P-07-0204 Updated Risk Assessment / Page 1 of 9

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

OFFICE OF
CHEMICAL SAFETY AND
POLLUTION PREVENTION

December 19, 2013

MEMORANDUM

SUBJECT: 

### Updated Risk Assessm ent for PMN P-07-0204.

FROM:

TO:

THRU:



### I. BACKGROUND

I.A.History

P-07-0207 PMN was placed into Standard Review by a FOCUS decision in early 2007 and was suspended by the Division Directors M eeting decision of May 09, 2007. A draft of a "SNUR" letter was prepared to issue a significan t new use rule under Section 5(a)(2) of the

Toxic Substances Control Act for P-07-204 with recommendation of following tests in order to help characterize the health effects of the PMN substance:

 A 28 –day dermal study in rats (OPPTS: 870.3200 test guidelines);

 A 90- day inhalation study (OPPT S: 870.3465 test guidelines); and

 A glove test (ASTM F 739 reported via ASTM F1194).P-07-0204 Updated Risk Assessment / Page 2 of 9

Since 2007, additional studies we re submitted by the Company:

 Acute Dermal Toxicity in Rats,

 5-Day Inhalation Toxicity in Rats,

 29-Day Inhalation Toxi city Study in Rats.

 Acute Eye Irritation Corrosion Study in the Rabbit,

 Primary Skin Irritation Corrosion in the Rabbit,

 Assessment of Contact Hypersen sitivity in the Mouse,

 Liver RNA Microarray Analysis, and

 Analysis of the Effect on Primary Cell Culture.

I.B. Chemical Identity

Submitter: 3M Company

Chemical Name: Pentane, 1,1,1,3,3-hexafluoro- 4-(1,1,2,3,3,3-hexafluoropropoxy)-

CAS RNs: 870778-34-0

Structure:

P-07-0204

F F

F F

H F

F O F

F F

H F

F F

Figure 1. Structure of submitted PMN P-07-0204. Manufacturing Information:P-07-0204 Updated Risk Assessment / Page 3 of 9

I.C. Concerns Identified at Focus (Relevant information Based on the 2007 Focus Report):

P-07-0204 was placed into Standard Review for hum an health concerns for neurotoxicity and liver effects based on submitted studies and analogue studies for . There were also concerns for cardiac sensitization by analogy to perfluoro compounds, and concerns for developmental toxicity by analogy to other fl uorocarbons. Also, the PMN was regulated under the exposure-based authority for human health. Th ere were potential risks to human health from inhalation exposures (calcula ted MOE = 10; acceptable MOE was 100). Data for P07-204 showed greater toxicity than its analogue . Potential risks to the environment were low,

and so are not considered further here.

SAT ratings: Health: 1 - 2, Ecotox: 2, O ccupational Exp: 2 -3, Consumer Exp: 2

II. TOXICITY / HAZARD SUMMARIES



### Test Data submitted after 2007

. Acute Dermal Toxicity in Rats.

No mortalities were observed a nd gross macroscopic examinatio n at necropsy was negative. Body weight gains were within normal paramete rs. Hunched posture was observed on day one and one animal had scabs in the treatment area. The NOAEL by the dermal route for P-07-0204 was 2,000 mg/kg.



### 5-Day Inhalation Toxicity in Rats.
Four male Sprague Dawley rats were exposed whole body to 0 and 1,000 ppm of the PMN for 6 hours/day for 5 days. Clinical observations did not reveal any treatment related effects. No macroscopic abnormalities were noted. Exposed animals gained slightly more weight than control and liver weights were incr eased in exposed animals. The clinical chemistry tests did not show any statistically signifi cant differences between exposed and control animals. The significance of the increase in liv er weights is uncertain because the clinical chemistry results were normal. However, the subsequent 29 day inhalation study also showed evidence of liver weight increase so the effect is probably compound related. The LOAEL for 5 days exposure to the PMN by the inhalation route is 1,000 ppm.



### 29-Day Inhalation Toxicity Study in Rats.
Wistar rats (5 male, 5 female) were exposed by whole body inhalation for 5 days per week for 4 weeks. Nominal exposures were to 0, 500, 1,0 00, and 1,500 ppm. The LOAEL in this 29 day study was 495 ppm whole body exposure for 6 hours a day, 5 days a week. The liver is the target organ displaying an increase in absolute an d relative liver weights as well as very slight to slight hepatocellular hypertrophy. There were changes in the clin ical chemistry as well that might be due to the liver response. The ma le is more susceptible than the female.



### Acute Eye Irritation Corrosion Study in the Rabbit.

The results showed that instillation of the test s ubstance resulted in no eye irritation in the three

male rabbits. The Draize scores of ocular irritation were 0 (0-4 scale) for corneal irritation, 0 (0- 2 scale) for iris irritation, 0 (0-3 scale) for conj unctival redness and discharge, and 0 (0-4 scale)P-07-0204 Updated Risk Assessment / Page 4 of 9

for chemosis (referring to swelling of eye surf ace membranes). There was also no evidence of ocular corrosion. Based on an acute eye toxicity study in rabbits, the test material would not be regarded as an eye irritant.



### Primary Skin Irritation Corrosion in the Rabbit.
The results showed that exposure resulted in no skin irritation (0, out of 0-4 range, erythema and edema scores in all three animals at all time poi nts examined). Based on these results, the test

material is a not an irritant to rabbit skin after 4 hour exposure



### Assessment of Contact Hype rsensitivity in the Mouse.
The results were expressed as Disintegrations per Minute (D PM) per mouse and also mean DPM/animal for each experimental group. The S timulation Index (SI), expressed as the mean radioactive incorporation for each treatment group divided by the mean ra dioactive incorporation of the vehicle control, was calculat ed. The results showed the SI values of the test item were 0.8, 0.9, and 1.7 at treatment concentrations of 25 %, 50 %, and 100 %, respectively. Because no

treatment resulted in an SI ≥ 3, the test substance would not be regarded as a skin sensitizer.



### Liver RNA Microarray Analysis.
The profile of gene expression changes on cy tochrome P450 genes in the CYP2B class is strongly indicative of an ability to activate the xenobiotic nuclear receptor CAR. It will be important in future studies to assess whether or not the CAR-mediated effects of on gene expression are 'phenot ypically anchored' by changes to clinical chemistry endpoints associated with intermediary metabolism.



### Analysis of the Effect on Primary Cell Culture.
The study authors stated that the test compound did not produce significant levels of cytotoxicity under the exposure concentrations and times evaluated. The test material did produced biochemical effects consistent with a low potency PPAR agonist. The primary biochemical effects of the test compound were on CAR signaling pathways and gluconeogenesis.

II.B. Environmental Release/Fate

Manufacturing releases to air a nd from incineration: Processing releases to air and from incineration: Use #1 releases to air and from incineration (may coincide with water or landfill):

Process #2 releases to air and from incinera tion (may coincide with water or landfill):

Use #2 releases to air or incineration (may coincide with water or landfill): Use #2 releases to air or incineration (may coincide with water or landfill):

II.B.1. Concentration of Concern

COC of 50 ppb was not significantly exceeded. Not regulated for ecotox concerns.P-07-0204 Updated Risk Assessment / Page 5 of 9

III. RELEASES AND EXPOSURES

III.A. Occupational Exposures

1. During Manufacture at , the following exposures would occur:

Inhalation :

r

Dermal

2. During Processing 1 at the following exposures would occur:

Inhalation

Dermal:

3. During Use 1 , the following exposures

would occur:

Inhalation

Dermal:P-07-0204 Updated Risk Assessment / Page 6 of 9

During Processing 2 , the following exposures would occur:

Inhalation

Dermal:

4. During Use 2 , the following exposures would occur:

Inhalation

Dermal:

5. Use 3 , the following exposures

would occur:

Inhalation

Dermal:

III.B. Consumer and General Population Exposure

Consumer exposure is not expected via ingesti on or drinking water. The PMN substance is unlikely to get into the water. EAB considered the potential for biocon centration, but expects most of it to volatilize before getting into wate r. Although bioconcentration is unlikely, if it did get into water through the use of solvents, vapor- phase bioaccumulation is possible. No testingP-07-0204 Updated Risk Assessment / Page 7 of 9

is wanted to address this possibili ty at this time (there are no prot ocols to address this issue), but the possibility should be noted. The vapor pressure is , and POTW removal is expected to be 90-99% via sorption and stripping.

IV. RISK ASSESSMENT

IV.A. Human Health Risk Discussion

IV.A.1. The Toxicity Effect Leve ls Used to Determine Risk.

Absorption: The PMN substance is expected to be absorbed via all routes, although absorption via the skin is expected to be limited

.

 SKIN: Flux = 0.0096 mg/cm2/h (0.1152 mg/kg) The flux for dermal absorption of isoflurane (MW = 185), a compound with a structure similar to that of the PMN

substance but with a somewhat lower mol ecular weight, in rats was 0.0096 mg/cm2/h (0.1 mg/kg/day)

 LUNG: From 51 to 61% of an inhaled dos e of 1,1-dichloro-2,2,2-tr ifluoroethane (MW = 153), an HCFC with a molecular weight somewh at lower than that of the PMN substance, was absorbed by rats

 GI TRACT: Based on the measured vapor pres sure of the PMN substance it is judged that the majority of PMN substance placed in the GI tr act of rats w ill be exhaled. It is further judged that GI absorption will be 100%.

Metabolism: Based on the increased urinary excretion of fluoride at 25000 and 50000 ppm and effects to the teeth at 50000 ppm in the 28-da y inhalation study in rats submitted with PMN , it is judged that there will be some metabolic defluorination of the current PMN substance.

The SAT highlighted concern for neurotoxicity a nd liver effects based on submitted studies and studies for the analogue . Th ere are also concerns for card iac sensitization by analogy to perfluoro compounds e.g., tetrafluorodimethyl et her and hexafluorodimethyl ether were both reported to be cardiac sensitizers in monkeys . In addition, th ere are concerns for developmental toxicity by analogy to other fluorocarbons.

as tested in an inhalation developmental toxicity study in rats. The NOAEL for developmental toxicity was 7500 ppm ( 21,026 mg/kg) with skeletal variations at 15,000 ppm (42,261 mg/kg).

Exposure Routes of Concern – Dermal and Inhalation. Populations of Concern – Occupational.

In initial (2007) risk assessmen t, MOE calculations for Dermal and Inhalation exposure were based on NOAEL of 25 mg/kg/day (males) and 250 mg/kg/day (females) from 28-day Oral Toxicity Study in Rats with the PMN. Based on the MOEs calculated this way, there is a potential health risk to workers exposed via the dermal route to the PMN chemical duringP-07-0204 Updated Risk Assessment / Page 8 of 9

Manufacturing, Process 1, Process 2, and Use 1.

Recently submitted test results of 29-Day Inhala tion Toxicity Study in Rats and Acute Dermal
Toxicity in Rats with LOAEL of 495 ppm (calculated NOAEL 49.5 ppm or 700.734 mg/m 3 in 6
hrs or 525 mg/m 3 during 8 hr of workday) and NOAE L of 2,000 mg/kg, correspondingly, could be used to update risk assessment for inhalation and dermal exposure.

Workers are expected to be exposed to the PMN chemical via the inhalation and dermal routes during manufacturing, Process 1, use 1, and Process 2. Inhalati on exposures are expected to range from The dura tion of exposure is exp ected to range from Dermal exposures are expected range from . The duration of exposure is expected to range from

IV.A.2. Occupational Exposure Discussion

Based on the LOAEL of 495 ppm (calculated NOAEL of 49.5 ppm) from the 29-Day Inhalation Toxicity Study, a low health risk for inhalation exposure is expected:

However, based on NOAEL of 2,000 mg/kg/da y from Acute Dermal Toxicity test there is health risk from dermal exposure for every operation when daily dose equal or exceeded 20 mg/day. This exposure exceed limit in all opera tions: Manufacturing, Process 1, Process 2, Use 1, Use 2 and Use 3.

Similarly, health risk from dermal exposure for every operation is also expected if the LOAEL of 495 ppm (calculated NOAEL of 49.5 ppm) from the 29-Day Inhalation Toxicity Study is used for the calculation of the MOE with an assumpti on of 50% lung absorption.

Dermal exposure risk from 2007 and 2013 Risk Assessments.

MOE range (Acceptable MOE > 100)

2007 Risk Assessment based on test data from the 28-Day Oral Toxicity Study 0.01 – 2 (males) 0.1 – 21 (females) 2013 Risk Assessment based on test data from the 29-Day Inhalation Toxicity Study 1.54 – 3.2

IV.A.3. Consumer and General Popula tion Exposure via Drinking Water Consumer exposure is not expected via ingesti on or drinking water. The PMN substance is intended for commercial use only.

IV.B. Environmental Risk Discussion

Potential risks to the environment were lo w based on no significant exceedence of the 50 ppb

COC.P-07-0204 Updated Risk Assessment / Page 9 of 9

V. CONCLUSIONS

V.A. Occupational Health Conclusion : Workers can be exposed to the PMN by inhala tion and dermal routes during manufacture, processing, and use. Based on the LOAEL of 495 ppm from the 29-Day Inhalation Toxicity Study, there is a low health risk from i nhalation exposure. However, there is a potential health risk to workers exposed via the dermal route to the PMN chemical during Manufacturing, Process 1, Process 2, Use 1 and Use 2.

V.B. General Population Health Conclusion : No exposures are expected.

V. C. Consumer Conclusion

No consumers use.

V.D. Environmental / Aquatic Conclusion : P-07-0204 presents a low ac ute and chronic risk to

the environment.

VI. RECOMMENDATIONS

VI.A. Human Health Recommendations :

Based on the predicted scenarios and calculated MO E, there is risk to workers from dermal exposure to the PMN chemical during Manufact uring, Process 1, Process 2, Use 1, Use 2 and

Use 3.

Personal protective equipment for all worker s should be used during all operations.

This risk assessment is based on results from re cently submitted data on Acute Dermal Toxicity in Rats and 29-Day Inhalation T oxicity Study in Rats. However, knowledge of the long-term effects is extremely important to reflect real s ituation when workers expo sed via the dermal route up-to 250 days/year. Suggested studies that might better inform this risk assessment are: a 28 – day dermal study in rats (OPPTS: 870.3200 test guidelines) and a glove permeation study.

VI.B. Environmental / Aquatic Recommendations:

Environmental and Aquatic Risk is not supported based on predicte d use and releases. No testing or regulatory limits recommended.