Phorbol

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop.；SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment.；INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. If symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop, call a physician and be prepared to transport the victim to a hospital. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing.；INGESTION: DO NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. (NTP, 1992)

Fires involving this material can be controlled with a dry chemical, carbon dioxide, foam or Halon extinguisher.

If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions.

SMALL SPILLS AND LEAKAGE: If you spill this chemical, you should dampen the solid spill material with water, then transfer the dampened material to a suitable container. Use absorbent paper dampened with water to pick up any remaining material. Seal your contaminated clothing and the absorbent paper in a vapor-tight plastic bag for eventual disposal. Wash all contaminated surfaces with a strong soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned.

SMALL SPILLS AND LEAKAGE: If you spill this chemical, you should dampen the solid spill material with water, then transfer the dampened material to a suitable container. Use absorbent paper dampened with water to pick up any remaining material. Seal your contaminated clothing and the absorbent paper in a vapor-tight plastic bag for eventual disposal. Wash all contaminated surfaces with a strong soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned.；STORAGE PRECAUTIONS: You should protect this chemical from exposure to light. Keep the container tightly closed under an inert atmosphere, and store it in a freezer. (NTP, 1992)

SRP: Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in air, soil or water; effects on animal, aquatic and plant life; and conformance with environmental and public health regulations. If it is possible or reasonable use an alternative chemical product with less inherent propensity for occupational harm/injury/toxicity or environmental contamination.

Excerpt from ERG Guide 154 [Substances - Toxic and/or Corrosive (Non-Combustible)]:；IMMEDIATE PRECAUTIONARY MEASURE: Isolate spill or leak area in all directions for at least 50 meters (150 feet) for liquids and at least 25 meters (75 feet) for solids.；SPILL: Increase the immediate precautionary measure distance, in the downwind direction, as necessary.；FIRE: If tank, rail tank car or highway tank is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. (ERG, 2024)

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter.

12-O-tetradecanoylphorbol 13-acetate (I) & phorbol (II) incr the recovery of ouabain-resistant mutants in N-methyl-N'-nitro-N-nitrosoguanidine- and methylazoxyethanol acetate-treated V79 chinese hamster cell cultures. In both cases I was more effective than II in promoting the mutant recovery.

Studies on the mechanism of skin tumor promotion. Phorbol given simultaneously with 12-o-tetradecanoylphorbol 13-acetate after 7,12-dimethylbenz[a]anthracene (DMBA) initiation in female mice had no effect on promotion.

A single s.c. injection of 200 uCi ((3)H)-thymidine into pregnant BALB/c mice followed by i.p. injections of phorbol twice weekly for 25 wk, in the offspring, resulted in higher tumor development in the lungs and livers of male and, to a lesser extent, of female offspring, than in their untreated littermates. The difference in overall tumor incidence was statistically significant, but the increases of the individual tumor types were only of borderline significance. Slight carcinogenic activity of ((3)H)thymidine alone was observed in the mothers and in the offspring without phorbol treatment. ((3)H)-thymidine may be useful as a broad spectrum initiator for transplacental 2-stage carcinogenicity studies to determine the organ specificity of different promoting agents.

Twice-weekly i.p. injections of 4 mg phorbol for 10 wk, after a single feeding of 6 mg dimethylbenz(a)anthracene (DMBA) in female Wistar rats, led to a significant augmentation of mammary adenocarcinoma incidence and of lymphatic leukemia incidence as compared to 6 mg DMBA alone. In female Sprague-Dawley rats, using the same doses of DMBA and phorbol and the same injection schedule, phorbol given after DMBA did not augment mammary adenocarcinoma incidence or lymphatic leukemia incidence as compared to DMBA given alone. There is a strain-related sensitivity between Wistar and Sprague-Dawley rats with regard to the promoting activity of phorbol when phorbol treatment follows DMBA treatment, and mammary adenocarcinoma incidence and lymphatic leukemia incidence are studied. Phorbol did not promote mammary fibroadenoma incidence in DMBA-treated rats, mammary adenocarcinoma incidence in procarbazine-treated rats and mammary adenocarcinoma incidence or mammary fibroadenoma incidence in X-ray-treated rats. DMBA and procarbazine, with or without phorbol, tended to induce more mammary neoplasms in the anterior (thoracic) than in the posterior (abdominal) mammary glands. X-Irradiation tended to induce mammary neoplasms in approximately equal numbers in the anterior and posterior mammary glands. Regional differences in chemically induced mammary carcinogenesis were due to a difference in the transport and delivery of the chemical carcinogens to the regions rather than a difference in the amount of mammary gland tissue in the regions. An analysis of the numbers of Sprague-Dawley rats that developed either no mammary neoplasms, or only mammary adenocarcinomas, or only mammary fibroadenomas, or both mammary adenocarcinomas and mammary fibroadenomas in response to DMBA, procarbazine and X-ray, suggested that the development of a mammary adenocarcinoma or the development of a mammary fibroadenoma are independent processes.

For more Interactions (Complete) data for PHORBOL (7 total), please visit the HSDB record page.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1060(SRC), determined from a structure estimation method(2), indicates that phorbol is expected to have low mobility in soil(SRC). Volatilization of phorbol from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 3.7X10-11 atm-cu m/mole(SRC), using a fragment constant estimation method(2). Phorbol is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.1X10-14 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2016). Phorbol absorbs at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis on soil surfaces exposed to sunlight(SRC). Phorbol is reported to be unstable to prolonged exposure to air, light and ambient temperatures(4).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1060(SRC), determined from a structure estimation method(2), indicates that phorbol is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 3.7X10-11 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). According to a classification scheme(4), an estimated BCF of 3(SRC), from an estimated log Kow of -0.54(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2016). Phorbol is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(3). Phorbol is an olefin and an alcohol and these functional groups react with photo-oxidants (such as hydroxyl radicals) in surface waters exposed to sunlight(5) with a combined half-life on the order of 15 days(SRC).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), phorbol, which has an estimated vapor pressure of 1.1X10-14 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase phorbol may be removed from the air by wet and dry deposition(SRC). Phorbol absorbs at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC). Phorbol is reported to be unstable to prolonged exposure to air, light and ambient temperatures(4).

IDENTIFICATION AND USE: Phorbol is a powder. It is used in biochemical and medical research. HUMAN EXPOSURE AND TOXICITY: Phorbol lacked the lymphocyte-activating inducing properties found in phorbol esters. Unlike phorbol esters, phorbol lacks tumor-promoting activity and it was either inactive or elicited poor response in inhibition of growth and stimulation of differentiated functions in human melanoma cells. ANIMAL STUDIES: Phorbol (20 ug/mL) was devoid of biological activity and had no effect on binding sites in prepn from mouse brain. Phorbol did not stimulate prostaglandin E2 synthesis in bone and bone resorption in neonatal mouse calvaria in organ culture. Phorbol showed no erythroid differentiation in Friend virus-transformed proerythroid C1 745 cells. Thus phorbol is inactive analog of phorbol esters.

The term 'phorbol' is used to describe the family of naturally occurring compounds that can be referred to as tigliane diterpenes. Phorbol esters are the tetracyclic diterpenoids generally known for their tumor promoting activity. The phorbol esters mimic the action of diacyl glycerol (DAG), activator of protein kinase C, which regulates different signal transduction pathways and other cellular metabolic activities. The biological activities of the phorbol esters are highly structure specific. The phorbol esters, even at very low concentrations, show toxicological manifestations in animals fed diets containing them. This toxicity limits the use of many nutritive plants and agricultural by-products containing phorbol esters to be used as animal feed. Besides, possessing antinutritional and toxic effects, few derivatives of the phorbol esters are also known for their antimicrobial and antitumor activities. The molluscicidal and insecticidal properties of phorbol esters indicate its potential to be used as an effective biopesticide and insecticide. The phorbols themselves do not induce tumors but promote tumor growth following exposure to a subcarcinogenic dose of a carcinogen. TPA and related phorbols were reported to be a potent stimulator for plasminogen activator synthesis. A good correlation was observed between plasminogen activator induction and tumor promotion with TPA, phorbol 12,13-didecanoate (PDD), and TPA beta-oxide (a derivative of TPA) in bioassays. The phorbol does not involve covalent binding to the cellular DNA, in fact it mimics the effects of transformation such as alteration in membrane morphology, increased saturation density, altered cell surface fucose glycopeptides, and increased the level of plasminogen activator and ornithine decarboxylase. (A15429) Various esters of phorbol have important biological properties, the most notable of which is the capacity to act as tumor promoters through activation of protein kinase C. They mimic diacylglycero

Phorbol was identified as an active constituent of the highly toxic tropical manchineel (beach apple) Hippomane mancinella(1). Phorbol can be isolated as a hydrolysis product of croton oil, which is the seed oil of Croton tiglium L. (Euphorbiaceae)(2,3). Phorbol esters occur in the seeds of Jatropha curcas L. (Euphorbiaceae) which has become an energy crop for the production of biodiesel with potential uses in animal feed and medicine(4).

Phorbol esters have been identified in Sapium indicum, S. japonicum, Euphorbia frankiana, E. cocrulescence, E. ticulli, Croton spareiflorus, C. tiglium, C. ciliatoglandulifer, Jatropha curcas, Excoecaria agallocha and Homalanthus nutans. These esters are toxic(1). /Phorbol esters/

Using a structure estimation method based on molecular connectivity indices(1), the Koc of phorbol can be estimated to be 1060(SRC). According to a classification scheme(2), this estimated Koc value suggests that phorbol is expected to have low mobility in soil.

Phorbol was identified as an active constituent of the highly toxic tropical manchineel (beach apple) Hippomane mancinella(1). Phorbol can be isolated as a hydrolysis product of croton oil, which is the seed oil of Croton tiglium L. (Euphorbiaceae)(2). Phorbol esters occur in the seeds of Jatropha curcas L. (Euphorbiaceae) which has become an energy crop for the production of biodiesel with potential uses in animal feed and medicine(3).

/HUMAN EXPOSURE STUDIES/ Nine compounds, based on 4 biogenetically-related polycyclic diterpene skeletons, were subjected to open and closed patch testing on human volunteer subjects. The tigliane esters phorbol-12,13,20-triacetate, 12-O-2Z-4E-octadienoyl-4-deoxyphorbol-13-acetate and 12-O-tigloyl-4-deoxyphorbol-13-isobutyrate, in increasing order of potency, produced symptoms of toxicity in closed patch tests, with the dose of the most potent compound in this series being 0.5 ug in 5 uL acetone. Phorbol, a tigliane alcohol, was inactive in closed tests at a dose level of 50 ug/5 uL. The daphnane derivative, daphnetoxin, produced bullae and vesiculation in closed patch tests, but daphnetoxin-5,20-diacetate was devoid of these effects when applied at 10 times the dose of daphnetoxin. The ingenane compounds, ingenol-3,5,20-triacetate and 20-deoxy-16-hydroxyingenol-3,5,16-triacetate, and the lathyrane compound, ingol-3,7,8,12-tetraacetate, were obtained from the hydrolyzed, acetylated irritant latex of Euphorbia hermentiana. At the doses tested, ingenol-3,5,20-triacetate was the only compound derived from this plant to exhibit irritant activity in closed patch tests. This compound is inactive as an irritant to the mouse ear at dose up to 250 ug/ear. Only 3 compounds, 12-O-2Z-4E-octadienoyl-4-deoxyphorbol-13-acetate, 12-O-tigloyl-4-deoxyphorbol-13-isobutyrate and daphnetoxin, produced dermatological toxicity in open patch tests at the doses used. Inflammatory signs and symptoms for several of the compounds under test persisted for over 4 days in open patch tests and for a week or more after application in closed patch testing.

/ALTERNATIVE and IN VITRO TESTS/ The tumor promoter 12-o-tetradecanoylphorbol-13-acetate induces the prodn of lymphocyte-activating factors in human lymphocyte cultures. Phorbol lacked the lymphocyte-activating inducing properties.

/ALTERNATIVE and IN VITRO TESTS/ Phorbol which lacks tumor-promoting activity was either inactive or elicited poor response in inhibition of growth & stimulation of differentiated functions in human melanoma cells.

/ALTERNATIVE and IN VITRO TESTS/ Phorbol esters, a class of potent tumor promoters, can promote differentiation in human malignant T(thymus-derived)-lymphoblast cell line molt-3, while phorbol had no effect.

/ALTERNATIVE and IN VITRO TESTS/ Autoradiography has been used to study the effect of 12-O-tetradecanoylphorbol-13-acetate (TPA), 4-O-methyl TPA, and phorbol on metabolic cooperation between human diploid fibroblasts. When the donors, hypoxanthine-guanine phosphoribosyl transferase+ (HGPRT+) cells, and recipients, HGPRT- cells, were plated together in the presence of [(3)H]hypoxanthine and either 4-O-methyl TPA or phorbol, nearly all interactions that developed in 4 hr were positive for metabolic cooperation whereas when high concentrations of TPA were used, the number of positive interactions was significantly less than the control. If the phorbol analogs were added after the donors and recipients had made contact, the number of positive interactions was the same as the control in all cases. However, although primary recipients in the cultures that had been treated with phorbol had the same number of grains as those in the control, primary recipients in cultures that had been treated with TPA or high concentrations of 4-O-methyl TPA had significantly fewer grains than those in the control. TPA treatment for 4 hr had no effect on total [(3)H]hypoxanthine incorporation or incorporation into acid-soluble and acid-insoluble fractions. Thus, the effect of TPA on metabolic cooperation is interpreted as a reduction in the transfer of [(3)H]nucleotides and is an indication of an interference with intercellular communication.

An estimated BCF of 3 was calculated in fish for phorbol(SRC), using an estimated log Kow of -0.54(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is low.

The Henry's Law constant for phorbol is estimated as 3.7X10-11 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that phorbol is expected to be essentially nonvolatile from water surfaces(2). Phorbol's Henry's Law constant indicates that volatilization from moist soil surfaces is not expected to occur(SRC). Phorbol is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.1X10-14 mm Hg(SRC), determined from a fragment constant method(1).

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In a repetition of a previous experiment, using a 20-fold higher dose ofphorbol, administered i.p., as a potential (systemic) promoter for skin carcinogenesis, 6/22 (27%) of the treated mice (after a single skin application of DMBA (7,12-dimethylbenz(a)anthracene) as initiator) developed papillomas, as compared to 1/20 (5%) in the DMBA control group. Though the difference is statistically no more than of borderline significance (P less than 0.05), it raises the possibility that unesterified phorbol is a weak promoter for skin carcinogenesis.

/ALTERNATIVE and IN VITRO TESTS/ /It is proposed/...that PMA (phorbol myristate acetate) interact/s/ with the external cell membrane...that unusual exchanges of various macromolecules &/or metal ions occur. Alterations in intracellular constituents induced this way can in term change control mechanisms inside the cell in undefined ways. ... By comparison the parent compd phorbol, which is inactive as tumor promoter, does not affect any of these properties of rat liver microsomal membranes in vitro.

/ALTERNATIVE and IN VITRO TESTS/ Nontumor promoter phorbol did not stimulate prostaglandin E2 synthesis in bone & bone resorption in neonatal mouse calvaria in organ culture.

/ALTERNATIVE and IN VITRO TESTS/ Nonpromoter phorbol showed no erythroid differentiation in Friend virus-transformed proerythroid C1 745 cells.

For more Non-Human Toxicity Excerpts (Complete) data for PHORBOL (6 total), please visit the HSDB record page.