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 This case was withdrawn.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.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/kg28 -day inhalation study in rats (100, 300, 500 ppm) - some liver and kidney effects at all dose levelsConclusions

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 Recommendations90 -day study

developmental toxicity study in 2 speciesAbsorption/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 includedincreased testicular weights, decreased epididymal sperm concentration, and an increase in abnormal sperm.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.