Tri-Ortho-Cresyl Phosphate

By Tuan Nguyen

slo1@netzero.net

Chem 377 Winter 2001

 

Background Information:  Jamaican Ginger Paralysis of the 1930’s

 

 

In the 1930’s, organized crime, gangs and the mafia were at an all time high due to the federal law of Prohibition.   The 18th amendment to the United States Constitution took away the license to do business from the brewers, distillers, and the retail sellers of alcoholic beverages.  This led to alcohol smuggling and corrupted manufacturing firms that found alternative ways to get around the new law and supplied alcohol to people that desperately wanted it.  One of these firms in Boston, Hub Products was one of the fraudulent companies that supplied Jamaica Ginger (commonly referred to as Jake) to grocery stores and the extract of Jamaica Ginger to available pharmacies.   Jake was sold as a headache remedy and general aid to digestion, however has an alcohol content of about 70%.(2)

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Figure 1.  Jamaica Ginger ( Zingiber officinale) is known as the best quality of ginger all over the world(4)

 

People would purchase Jake and mix the 2 oz. contents with a soft drink to help dilute the strong ginger flavor and drink this mixture as a means to get around Prohibition.  The Prohibition Bureau did not classify this extract under the 18th amendment because it contained enough of the ginger to give it a very bitter taste, which they assumed to be not a desirable beverage.   Many manufactures would dilute the ginger extract with ingredients such as molasses, glycerin, and castor oil to reduce the strong pungent taste.  

The President of Hub Products, Harry Gross diluted Jake with tri-ortho-cresyl phosphate.  Tri-ortho-cresyl phosphate was sold in large quantities and was extremely inexpensive as a liquid plasticizer.  It was also soluble in alcohol as well as miscible with the ginger extract.   From this, Harry Gross and Hub Products initiated the episode of the Jamaica Ginger Paralysis of the 1930’s.

Early in the 1930’s, newspapers in the South and Midwest reported a strange paralytic illness that affected a large amount of people.   Victims of this disease reported numbness in the legs and paralysis in the feet.  A week later, the victims experienced a similar process in the arms and hands.   The majority of the victims were adult males.   The sufferers of this epidemic at first denied about the use of Jake, fearing that they may be charged and prosecuted for consuming the extract.  After interviewing the victims even more, they found that the paralytic symptoms appeared about two weeks after consumption of Jake.  Investigators had a hard time figuring out what the actual cause of paralysis was because of the fact that Jamaica Ginger had been in long use even prior to 1930.  They concluded that the manufacturer had adulterated the extract with some poisonous ingredient, and after a long investigation and numerous tests found that the ingredient was tri-ortho-cresyl phosphate (TOCP).(2)      

 

Toxicology

 

In the Jamaican Ginger incident, although there wasn’t a very high mortality rate, recovery time was extensive and in most cases, no complete recovery was apparent.  In various sites in the central and peripheral nervous systems, degeneration of nerves was apparent after the exposure to TOCP.  The principal degeneration is believed to occur in the medulla, spinal cord and sciatic nerve. It is also believed that TOCP acts mainly on the axon, primarily on the myelinated fibers.(7)  

Species differ in responses to TOCP.  The chicken and cat have been used extensively especially because the responses in those species are very similar to those of man.   Rabbit, dog, monkey and guinea pig react inconsistently while rats and mice are reported to be resistant to paralysis although they still have nervous tissue damage.

The metabolism of TOCP has been shown to produce a potent cholinesterase inhibitor, CBDP.  However, this inhibition has not been proven to be directly associated with paralysis.(3)

            Paralysis is usually delayed after absorption.   In the case of the Jamaican Ginger Paralysis episode, people reported to have not felt any affects associated with paralysis until after a week or two.  TOCP can be absorbed through the skin and inhaled, but more harmful and faster affects were apparent after ingestion.(5)

            Excretion of TOCP is extremely slow.  In a study, two human subjects absorbed TOCP through the skin and the results were 0.1 and 0.4% of the administered dose were apparent in the urine within 3 days.(7)  This might explain why recovery of paralysis is extensive as well as the fact that the damaged axons are irreparable.

 

Toxicity in various species(1)

 

Key:            LD50 = Lethal concentration in 50% fatality of those tested.

LDLo = Lowest published lethal concentration

Orl = oral administration

Scu = subcutaneous administration

Ivn = intravenous administration

Ims = intramuscular administration

                                                                                                                                   

 

Type of Dose           Mode              Specie           Amount         Units

LD50                          Orl                   Rat                  1160               mg/kg

LDLo                          Scu                 Dog                 500                 mg/kg

LDLo                          Scu                 Cat                  185                 mg/kg

LDLo                          Orl                   Rabbit             50                    mg/kg

LDLo                          Scu                 Rabbit             100                 mg/kg

LDLo                          Ivn                    Rabbit             100                 mg/kg

LDLo                          Ims                  Rabbit             135                 mg/kg

LDLo                          Scu                 Guinea pig     300                 mg/kg

 

 

Symptoms and Diagnosis

 

            Sudden diarrhea and nausea or vomiting during or shortly after ingestion occurs, which may reflect directly with cholinesterase inhibition.   This gastrointestinal upset doesn’t usually last longer than 48 hours.  Following this is a dormant period lasting anywhere between 8 and 35 days.   Then an abrupt feverish feeling is apparent in spite of a normal body temperature.  Cramping pains in the caves, tingling of the lower extremities especially in the feet and toes, followed by an abrupt paralysis after 10 to 40 days after the end of the dormant period.  The same occurs in the arms and hands, but delayed about 4 to 5 days after the lower extremities. 

Paralysis may be followed by frequent spasms of the lower parts of the body and victims are characterized by their high steps as well as "foot drop" (commonly referred to as Jake walk).  Although the symptoms may appear to be horrendous, the mortality rate is actually extremely low.  About 3/4th’s of all reported cases recover to the point of not requiring further treatment after a couple of years.(7)

 

Treatment

 

The delayed paralysis due to TOCP has not been adequately explained, nor has there been any specific treatment for TOCP paralysis except for physical and occupational therapy.

1.       Daily doses of vitamin B1 (300 mg) combined with 100ug vitamin B1 by intramuscular injection over 45 days may prevent the effects after ingestion of TOPC, but doesn’t help in regeneration of damaged neurons and axons.(7)

2.       Pilocarpine (10 to 20 mg. by daily subcutaneous injection) has been proven to temporarily improve motor activity.

3.       Aspirin or phenylbutazone will help in ridding of muscle cramps and pains.

4.       Physical therapy, occupational therapy and orthopedic programs will help in recovering from paralysis.

5.       In the case of ingestion, immediately induce vomiting followed be massive consumption of water.(6)

6.       In the case of absorption especially through the eyes, flush and rinse the affected area with large amounts of water.(6)

 

Uses

 

          Tri-ortho-cresyl phosphate has many uses as a liquid plasticizer.   It is primarily used as a plasticizer for paint products, lacquers and PVC.  Also, it is used as a fire retardant for plastics, an additive to extreme pressure lubricants and as a nonflammable fluid in hydraulic systems.(9)   Earlier, in the beginning of the 20th century, the meta and para isomers of tri-cresyl phosphate (neither of which are toxic) were used to treat tuberculosis.  Some of the patients receiving this treatment claimed to have had symptoms similar to those of the ortho isomer poisoning; paralysis in the extremities.   The phenol derivatives used to make tri-cresyl phosphate were obtained from the distillation of coal and wood tar.   Further studies showed that improper distillation lead to the presence of tri-ortho-cresyl phosphate instead of the desired isomers.(9)

 

Structure of Tri-ortho-cresyl phosphate:

 

Figure 2.  Chemical structures of Tri-ortho-cresyl phosphate that I skillfully drew myself using 3D Molecular Builder.(8)

 

Tri-ortho-cresyl phosphate is prepared from cresol and phosphoric oxychloride, phosphoric acid or pentachloride.(9)

 

 

 

 

 

 

 

Chemical/Physical Properties(1)

 

CAS #: 78-30-8

Molecular Formula: C21 H21O4P   Molecular Weight: 368.36

Melting Point (DEG C): -25 to –30 C

Boiling Point (DEG C): 410 C

Solubility:

Water: <1 mg/mL @ 20 C

DMSO: >=100 mg/mL @ 20 C

95% Ethanol: 50 –100 mg/mL @ 20 C

Acetone: >=100 mg/mL @ 20 C

Volatility:

Vapor pressure: 1.7 x 10E-6 mm Hg

Vapor density: 12.7

Refractive Index: 1.5575 @ 20 C

 

Conclusion to the Jake Ginger Paralysis

 

The 1906 Federal Food and Drug act did not contain any requirements for the pre-market testing and approval of drug products.   However, the ginger extracted was adulterated and labeled improperly, thus subject to prosecution under the same 1906 act.   The FDA and the Prohibition Bureau seized various shipments of the contaminated product.  The product was sold under numerous brand labels.   Most cases were unclaimed and some of the manufacturing firms existed in name only.  These companies were often not traceable, and the sellers had numerous aliases and mailing addresses.  One company, S.A. Hall in Brooklyn had only a post office box used by one of the sellers.   The post office was adjacent to a Salvation Army store hence the name S.A.  Hub products and Harry Gross were the main producers of the contaminated extract and he received a thousand dollar fine as well as two years in prison.   This incident affected over 35,000 victims and some individuals founded the United Victims of Ginger Paralysis Association in an attempt for retribution and compensation from the Federal government, but failed to receive any help.  Because most of the afflicted victims never fully recovered from the illness, most of them were desperate to try anything that was a promising cure.   One reported story, found that victims were so desperate that they were persuaded by “unscrupulous entrepreneurs” and paid a small fee to swim painfully in oil slush ponds in the surrounding areas of refineries.(2) 

This episode was a precursor to more effective food and drug legislation and paved the way for the Federal Food, Drug and Cosmetics act of 1938.

As a fellow consumer of alcohol, I understand the disparity of many individuals to find a way around the Prohibition act.   However, consuming molasses, lubricating oils and tri-ortho-cresyl phosphate to get a “buzz” takes drinking to another level.   

 

Useful links and references

 

1.Chemfinder – http://www.chemfinder.com

2.John Parascandola Ph.D. - http://www.healthy.net/Library/journals/HerbalGram/1995/Summer/features/pharm.htm

3.Esther database - http://www.ensam.inra.fr/cgi-bin/ace/inhibitor/Achedb?name=Tri-o-cresylphosphate&class=Inhibitor

4.Jamaican Ginger - http://wwwchem.uwimona.edu.jm:1104/lectures/ginger.html

5.International Chemical Safety Cards - http://www.itcilo.it/english/actrav/telearn/osh/ic/78308.htm

6.Beers, Mark H., editor.  The Merck Manual of Diagnosis and Therapy, 17th ed., Merck Research Laboratories, Merck & Co., Inc.; 1999, NJ

7.Gosselin, Robert E.; Smith, Roger P.; Hodge, Harold C.; Clinical Toxicology of Commercial Products, 5th ed., Williams and Wilkins Co., 1984.

8.Lide, David R.; CRC Handbook of Chemistry and Physics, 75th ed., CRC press, Boca Ranton, FL.

9.Budavari, Susan, editor. The Merck Index, 12th ed., Merck Research Laboratories, Merck & Co., Inc., NJ