Advantage Avantrx!

                                             

Excess Weight and Disease

• reduce caloric intake
• improve macro- and micronutrient intake
• increase amount of calories burned.

• Responders: 94.1%
• Average 4-week weight loss: 7.6 lbs (4.2% body mass)
• Average number of capsules taken per day: 2
• Average reduction in meal portion size: 34.3%
• Average rating of hunger control effectiveness: 86.7%
• Average time to feel fullness effect: 33 minutes
• Average duration of fullness effect: 2.5 hours
• Total doses administered during study period: >2,000

 
In the first graph, participants were asked to rate their responses from the formula's effects at each breakfast, lunch and dinner. The formula generated a sensation of fullness or early satiety 94.1% of the time. In 5.9% of meals, patients described that "No Effect' was noted. 

    

Super Absorbent Polymers (SAP), [like SWELL, the ingredient in Avantrx, which is the subject of this GRAS determination], are used in a variety of consumer, medical and industrial products. SAP products are cross-linked homopolymers of partially neutralized acrylic acid, i.e., hydrogels. Neutralization is accomplished by sodium hydroxide solution. In the dry form SAP is a granular powder of crystalline structure. Commercial SAP is practically dust free because it contains much less than 0.1% of granules below 10 ?m of diameter.

Upon swelling with water, it yields a gel-like suspension. The retention of water is facilitated by the negative carboxylic groups of the polymer and their hydration with water molecules. Due to its cross linking, SAP is essentially insoluble in water. However, should incomplete polymerization occur, small amounts of a water extractable fraction can exist within the polymer matrix.

SAPs have been evaluated in various test systems to elucidate their toxicological profile for both handling during production and use in an article like a diaper, or in their purified forms for ingestible purposes like: pharmacologic agents, excipients, adjuvants, bulking agents, rheologic agents. These toxicity data are substantial to draw conclusions on the potential risk of SAPs to human health through its whole lifetime.

Note: Not all of the different variations of the super absorbent polymers were tested with all the following test systems due to ethical and economical reasons. Some data has been drawn in analogy.

Acute oral toxicity

LD₅₀ > 5,000 mg/kg body weight. Up to 5% (w/v) SAP as a gel in 0.9% (w/v) saline were applied with a stomach tube to 5 male and 5 female rats each. No toxic symptoms were observed and body weight development was normal during observation over 14 days after single application. Necropsy revealed no visible organ alterations.

Application of a watery extract of SAP (in the drinking water) to 6 male and 6 female rats for 1 day led to no symptomatic effects. No fatalities or any visible organ changes were observed.

Subacute oral toxicity

The oral toxicity of SAP, when administered daily to 10 male and 10 female rats per group via the diet over 4 consecutive weeks at concentrations of up to 5% weight of SAP by volume were investigated. No changes of toxicological significance were induced. The differences observed between treated and control animals were limited to increases in water consumption and modification in urinary ion excretion in treated animals. Both findings were considered to be related to the relatively high concentration of sodium in the test substance and therefore of no toxicological significance. (Research Toxicology Centre, Italy)

Elimination after oral application

The elimination of radio-labeled [¹⁴C]-SAP in the rat model following single oral administration has been investigated and the rates and routes of excretion and tissue distribution of total radioactivity were determined. By a recovery rate in excess of 96% nearly the entire administered dose was excreted within 5 days and the main route of excretion was via feces. Levels of radioactivity in tissues and organs were low. Biliary elimination of total radioactivity did not occur to any significant extent. Determination of the whole blood kinetics has shown also low levels of radioactivity in blood with peak levels attained between 0.5 - 1 hour post dosing. The results indicate that SAP is very poorly absorbed following oral administration. (Inveresk Research International Ltd., U.K.)

Acute inhalation toxicity on SAP dust

The acute inhalation toxicity of fine dust of SAP was determined in rats in a single 4 hour snout only exposure. The actual exposure concentrations ranged from 0.95 to 5.54 g/m³ with respirable fractions (mass medium aerodynamic diameter (MMAD) < 3.5 ?m) of 25-40% of the total dust. A reduced respiration rate was noted during exposure for all treated groups and mortality at exposure concentrations at or in excess of 3.73 g/m³ was produced. Histological examination of respiratory tissues showed evidence of an inflammatory response, primarily in the lungs consisting mainly of increased macrophages and mild lymphocytic infiltration. Based on the observations recorded during the study and the histological findings 0.98 g/m³ of fine dust is considered to be a sublethal dose level. (Inveresk Research International Ltd., U.K.)

Elimination after intratracheal administration

The elimination of radio-labeled [¹⁴C]- SAP in the rat following single intratracheal administration has been investigated. The levels of total radioactivity in the lung decreased throughout the study period of one week, indicating absorption of radio-labeled components. At the end of study approximately 15% of administered radioactivity was left in the lung. Of the tissues examined, highest levels of total radioactivity were found in the liver (5%) and in the kidney (1%) at 1 hour post dose. Urinary excretion of radio-labeled components was 26% after one week after administration. The mechanism of absorption and the components are unknown. (Inveresk Research International Ltd., U.K.)

Subacute inhalation toxicity on SAP dust

20 male and 20 female rats were exposed to particulate SAP of a mass median aerodynamic diameter (MMAD) of < 10 ?1m for 6 hours/day; 5 days/ week, for 4 weeks to nominal exposure levels of 0.1, 1.0 and 10.0 mg/m³; the actual concentrations were 1.7,4.0 and 21.1 mg/m³. No biologically significant findings regarding ophthalmology, growth behavior, wet organ weights, hematology, clinical chemistry and pulmonary function were reported. Histological examination revealed a mild inflammatory reaction with increased numbers of macrophages in the alveoli and minimal lymphocyte response. There was some minimal evidence of a dose dependency but no evidence of significant inflammation, tissue destruction or fibrosis. (Temple University, Philadelphia, U.S.A.)

Note: Chronic inhalation of fine dust may exert inflammatory reactions in the lung. SAP was not tested in a chronic inhalation study. However, a chronic (2-year) lifetime inhalation study with another intentionally micronized super absorbent polymer dust (to get completely respirable particles) performed on rats resulted in a non-specific inflammatory response in the lungs of the rats, followed in the highest chronic exposure level by tumor development in some animals. The no observed effect level (NOEL) was 0.05 mg/m³. Therefore an occupational guidance value (OGV) of 0.05 mg/m³ is recommended.

Acute dermal toxicity

LD₅₀ 2,000 mg/kg body weight of up to 5% (w/v) of SAP as a gel in a 0.9% (w/v) saline applied to the shorn skin of 5 male and 5 female rats. No toxic symptoms were observed; body weight development was normal for 14 days after application; necropsy revealed no visible organ alterations; no deaths occurred: SAP is practically non-toxic when applied dermally.

Subacute dermal toxicity

Application of 0.5 g of SAP on shorn and scarified skin of rabbits for five consecutive days under occlusion led to no abnormal findings with respect to any local (i.e. irritation) or systemic effects. Systemic effects were evaluated with hematological and clinical parameters. (International Bio Research-IBR, Germany)

Subchronic dermal toxicity

Repeated application of 0.05 ml of a saline extract of SAP onto the shorn skin, without occlusion, of 10 female mice of the strain, transiently and occasionally very slight edemas accompanied with a slight increase in skinfold thickness. The test substance was applied 3 times/week over 8 weeks. Body weight was within normal range; no systemic effects, due to the test substance, were observed.

A test for skin compatibility as a subchronic dermal assay was performed. 10 female mice were exposed to 0.05 ml of 5% and 7.5% (w/v) suspensions of SAP in 0.9% (w/v) saline, three times a week. Toxicity or any other adverse effects to the skin were not observed. There were no deaths. Body weight development was normal.

Acute skin irritation

Application of 0.5 ml of a saline extract of SAP onto the shorn skin of 3 rabbits (both sexes) under occlusion over a period of 4 hours showed no edema or erythema formation. No other skin lesions were observed, as there were no systemic effects. Test duration was 7 days.

Acute eye irritation

Application of 0.1 g of SAP into the conjunctival sac of the eyes of rabbits caused very slight erythema and mild transient corneal injury. There were no systemic symptoms due to the application of the test substance. The observed very slight irritative effects onto mucous membranes of the eyes and the cornea are caused by the somewhat abrasive properties of the dry, crystalline powder of SAP, and the capacity of SAP to dry out the membranes due to the uptake of fluid during swelling. A watery suspension of SAP exerts no such effects on the eyes of rabbits.

HET-CAM-Test

Chorioallantoic membrane (CAM) assay (HEN'S EGG TEST): 200 mg of dry SAP was applied onto the CAM of hen embryos of 10 days of age. There were no adverse effects with respect to vascular injection, hemorrhaging, or coagulation. Potential for cell toxicity and adverse effects on membranes seems to be very low.

Cytotoxicity in vitro

Cell toxicity: SAP has been examined regarding its influence on mammalian cells in a cell culture system using a fibroblastic cell line derived from mice. The cells were incubated for 24 hours with an extract of SAP (15 g/l of 0.9% sodium chloride solution) in concentrations up to 10% (v/v) in cell culture medium. No adverse effects on the morphology or viability of the cells were observed. Extraction of SAP with cell culture medium (10 g/l of medium) led to a concentration dependent decrease in cell viability due to complex formation (binding) of essential cations in the medium. Following supplementation of the bound cations, adverse effects were not observed any longer. Further cell toxicity tests were executed using the agar diffusion cell culture technique, which is appropriate for solid specimens as well. SAP was applied as dry granulate and as a suspension (30 g/l of 0.9% sodium chloride solution). There was no indication of cytotoxic effects.

Intravenous and intraperitoneal application

Intravenous and intraperitoneal compatibility of SAP was tested after systemic injection in mice. Following intraperitoneal application of 50 ml/kg extract in sesame oil or 10 g/kg extract in polyethylene glycol no toxic reactions of the animals were observed within 72 hours. Intravenous instillation of a SAP extract (15 g/l of 0.9% of sodium chloride solution) produced systemic effects and mortality in dose levels greater than 40 ml/kg. Histopathological examination revealed dose dependent toxic alterations to liver and spleen. The no observed effect level (NOEL) is less than 10 ml/kg, a dose where only minimal hepatic effects have been observed.

Subcutaneous and intramuscular implantation

Subcutaneous and intramuscular compatibility of a gel and the granulate of SAP was tested in rabbits after implantation. Histopathology revealed no abnormal reactions in the surrounding tissue. Furthermore, there were no significant deviations from normal values in hematology, clinical chemistry, and other standard toxicological parameters. No signs of toxicity were observed. (International Bio Research - IBR, Germany)

Hemocompatibility

Hemocompatibility of SAP was tested with the extract and a gel-like suspension of the polymer against human erythrocytes of different blood groups. No hemolysis could be observed under the test conditions employed. Therefore SAP is compatible to blood.

Influence on the vaginal mucosa

SAP was examined with respect to its influence on vaginal mucosa tolerance through single intravaginal administration to rabbits. The dosage levels used were 0.33 and 3.0 g/animal. There were no observed toxic symptoms, nor any deaths. Body weight development was normal, as were the amounts of food and drinking water consumed. The mucosa of the vagina was examined macroscopically and microscopically. No pathological changes were observed relating to SAP. (Laboratory for Pharmacology & Toxicology, Hamburg, Germany)

Allergic contact sensitization (GPMT)

SAP has been tested with respect to its potential to sensitize animals after skin contact according to the maximization test of Magnusson and Kligman. Twenty (20) guinea pigs of either sex were treated intradermally with a water extract [1% (w/v)] and dermally with 1% and 7.5% (w/v) gels in 0.9% (w/v) saline during the induction period. The challenge was executed with 1%,5% and 7.5% (w/v) gels in 0.9% (w/v) saline: No erythemas or edemas were observed; therefore, it is unlikely for SAP to exhibit a potential for skin sensitization.

Human allergic contact sensitization

Human repeat insult patch test (HRIPT): Saline [O.9% (w/v)] extracts of SAP were applied repeatedly as patches on the upper arm of 44 human volunteers, of either sex, aged 18 years or more. Nine induction patches each, to be worn for 24 hours, were used over a period of 3 weeks (3 for each week). One challenge patch was applied for 24 hours with reading and grading 48 and 96 hours after application. The test showed no evidence of skin sensitization for SAP. (CTC International Ltd., U.K.)

Human irritation test

A cumulative irritation test over 21 consecutive days was performed with 0.3 g of a gel of SAP [10% (w/v) in isotonic saline] on volunteers. The gel scored 0.01 points out of 4.0, and was rated "very mildly" irritating. (Harris Laboratories, Inc., Lincoln, Nebraska, U.S.A.)

Teratogenicity

Pregnant female rats were exposed in a teratology study to respirable levels (particle size < 10 ?m) of SAP at 0.3, 1.0 and 10 mg/m³ for 6 hours/day from day 6 to day 15 of gestation. On day 20 of gestation the rats were necropsied and examined by number of implantations, early and late resorptions, live and dead fetuses and number of corpora lutea. The fetuses were observed for weight, external, soft tissue and skeletal alterations. No effects were observed: The no observed effect level (NOEL) is greater than the highest concentration applied. (Texas Tech University, Department of Physiology, U.S.A.)

Salmonella typhimurium reverse mutation assay

Mutagenicity was tested with an extract of SAP [10 g/l of 0.9% (w/v) sodium chloride solution] which contains constituents extractable with water: The test was done with the AMES-Salmonella-plate test (in vitro) with and without metabolic activation by rat liver microsomes for screening for mutagenic properties. The strains TA 100 and TA 1535 were used (base pair substitution) as well as TA 98 and TA 1537 (frameshift mutation). Cytotoxic effects were not observed up to a quantity of 100 ?l of the above mentioned extract per plate. An increase in the revertants was not detected in any of the examined cases. Therefore, there was no indication of a mutagenic potential in S. typhimurium of the extract of SAP. (Laboratory for Pharmacology & Toxicology, Hamburg, Germany)

A further AMES test was executed with an extract of SAP [20 g/l of 0.9% (w/v) saline with 10% (v/v) ethanol] which contains constituents extractable with water and alcohol, with and without metabolic activation by rat liver microsomes. The strains TA 100, TA 1535, TA 98 and TA 1537 were used. An increase in the revertants was not detected in any of the examined cases. Therefore, there were no indications of a mutagenic potential in S. typhimurium of the extract of AP up to the equivalent of 20 mg/plate. (Microtest Research Ltd., U.K.)

Escherichia coli reverse mutation assay

Extracts of SAP were tested in tryptophan requiring strains of Escherichia coli for their ability to induce point mutations with and without the presence of a metabolic activation system. Up to 5,000 ?g/plate no mutagenic events could be observed. Furthermore, cytotoxicity was not detected up to 5,000 ?g/plate. (Hazleton Microtest, U.K.)

In vitro mammalian cell gene mutation test

Mouse lymphoma L-5178-Y cells were exposed with (S 9 mix from Aroclor induced rat liver) and without metabolic activation to an extract of SAP [20 g/l in 0.9% (w/v) saline with 10% (v/v) ethanol]. The test substance failed to induce point mutations at the hypoxanthine guanine phosphoribosyltransferase (HGPRT) locus up to the equivalent of 200 ?g/ml. (Microtest Research Ltd., U.K.)

Mouse lymphoma L-5178-Y cells were exposed with (S 9 mix from Aroclor induced rat liver) and without metabolic activation to an extract of SAP in 0.9% (w/v) saline with 10% (v/v) ethanol. The test substance failed to induce point mutations at the thymidine kinase (TK) locus up to the equivalent of 1.5 mg/ml. No cytotoxicity was observed. (Hazleton America, Inc., U.S.A.)

UDS in rat hepatocytes in vitro

SAP was tested for its ability to induce unscheduled DNA synthesis (UDS) in isolated rat hepatocytes in vitro. Treatment with up to 1,500 ?g/ml of equivalent extracted material [i nO. 9% (w/v) saline with 10% (v/v) ethanol] did not produce a mean net grain count greater than zero (0), nor were 20% or more cells to be found in repair. The test substance therefore failed to produce genotoxic activity. (Hazleton Microtest, U.K.)

In vivo mouse bone marrow micronucleus test

SAP was assayed in an in vivo mouse bone marrow micronucleus test at the highest oral dose level (375 mg/kg) due to its thick consistency. Groups of 5 male and female animals were used and were killed at intervals of 24, 48 and 72 hours after treatment. At no time point was there a significant increase in micronucleus frequency in any group. Therefore, it is concluded that SAP is not able to induce micronuclei in polychromatic or normochromatic erythrocytes of bone marrow of mice. (Microtest Research Ltd., U.K.)

Growth of pathogenic microorganisms

In order to answer the question if pathogenic microorganism can grow on SAP, which may be used in hygiene products, pharmaceutical applications, food additives or in food packaging, the growth behavior of pathogenic microorganisms and the potential production of toxins where investigated:

Growth behavior of the pathogenic microorganisms Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans alone or in combination was determined with a saline (0.9%) extract of SAP at 37 ?C for 24 hours. No significant growth could be determined, i.e. the aqueous extract of SAP does not serve as an important additional carbon source, especially when a free water phase is lacking. Furthermore, cytotoxic effects of the extract could not be observed.

Additionally, the native product was tested against its resistance to microbiological attack and subsequent growth of microorganisms. Without addition of a culture medium, no growth was observed, i.e. SAP does not serve as an additional carbon source.

Inhibitory effects of extracts of SAP on the growth behavior of the potential pathogens E. coli and C. albicans were not observed, i.e. cytotoxic, cytostatic or biocidal effects are not to be expected. Furthermore, significant growth was not observed.

Production of bacterial toxin

Extracts and the gel of SAP were incubated with a TOXIC SHOCK SYNDROM TOXIN 1 (TSST 1) producing strain of Staphylococcus aureus to search for any abnormalities in the growth behavior of the microorganism and its ability to produce the toxin. The super absorbent polymer SAP exhibited no observed influence on the aforementioned parameters. (Laboratory for Toxicology & Ecology, Stockhausen, Germany)

Summary

SAP products are super absorbent polymers which exhibit a very low toxicological profile: Under appropriate test conditions there have been no signs of acute oral toxicity (> 5,000 mg/kg, rat) and acute dermal toxicity (> 2,000 mg/kg, rat). Furthermore, subacute oral toxicity and subchronic dermal toxicity have not been observed in rats. The eye irritative potency (rabbit) seems to be very low. SAP has a good compatibility following systemic injection or implantation and against blood. It is not per se cytotoxic. Absorption after oral uptake is negligible. Some absorption is observed after intratracheal application but without any systemic toxicity.

SAP shows no evidence of an allergic contact sensitization in guinea pigs and humans. The same applies for irritative properties. No mutagenic and teratogenic potency was found. SAP does not serve as a growth substrate for pathogenic microorganisms. However, chronic (2 year) inhalation of intentionally micronized fine dust of a super absorbent polymer caused tumor formation in rat lungs but in the highest concentration only. Therefore an occupational guidance value (OGV) of 0.05 mg/m³ is recommended by Neutra-Labs.

Conclusion: