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 Assessment 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 Meeting decision of May 09, 2007. A draft of a 

"SNUR" letter was prepared to issue a significant 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 (OPPTS: 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 were submitted by the Company: 

 Acute Dermal Toxicity in Rats, 

 5-Day Inhalation Toxicity in Rats, 

 29-Day Inhalation Toxicity Study in Rats. 

 Acute Eye Irritation Corrosion Study in the Rabbit, 

 Primary Skin Irritation Corrosion in the Rabbit, 

 Assessment of Contact Hypersensitivity 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 human 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 fluorocarbons. Also, the PMN was regulated under 

the exposure-based authority for human health. There were potential risks to human health from 

inhalation exposures (calculated 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, Occupational Exp: 2 -3, Consumer Exp: 2 

II. TOXICITY / HAZARD SUMMARIES 

Test Data submitted after 2007

. 

Acute Dermal Toxicity in Rats. 

No mortalities were observed and gross macroscopic examination at necropsy was negative. 

Body weight gains were within normal parameters. 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 increased in exposed animals. The clinical chemistry tests did not 

show any statistically significant differences between exposed and control animals. The 

significance of the increase in liver 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, 1,000, 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 and relative liver weights as well as very slight to 

slight hepatocellular hypertrophy. There were changes in the clinical chemistry as well that 

might be due to the liver response. The male is more susceptible than the female. 

Acute Eye Irritation Corrosion Study in the Rabbit. 

The results showed that instillation of the test substance 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 conjunctival 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 surface 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 points examined). Based on these results, the test 

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

Assessment of Contact Hypersensitivity in the Mouse. 

The results were expressed as Disintegrations per Minute (DPM) per mouse and also mean 

DPM/animal for each experimental group. The Stimulation Index (SI), expressed as the mean 

radioactive incorporation for each treatment group divided by the mean radioactive incorporation 

of the vehicle control, was calculated. 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 cytochrome 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 'phenotypically 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 and 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 incineration (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 ingestion or drinking water. The PMN substance is 

unlikely to get into the water. EAB considered the potential for bioconcentration, but expects 

most of it to volatilize before getting into water. Although bioconcentration is unlikely, if it did 

get into water through the use of solvents, vapor-phase bioaccumulation is possible. No testing 
P-07-0204 Updated Risk Assessment / Page 7 of 9 

is wanted to address this possibility at this time (there are no protocols 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 Levels 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 molecular weight, in rats was 0.0096 mg/cm2/h 

(0.1 mg/kg/day) 

 LUNG: From 51 to 61% of an inhaled dose of 1,1-dichloro-2,2,2-trifluoroethane (MW = 

153), an HCFC with a molecular weight somewhat lower than that of the PMN substance, 

was absorbed by rats 

 GI TRACT: Based on the measured vapor pressure of the PMN substance it is 

judged that the majority of PMN substance placed in the GI tract of rats will 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-day 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 and liver effects based on submitted studies and 

studies for the analogue . There are also concerns for cardiac sensitization by analogy to 

perfluoro compounds e.g., tetrafluorodimethyl ether and hexafluorodimethyl ether were both 

reported to be cardiac sensitizers in monkeys . In addition, there 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 assessment, 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 during 
P-07-0204 Updated Risk Assessment / Page 8 of 9 

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

Recently submitted test results of 29-Day Inhalation Toxicity Study in Rats and Acute Dermal 

Toxicity in Rats with LOAEL of 495 ppm (calculated NOAEL 49.5 ppm or 700.734 mg/m3 in 6 

hrs or 525 mg/m3

 during 8 hr of workday) and NOAEL 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. Inhalation exposures are expected to 

range from The duration of exposure is expected 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/day 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 operations: 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 assumption 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 Population Exposure via Drinking Water 

Consumer exposure is not expected via ingestion or drinking water. The PMN substance is 

intended for commercial use only. 

IV.B. Environmental Risk Discussion 

Potential risks to the environment were low 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 inhalation 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 inhalation 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 acute and chronic risk to 

the environment. 

VI. RECOMMENDATIONS 

VI.A. Human Health Recommendations: 

Based on the predicted scenarios and calculated MOE, there is risk to workers from dermal 

exposure to the PMN chemical during Manufacturing, Process 1, Process 2, Use 1, Use 2 and 

Use 3. 

Personal protective equipment for all workers should be used during all operations. 

This risk assessment is based on results from recently submitted data on Acute Dermal Toxicity 

in Rats and 29-Day Inhalation Toxicity Study in Rats. However, knowledge of the long-term 

effects is extremely important to reflect real situation when workers exposed 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 predicted use and releases. No testing 

or regulatory limits recommended.