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1) Aug 2005

Genotoxicity: Chromosomal Aberration Study Dose Range finding (File: TS39)

Investigator

NAMSA, Northwood, Ohio

Summary

Chinese Hamster Ovary (CHO) cells were grown in monolayer with and without

metabolic activation. Various concentrations of the product were placed in the growth

medium and incubated for 20 hours. Cells were stained and visually examined

microscopically for any visual signs of toxicity or chromosome aberration.

Conclusion

The product does not cause any visually detectable damage to the chromosomes up to

very large doses (50% solutions).

1) Aug 2005

In Vitro Chromosomal Aberration Study – Cytotoxicity (File: TS39

Investigator

NAMSA, Northwood, Ohio

Summary

Chinese Hamster Ovary (CHO) cells were grown in monolayer with and without

metabolic activation. Growth medium was replaced by the product with various

concentrations and incubated. Cytotoxicity was monitored by means of microscopically

observing inner-cell structures and chromosomes and scanning for damage.

Conclusion

No cytotoxicity can be detected at concentrations up to 100%.

2) Dec 2005

Genotoxicity: Chromosomal Aberration Study in Mammalian Cells (File: TS

Investigator

NAMSA, Northwood, Ohio

Summary

Chinese Hamster Ovary (CHO) cells were grown in monolayer with and without

metabolic activation. Concentrations of the product up to 50% were placed in the

growth medium and incubated for 20 hours. Cells were stained and visually examined

microscopically for chromatid gaps or breaks, chromosome breaks or fragments of

several different types, or chromosome interchanges. Percentages of chromosomal

aberrations were determined and statistically analyzed for each aberration class.

Conclusion

The product does not cause damage to the chromosomes. There was often less

chromosomal aberration in the cultures with the product than in cultures with the salt

water control. No evidence of increased chromosome damage of any sort was found.

Investigator

NAMSA, Northwood, Ohio

Summary

Chinese Hamster Ovary (CHO) cells were grown in monolayer with and without

metabolic activation. Various concentrations of the product were placed in the growth

medium and incubated for 20 hours. Cells were stained and visually examined

microscopically for any visual signs of toxicity or chromosome aberration

Conclusion

The product does not cause any visually detectable damage to the chromosomes up to

very large doses (50% solutions).

2) Dec 2005

Genotoxicity: Chromosomal Aberration Study in Mammalian Cells (File: TS35)

Investigator

NAMSA, Northwood, Ohio

Summary

Chinese Hamster Ovary (CHO) cells were grown in monolayer with and without

metabolic activation. Concentrations of the product up to 50% were placed in the

growth medium and incubated for 20 hours. Cells were stained and visually examined

microscopically for chromatid gaps or breaks, chromosome breaks or fragments of

several different types, or chromosome interchanges. Percentages of chromosomal

aberrations were determined and statistically analyzed for each aberration class.

Conclusion

The product does not cause damage to the chromosomes. There was often less

chromosomal aberration in the cultures with the product than in cultures with the salt

water control. No evidence of increased chromosome damage of any sort was found.

3) Jan 2006

Genotoxicity: Reverse Mutation Study (File: TS39)

Investigator

NAMSA, Northwood, Ohio

Summary

Reverse genetic mutations were counted in 5 different strains of specially prepared

mutant bacteria, sensitive to genetic reverse mutation due to toxicity. Cultures were

exposed to various high concentrations of the product and compared to cultures with

negative and positive controls. The number of reverse mutations indicates how strong

the expected mutagenic effect of the product has on DNA. All tests were run in

triplicate

Conclusion

The product is not a potential mutagen. No significant changes in reverse mutation

were observed in any of the bacterial strains at any dose

4) 2005

Gene Expression Analysis for Toxicity in Rabbits (File: TS22)

Investigator

Affimetrix, Functional Genomics Center, University of Albany

Summary

4 Groups of New Zealand white rabbits received daily injections of various

concentrations of MDI-P or saline for 3 days. Full genetic activity for over 10,000

different genes was analyzed from samples taken before and after exposure and from

the control groups. From this analysis the genetic expressions of inflammatory

cytokines, immune activation messengers and other genetic markers of toxic response

were measured.

Conclusion

No genes were expressed that indicated a toxic response to MDI-P. There was a

significant 2X down regulation of the SOCS2 gene families, indicating a reduction of

inflammation and a significant 7X up regulation in the TIA1 genes calling for

programmed cell death of damaged cells.

1) Jun 1994

Fourteen Day Acute Intravenous Toxicity Study of the Product in Mice (File: TS6)

Investigator

Biological Test Center, Irvine, California

Summary

The product was injected into 4 groups of 5 mice, 4 times on the first day, and once a

day thereafter for 14 days. The 4 groups received various doses up to 8 ml/kg body

weight (over 50 times the equivalent amount expected to be in the blood of a typical

human adult). The mice were monitored carefully for any signs of toxicity including

death, signs of irritation or illness, and behavioral abnormalities.

Conclusion

Extremely large daily amounts of the product in the blood of dogs do not cause any

abnormal vital signs, weight loss, blood chemistry or signs of illness or adverse

behavioral changes over a period of 7 days.

3) Feb 2002

A 4-Week Toxicity Study of the Product in Dogs (File: TS11)

Investigator

WIL Research, Ashland, Ohio

Summary

The product was injected into four groups of 3 male and 3 female Beagle dogs, with

doses from 5 to 20 ml/Kg every day for 28 consecutive days (many hundreds of times

the maximum amount expected to be in the blood of a typical human adult). Blood

pressure, body weight, and heart ECG’s were recorded before and after each dosing.

Comprehensive blood and urine tests were also done. Careful monitoring for any signs

of toxicity or behavioral abnormalities was done daily. Nothing out of the normal was

observed for any animal. Blood pressure, ECG scans and blood/urine work were all

normal across the board. Literally volumes of data were collected on each animal.

4) Jan 2006

Mouse Peripheral Blood Micronucleus Study: Dose Range Finding (File: TS40)

Investigator

NAMSA, Northwood, Ohio

Summary

The product was injected into 4 groups of 10 mice at various doses up to 20 ml/Kg (50

times the maximum equivalent amount expected in the blood of a typical adult) once a

day for 3 days. Body weight and careful behavioral observations were made. All

animals had normal body weight and behavior during testing.

5) 2005

Toxicological Study – 3 Day Acute Toxicity Study of the Product in Rabbits (File: TS27)

Investigator

James Clagett, Ph.D., Snohomish, Washington

Summary

Various concentrations of the produc t or saline were injected into 4 groups of New

Zealand white rabbits for 3 days. Comprehensive blood analysis, including white blood

cell counts, ALT, GLU, BUN, Albumin and hematocrit levels were done. Histopathologies

of the colon, esophagus, eye, heart, kidney, intestines, liver, lung , reproductive organs,

muscle, spleen, stomach and tongue were microscopically performed to check for any

abnormalities. After MDI-P exposure, the AST:ALT ratio was lower by 60%, serum

protein and albumin levels were reduced 48%. No signs of toxicity were observed.

Conclusion

Extremely large concentrations of the product in the blood of rabbits do not cause any

adverse effects or tissue damage to major organs. Changes in blood composition were

potentially beneficial.

6) Jan 2006

Central Nervous and Behavioral Effects of Mice Exposed Nasally to the Product (File:

TS41

Investigator

James Clagett, Ph.D., Snohomish, Washington

Summary

4 groups of 5 mice were exposed to nebulized vapor of the product through a nose cone

over a 28 day dosing period. Breathing volumes, respiratory rates were monitored 3

times a week. Telemetric body movements and body temperature to measure normal

function of the central nervous system was sampled every 3 minutes over a 15 to 17

hour period every other day. Blood/urine samples and microscopic observations of

select organs were made. There was no irritation to the soft tissues of the nose, mouth,

throat and eyes due to long-term contact of the product vapor. No change was

observed in respiratory rates, breathing volumes, blood/urine markers or major organs.

There was no evidence of central nervous system damage.

Conclusion

Nebulized product does not cause irritation to soft tissues of the nose, mouth, throat,

eyes or lungs in mice over long-term exposures. There are no signs of toxicity,

inflammation or damage to any of the major organs due to breathing the product.

7) Mar 2006

Cardiovascular, Pulmonary and Residual Toxic Effects on Dogs Exposed Nasally to the

Product (File: TS21,TS32)

Investigator

MPI Research, Mattawan, Michigan

Summary

Nebulized product, through a mask, was administered to 1 control group and 3

treatments groups of 4 male and 4 female Beagle dogs about 5 hours every day for 28

days. Cardiovasular (ECG) and pulmonary activity was monitored before, during and

after dosing. Blood and urine panels were taken every week, with full blood-gas

analysis. Full histopathological analysis was done on all major organs/systems. Dogs

often slept comfortably through the procedure.

Conclusion

Nebulized product vapor does not cause irritation to the soft tissues of the nose, mouth,

throat, eyes or lungs in dogs over long-term exposures. No abnormal macroscopic or

microscopic damage, blood or urine markers, blood gas findings, are observed.

1) Jan 2005

A Chronic Six-Month Toxicology Study of the Product in Mice (File: TS30)

Investigator

James Clagett, Ph.D., Snohomish, Washington

Summary

The product was injected into 4 groups of 4 mice at various concentrations (up to 50

times the maximum equivalent amount expected in the blood of a typical adult) once a

week for 28 weeks. Body weight and careful behavioral observations were made. All

animals had normal body weight and behavior during testing. Heart, liver, kidney,

spleen, intestine and lung histopathologies were performed and all normal for every

animal.

Conclusion

Long-term, high concentrations of the product in the blood of mice do not cause any

abnormal or adverse behavioral effects, signs of toxicity or tissue damage.