEL from the range-finding developmental toxicity 

study for the hydrolysis product are 1500 and greater. The MOEs 

for developmental toxicity based on the LOEL of 151 mg/kg from 

the 2-generation reproduction study for tert-amyl methyl ether 

are slightly higher than those calculated for systemic toxicity 

(lowest MOE based on the high end exposure estimate for 

inhalation of vapor during processing is 460 with a MOE of 

27,500 for the typical inhalation exposure). These MOE values 

indicate that the use of respiratory protection in these 

scenarios is not warranted. 

The MOEs for dermal exposure in all of the scenarios 

indicate a potential for risk from both systemic effects and 

developmental toxicity. The MOEs range from less than 1 for 

dermal contact during processing to 100 for the use scenarios. 

There is a potential for risk for developmental toxicity 

from inhalation and dermal contact for consumer use of the PMN 

material b otential exposures estimated during the 

review of Systemic toxicity was not evaluated for 

consumer u e consumer use is expected to be episodic 

rather than continuous. The MOE for developmental toxicity is 

50-60 for inhalation and 55 for dermal contact based on the NOEL 

from the range-finding developmental toxicity study for the 

hydrolysis product. 

Testing Recommendations

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90-day study 

developmental toxicity study in 2 species 

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Absorption/Metabolism

The SNUN substance is expected to be well absorbed via all 

routes. 

Estimated percent absorbed: 

skin: ca. 70% 

lung: 100% 

GI tract: 100% 

The acetate ester of the SNUN substance is expected to 

undergo rapid enzymatic hydrolysis. 

Short-term Toxicity

A 28-day inhalation study on the expected metabolite, 3-

methoxy-3-methyl-1-butanol, produced signs of liver damage. No 

NOEL was established in this study because SGOT was elevated at 

all dose levels. No significant histological changes in the 

liver were noted. Kidney weights were increased in exposed 

rats. The LOEL from this study is 100 ppm (118.5 mg/kg). 

Developmental Toxicity

The hydrolysis product of the PMN compound was tested in a 

range-finding oral developmental toxicity study in rats. 

Reduced food consumption and reduced maternal weight gain were 

seen at 2000 mg/kg. Reduced fetal body weight was seen at 1000 

mg/kg. No internal or skeletal examinations were conducted. 

A LOEL of 151 mg/kg was determined for developmental 

toxicity from a 2-generation reproductive toxicity study in rats 

where tert-amyl methyl ether was administered by inhalation. 

The effects seen in the F1 generation are reduced pup body 

weight and delayed preputial separation. The same effects were 

noted in the F2 pups along with delayed vaginal patency, 

decreased survival, and shortened anogenital distance. 

Reproductive Toxicity

A NOEL of 922 mg/kg was identified for male reproductive 

effects in the 2-generation reproductive toxicity study in rats 

for tert-amyl methyl ether. The effects noted included 

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increased testicular weights, decreased epididymal sperm 

concentration, and an increase in abnormal sperm. 

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Occupational Exposure

Scenario No. 

of 

Sites

No. of 

Workers

Days

per

yr

Inhalation 

- vapor 

mg/day

Inhalation 

- mist

(mg/day) 

Dermal 

(mg/day

)

Processing 4 12 250 0.33 to 

20

- 1800 

Use #1: Wood 

Furniture 

Coating

143 1000's 250 0.017 to 

0.99 

10 120 to 

610 

Use #2: Auto 

OEM

1 17 237 0.31 to 

18

6.4 120 to 

610

Use #3: 

Cleaning 

Agent

189 567 250 0.002 to 

0.09 

- 120 

Use #4: 

Screen 

Printing Ink

27 222 250 0.008 to 

0.49 

0.3 to 

4.3 

120 

Consumer Exposure

No consumer uses were identified by the submitter. 

However, in the review for the original submission,

consumer scenario for use by hobbyists was assessed. Exposure 

due to consumer use was estimated to be 9,450 mg/year, dermal, 

11,273 mg/year user inhalation, and 6,751 mg/year for non-user 

inhalation. These estimates were based on 10% PMN compound in a 

paint formulation that is used 12 times per year for application 

of 3 coats each time. 

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