Scientific Name(s): Kaolin , hydrated aluminum silicate
Common Name(s): Heavy or light kaolin , China clay , bolus alba , porcelain clay , white bole , argilla 1
Kaolin has traditionally been used internally to control diarrhea. Kaolin has also been used topically as an emollient and drying agent. Specifically, it has been used to dry oozing and weeping poison ivy, poison oak, and poison sumac lesions. It has also been used as a protectant for the temporary relief of anorectal itching and diaper rash.
Diarrhea: 12 years of age and older: 26.2 g after each loose stool every 6 hours until firm stool; do not exceed more than 262 g per 24 hours; do not use longer than 2 days. Younger than 12 years of age: seek advice from physician. Diaper rash: 4% to 20% kaolin-containing products applied topically. Radiation- and chemotherapy-induced mucositis: 15 mL of kaolin/pectin and diphenhydramine in a 50:50 mixture; hold in mouth for 3 minutes.
Contraindications have not yet been identified.
FDA Pregnancy: Category C. Kaolin does not cross the placenta. There are no data regarding kaolin in breast-feeding.
Kaolin pectin may decrease the absorption of drugs that chelate with aluminum salts (eg, digoxin, clindamycin, lincomycin). Until more information is available, avoid taking kaolin with drugs that chelate with aluminum. It may also decrease the absorption of trimethoprim and quinidine.
Inhalation of kaolin through occupational exposure may cause pneumoconiosis.
Inhalation may predispose miners to pulmonary diseases.
Kaolin is a hydrated aluminum silicate. It occurs naturally as a clay that is prepared for pharmaceutical purposes by washing with water to remove sand and other impurities.
Kaolin has been used commercially and medicinally for hundreds of years. It is currently used in the manufacture of pottery, bricks, cement, ceramics, paints, plastering material, color lakes (insoluble dyes), and insulators. As a raw material, it is commonly found in paper, plastics, cosmetics, and pharmaceuticals, 2 and it is also used in pharmaceutical preparations as a filtering agent to clarify liquids. Evidence also suggests that kaolin may be useful in the decolorization of dye wastewater via the electrocoagulation method. 3 When applied topically, it serves as an emollient and drying agent. When ingested, it acts as an adsorbent to bind GI toxins and control diarrhea.
Kaolin has been added to dusting powders and is used as a tablet excipient. It is also utilized in a variety of automated laboratory chemistry tests, including the determination of activated clotting time (ACT) 4 and in the serodiagnosis of tuberculosis using the kaolin agglutination test (KAT). 5 Kaolin has also been used experimentally to induce hydrocephalus in animal models in order to assess the effects of the condition on sensorimotor development. 6
Kaolin has the approximate chemical formula of H 2 Al 2 Si 2 O 8 (H 2 O) and is a white or yellow-white powder that has a slightly oily feel. It is an environmentally benign aluminosilicate mineral 7 that is insoluble in water. 1 Light kaolin is the preferred material for use in pharmaceutical preparations. The finely divided particles yield a very large surface area that adsorbs a wide variety of compounds.
Kaolin's ability to enhance citric acid production by Aspergillus niger , a thermophilic fungus, has been studied. Aqueous suspensions of kaolin were added to the fungus medium in concentrations of 5 to 25 ppm. A maximum yield of citric acid (74.62 g/L) occurred within 96 hours after the production phase when using the 15 ppm aqueous suspension. Kaolin is effective in improving citric acid concentrations because of its ability to adsorb metal cations in the medium. This results in an increase in the activity of citrate synthase, an enzyme essential for the production of citric acid. 8
Uses and PharmacologyDiarrhea
When given orally, kaolin, especially light kaolin, adsorbs substances from the GI tract and increases the bulk of feces. 9 Kaolin improves stool consistency within 24 to 48 hours; however, it does not decrease the number of stools passed or reduce the amount of fluids lost. 10 , 11 Data regarding the effects of kaolin on travelers' diarrhea are lacking. 12Animal data
A study of 252 crossbred pigs was conducted to assess the effects of dietary oats and kaolin on performance and diarrhea during the weaning period. This phenomenon, referred to as postweaning check period, can last for 7 to 14 days and often leads to death. Diets consisting of 10%, 20%, or 30% oats and kaolin at 1% and 3% were used. All pigs experienced stress lasting 7 to 14 days after weaning, regardless of diet. However, heavier pigs demonstrated superior performance compared with lighter pigs. Diarrhea was not problematic in this study. 13 Though clinical studies lack any evidence of benefit for the treatment of diarrhea in animals, it is often given to small animals, foals, calves, lambs, and kids. The recommended dose of kaolin pectin for animals is 1 to 2 mL/kg by mouth 4 times daily. 14Clinical data
Antidiarrheal preparations containing kaolin have been used in the treatment of enteritis, cholera, and dysentery. Kaolin preparations, however, have no intrinsic antibacterial activity and should not be used as the sole treatment in infectious diarrheas.Ulcerative Colitis
A small study involving male Wistar rats was conducted to assess the effects of enteral administration of activated charcoal (25 mg), kaolin (105 mg), hydrated aluminum silicate (300 mg), and water as adsorbents to prevent endotoxemia during a state of colitis. In a similar study, colitis-induced mice were divided into the 4 previously mentioned treatment groups and compared with a healthy control group. The treatments were given 5 days after the induction of colitis and were administered twice daily for 3 days. After the treatment period, the mice receiving kaolin and hydrated aluminum silicate demonstrated a reduction in systemic endotoxemia when compared with the healthy control group. Thus, the authors concluded that enteral administration of adsorbents such as kaolin were effective for the treatment of systemic endotoxemia in an animal model. 15Clinical data
No clinical studies of kaolin in the treatment of ulcerative colitis in humans have been documented.Antacid Effects
No studies of kaolin used as an antacid in animals have been documented.Clinical data
Venezuelan kaolin was hydrothermally transformed and placed in contact with various sodium carbonate solutions ranging in strength from 0.5 to 2 M. This modified kaolin clay was tested in the presence of hydrochloric acid and pepsin in order to determine its neutralization capacity. Achievement of normal gastric pH occurred with 250 mg of the modified kaolin clay compared with 400 mg of original clay, leading to the conclusion that modified kaolin clay might be useful as a cheap and effective antacid. 16Radiation/Chemotherapy-Induced Mucositis/Stomatitis
No studies of kaolin in the treatment of radiation/chemotherapy-induced mucositis in animals have been documented.Clinical data
In a prospective, double-blind study, the effects of oral hygiene instruction plus sucralfate compared with diphenhydramine and kaolin/pectin on reducing severity and pain of radiation-induced mucositis were assessed. Fourteen patients were randomized to use 1 of the 2 mouth rinses 4 times daily during radiation beginning at 1,600 centigray (cGy) up to 4,600 cGy. They were instructed to rinse their mouths with a baking soda and salt water solution after meals and at bedtime and then to hold 15 mL of the mouth rinse in their mouths for 3 minutes. Systemic analgesics and antifungals were allowed. There were no differences between the 2 groups with regard to perceived pain, mucositis grade, weight change, or interruption of radiation therapy. However, patients in the sucralfate group reported less pain and a longer duration of pain relief compared with the kaolin/pectin group. Of note, all patients requested to continue using a mouth rinse until resolution of the mucositis. The authors concluded that while sucralfate appears to be protective and palliative, it has high affinity for ulcerated mucosa. Thus, patients with stage 1 or slight mucositis may benefit more from treatment with a mixture of kaolin/pectin and diphenhydramine. 17
Eighteen patients treated with chemotherapy or radiation were included in a prospective, double-blind study to determine the efficacy of several topical solutions used for the treatment of stomatitis. The 4 solutions tested were the following: (1) viscous lidocaine with 1% cocaine, (2) dyclonine hydrochloride 1%, (3) kaolin/pectin, diphenhydramine, and saline mixture, and (4) placebo. There were 2 arms to this study. In the first arm, patients were given a different mixture for 4 consecutive days with self-instructions of gargling the solution or applying it directly onto the lesions and asked to document the effects. During the second arm of the trial, patients continued on the most effective regimen from the first arm for as long as needed. The dyclonine solution was the most effective solution for pain relief, with a relief duration of about 50 minutes. The viscous lidocaine and cocaine solution had approximately the same duration of pain relief. The duration of pain relief reported for kaolin/pectin, diphenhydramine, and saline solution was approximately 35 minutes, which was similar to that of placebo. However, no statistical differences were noted among the 4 groups with regard to pain relief ( P = 0.7334) or duration of relief ( P = 0.4673). No adverse reactions were noted. 18Spontaneous Pneumothorax
Kaolin has been reported to be effective in the treatment of spontaneous pneumothorax. Small crystals act as an abrasive on the endothelial lining of the pleura to produce pleurodesis. 19Animal data
No studies of kaolin in the treatment of spontaneous pneumothorax in animals have been documented.Clinical data
A study of 26 patients with spontaneous pneumothorax was conducted. An injection of 3 to 5 mL of kaolin 25% suspension or 2 to 3 mL of kaolin 50% suspension was administered through a thorascopic cannula to induce pleurodesis. One or 2 more injections of 2 to 3 mL of kaolin 25% suspension were injected via a needle in the pleural cavity within 7 to 10 days postoperatively to allow for complete pleurodesis. Sixteen of the 26 patients (62%) had complete pleurodesis on the first attempt. Though a more conservative approach is commonly recommended due to increased morbidity associated with chemical pleuritis, it was concluded that this method was effective and efficient. 19Insecticide
Kaolin has been used as an insecticide against various arthropods that affect crops. Specifically, kaolin is commonly incorporated into particle film technology for purification, sprayed onto crops in the form of an aqueous suspension, and allowed to dry, yielding its insecticidal effects and leaving a white appearance. 20 , 21 Kaolin is nontoxic to plants and animals, as it remains chemically inert over a range of pH values. 21
In a laboratory, greenhouse, and field study, the insecticidal effects of kaolin-containing particle film on the pink bollworm were assessed. In the lab setting, there were 7 times more eggs laid per boll in untreated cotton compared with bolls treated with kaolin ( P < 0.0001). Additionally, establishment of boll mines occurred in untreated areas of cotton compared with treated areas ( P < 0.01). In the greenhouse setting, there were 5 times more eggs laid on untreated bolls compared with treated bolls, resulting in the conclusion that kaolin-based particle film treatment deters oviposition and larval mining. 7
Another study assessed the insecticidal effects of kaolin-containing particle film on Myzus persicae . Plants were infected with the aphid vector and then treated with either water or kaolin suspension. Survival times were not significantly different between the treatment groups ( P = 0.275), nor were there differences in the total number of nymphs produced per aphid per day ( P = 0.124). However, when given the choice of untreated versus kaolin-treated areas, both adults and nymphs preferred untreated areas. The authors concluded that, under laboratory conditions, kaolin particle technology does not appear to affect the growth rate, reproduction, or survival of Myzus persicae species. These results may be attributed to the type of formulation used in the study and/or species-specific features. 20
Water-treated versus kaolin-treated plants were studied to determine insecticidal effects against Plutella xylostella , also known as the diamondback moth. Applying kaolin to the eggs did not appear to have a significant effect on their hatch rate ( P = 0.815). However, treatment with kaolin did have a negative effect on survival ( P = 0.007). Additionally, development time to adult emergence was significantly longer for plants treated with kaolin on the upper surfaces of the leaves ( P = 0.022) and those treated with kaolin on both leaf surfaces (0.004) when compared with those treated with water. Significantly more eggs were laid on plants treated with kaolin compared with water ( P = 0.036). 19
In another small study, the effects of kaolin on Choristoneura rosaceana (Lepidoptera: Tortricidae) behavior and fitness as a physical barrier and physiological toxin were assessed. Kaolin was either applied to apple leaves or mixed in an artificial diet for the larvae. Mortality and time to larvae pupation increased and pupal mass declined when larvae fed on kaolin-treated apple leaves. The purpose in mixing kaolin into an artificial diet was to eliminate any possibility that kaolin's insecticidal effects could be due to a physical barrier. Although consumption of the diet was not measured, making it difficult to extrapolate any results from this group, some physiological effects may exist when kaolin is consumed in high concentrations because these larvae took longer to pupate than those on a normal control diet. 22Laboratory Testing
Kaolin has been recognized as a coagulation activator and has been incorporated into various laboratory testing to measure ACT. These measurements are imperative during cardiopulmonary procedures in order to guide heparin anticoagulation to prevent thrombosis and reduce inflammation. 23
Additionally, kaolin has been studied for its effects when testing horse serum for seroconversion against equine influenza virus, which causes a major respiratory disease among horses. The hemagglutination-inhibition assay is very rapid and has a reproducibility of 84% to 96%. However, this test is affected by the presence of nonspecific inhibitors found in the horse serum. Thus, kaolin was studied to determine its ability to remove these nonspecific inhibitors. When testing for antibodies against equine influenza virus subtype 1 (H7N7), false-positive results occurred. However, when testing against antibodies for equine influenza virus subtype 2 (H3N8), false-positive results did not occur. Additionally, titers of sera treated with kaolin were similar to those that were untreated, indicating that kaolin was not effective in removing nonspecific inhibitors from equine serum. 24Wastewater Purification
One small study suggested that the addition of kaolin to oil field wastewater can result in removal of chemical oxygen demand, removal of scaling ions, such as iron, calcium, and magnesium, improvement in membrane filter index, bacteriocidal effects, and inhibition of corrosion. 25
12 years of age and older
26.2 g after each loose stool every 6 hours until firm stool; do not exceed more than 262 g per 24 hours; do not use longer than 2 days.Younger than 12 years of age
Seek advice from physician. 26Diaper rash
4% to 20% kaolin-containing products can be applied topically. 13Radiation- and Chemotherapy-Induced Mucositis
15 mL of kaolin/pectin and diphenhydramine in a 50:50 mixture; hold in mouth for 3 minutes. 17
Because kaolin-containing preparations are not systemically absorbed and do not cross the placenta, kaolin is listed as Pregnancy Category C. However, there is a possible association between kaolin ingestion and the development of iron deficiency anemia and hypokalemia, especially during pregnancy. 27 , 28
In a small study of female rats, hemoglobin, hematocrit, and red blood cell levels were reduced in the groups of rats that ingested a kaolin-containing diet. Additionally, the pups born to these rats exhibited low birth weights. 29
There are no human data regarding breast-feeding and kaolin usage. 27
Most drug interaction studies of kaolin have involved administration of kaolin pectin. Kaolin pectin can form insoluble complexes with a number of drugs and should be avoided in patients receiving drugs that may chelate with aluminum salts (eg, digoxin, 30 , 31 , 32 clindamycin, 33 lincomycin, 34 and penicillamine 35 ). Until more information is available, interactions that occur with kaolin pectin should be considered to occur with kaolin alone. Additionally, concomitant administration of kaolin pectin and trimethoprim resulted in a reduced area under the curve for trimethoprim and decreased the average blood concentration of trimethoprim by 29.42%. 36 An in vitro study suggests that quinidine absorption may be reduced with concomitant administration of kaolin-pectin preparations. 37 To avoid potential drug interactions, kaolin should be used at least 3 hours before or after any other medications. 38 When used topically for anorectal itching, petrolaturm or greasy ointments should be removed before applying kaolin-containing products in order to allow for proper adherence to the skin. Additionally, cocoa butter, cod liver oil, hard fat, lanolin, mineral oil, shark liver oil, petrolaturm, or white petrolaturm cannot be combined with kaolin because of limited skin adherence. 10
Kaolin is highly insoluble and is not absorbed systemically. Therefore, it is not generally associated with severe toxicity.
Inhalation of nonfibrous silicate compounds such as kaolin may predispose miners to pulmonary diseases. 39 In a small study of 65 kaolin miners in Georgia, 5 workers with more than 5 years of exposure had radiographic evidence of kaolin pneumoconiosis. These workers spent most of their time in the processing area of the mine where exposure to kaolin dust was the highest. The forced vital capacity (FVC) and forced expiratory volume after 1 second (FEV 1 ), expressed as a percentage of predicted values, were slightly but statistically lower in the workers with pneumoconiosis. These values declined the longer they worked in the mining area. Additionally, radiographic evidence worsened with increased exposure. However, the FEV 1 /FVC ratio did not differ for workers with pneumoconiosis, suggesting the presence of restrictive lung disease resulting from inhalation of dust as opposed to obstructive lung disease caused by smoking. 40
Bibliography1. Windholz M , ed. The Merck Index . 10th ed. Rahway, NJ: Merck & Co; 1983 .
2. Kwan CC , Chu WH , Shimabayashi S . Effect of polyvinylpyrrolidone and sodium lauroyl isethionate on kaolinite suspension in an aqueous phase . Chem Pharm Bull . 2006 ; 54 ( 8 ): 1082-1087 .
3. Zhuo Q , Ma H , Wang B , Gu L . Catalytic decolorization of azo-stuff with electro-coagulation method assisted by cobalt phosphomolybdate modified kaolin . J Hazard Mater . 2007 ; 142 ( 1–2 ): 81-87 .
4. Huyzen RJ , Harder MP , Huet RC , Boonstra PW , Brenken U , van Oeveren W . Alternative perioperative anticoagulation monitored during cardiopulmonary bypass in aprotinin-treated patients . J Cardiothorac Vasc Anesth . 1994 ; 8 ( 2 ): 153-156 .
5. Sarnaik RM , Sharma M , Kate SK , Jindal SK . Serodiagnosis of tuberculosis: assessment of kaolin agglutination test . Tuber Lung Dis . 1993 ; 74 ( 6 ): 405-406 .
6. Khan OH , Enno TL , Del Bigio MR . Brain damage in neonatal rats following kaolin induction of hydrochephalus . Exp Neurol . 2006 ; 200 ( 2 ): 311-320 .
7. Sisterson MS , Liu YB , Kerns DL , Tabashnik BE . Effects of kaolin particle film on oviposition, larval mining, and infestation of cotton by pink bollworm (Lepidoptera: Gelechiidae) . J Econ Entomol . 2003 ; 96 ( 3 ): 805-810 .
8. Ali S . Application of kaolin to improve citric acid production by a thermophilic Aspergillus niger . Appl Microbiol Biotechnol . 2006 ; 73 ( 4 ): 755-762 .
9. Bowman WC . Textbook of Pharmacology . 2nd ed. London: Blackwell Scientific Publications; 1980 .
10. Berardi RR , Kroon LA , McDermott JH , et al. Handbook of Nonprescription Drugs . 15th ed. Washington, DC: American Pharmacists Association; 2006 : 340,357,358,769 .
11. Wald A . Constipation, diarrhea, and symptomatic hemorrhoids during pregnancy . Gastroenterol Clin North Am . 2003 ; 32 ( 1 ): 309-322 .
12. Ericsson CD . Nonantimicrobial agents in the prevention and treatment of travelers diarrhea . CID . 2005 ; 41 ( suppl 8 ): S557-S563 .
13. Rivera ER , Armstrong WD , Clawson AJ , Linnerud AC . Effect of dietary oats and kaolin on performance and incidence of diarrhea of weanling pigs . Journal of Animal Science . 1978 ; 46 ( 6 ): 1685-1693 .
14. Kahn CM , ed. The Merck Veterinary Manual . 9th ed. Whitehouse Station, NJ: Merck & Co; 2005 : 1984-1985 .
15. Gardiner KR , Anderson NH , McCaigue MD , Erwin PJ , Halliday MI , Rowlands BJ . Adsorbents as antiendotoxin agents in experimental colitis . Gut . 1993 ; 34 ( 1 ): 51-55 .
16. Linares CF , Rosa-Brussin M . Modified Venezuelan kaolin as possible antacid drug . J Applied Sci . 2004 ; 4 ( 3 ): 472-476 .
17. Barker G , Loftus L , Cuddy P , Barker B . The effects of sucralfate suspension and diphenhydramine syrup plus kaolin-pectin on radiotherapy-induced mucositis . Oral Surg Oral Med Oral Pathol . 1991 ; 71 ( 3 ): 288-293 .
18. Carnel SB , Blakeslee DB , Oswald SG , Barnes M . Treatment of radiation- and chemotherapy-induced stomatitis . Otolaryncol Head Neck Surg . 1990 ; 102 ( 4 ): 326-330 .
19. Joynt GH , Laird RC . Treatment of spontaneous pneumothorax with kaolin . Chest . 1958 ; 34 ( 5 ): 514-520 .
20. Barker JE , Holaschke M , Fulton A , Evans KA , Powell G . Effects of kaolin particle film on Myzus persicae (Hemiptera: Aphididae) behaviour and performance . Bull Entomol Res . 2007 ; 97 ( 5 ): 455-460 .
21. Barker JE , Fulton A , Evans KA , Powell G . The effects of kaolin particle film on Plutella xylostella behaviour and development . Pest Manag Sci . 2006 ; 62 ( 6 ): 498-504 .
22. Sackett TE , Buddle CM , Vincent C . Effect of kaolin on fitness and behavior of Choristoneura rosaceana (Lepidoptera: Tortricidae) larvae . J Econ Entomol . 2005 ; 98 ( 5 ): 1648-1653 .
23. Dalbert S , Ganter MT , Furrer L , Klaghofer R , Zollinger A , Hofer CK . Effects of heparin, haemodilution and aprotinin on kaolin-based activated clotting time: in vitro comparison of two different point of care devices . Acta Anaesthsiol Scand . 2006 ; 50 ( 4 ): 461-468 .
24. Boliar S , Stainislawk W , Chambers TM . Inability of kaolin treatment to remove nonspecific inhibitors from equine serum for the hemagluttination inhibition test against equine H7N7 influenza virus . J Vet Diagn Invest . 2006 ; 18 ( 3 ): 264-267 .
25. Ma HZ , Wang B . Multifunctional microsized modified kaolin and its application in wastewater treatment . J Hazard Mater . 2006 ; 136 ( 2 ): 365-370 .
26. Part 335—Antidiarrheal drug products for over-the-counter human use . Food and Drug Administration HHS . http: / / a257.g.akamaitech.net / 7 / 257 / 2422 / 26mar20071500 / edocket.access.gpo.gov / cfr_2007 / aprqtr / pdf / 21cfr335.50.pdf . Accessed December 19, 2007.
27. Briggs GG , Freeman RK , Yaffe SJ , eds. Drugs in Pregnancy and Lactation . 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005 : 875 .
28. Black RA , Hill DA . Over-the-counter medications in pregnancy . Am Fam Physician . 2003 ; 67 ( 12 ): 2517-2524 .
29. Patterson EC , Staszak DJ . Effects of geophagia (kaolin ingestion) on the maternal blood and embryonic development in the pregnant rat . J Nutr . 1977 ; 107 ( 11 ): 2020-2025 .
30. Albert KS , Ayres JW , DiSanto AR , et al. Influence of kaolin--pectin suspension on digoxin bioavailability . J Pharm Sci . 1978 ; 67 ( 11 ): 1582-1586 .
31. Brown DD , Juhl RP . Decreased bioavailability of digoxin due to antacids and kaolin-pectin . N Engl J Med . 1976 ; 295 ( 19 ): 1034-1037 .
32. Albert KS , Elliot WJ , Abbott RD , Gilbertson TJ , Data JL . Influence of kaolin-pectin suspension on steady-state plasma digoxin levels . J Clin Pharmacol . 1981 ; 21 ( 10 ): 449-455 .
33. Albert KS , DeSante KA , Welch RD , DiSanto AR . Pharmacokinetic evaluation of a drug interaction between kaolin--pectin and clindamycin . J Pharm Sci . 1978 ; 67 ( 11 ): 1579-1582 .
34. Wagner JG , et al. Design and data analysis of biopharmaceutical studies in man . Can J Pharm Sci . 1966 ; 1 : 55-68 .
35. Ifan A , Welling PG . Pharmacokinetics of oral 500-mg penicillamine: effect of antacids on absorption . Biopharm Drug Dispos . 1986 ; 7 ( 4 ): 401-405 .
36. Babhair SA , Tariq M . Effect of magnesium trisilicate and kaolin-pectin on the bioavailability of trimethoprim . Res Commun Chem Pathol Pharmacol . 1983 ; 40 ( 1 ): 165-168 .
37. Bucci AJ , Myre SA , Tan HS , Shenouda LS . In vitro interaction of quinidine with kaolin and pectin . J Pharm Sci . 1981 ; 70 ( 9 ): 999-1002 .
38. Pray WS , ed. Nonprescription Product Therapeutics . 2nd ed. Baltimore, MD: Lippincott Williams & Wilkins; 2006 : 176,199,620,631,841 .
39. Short SR , Petsonk EL . Respiratory health risks among nonmetal miners . Occup Med . 1993 ; 8 ( 1 ): 57-70 .
40. Altekruse EB , Chaudhary BA , Pearson MG , Morgan WK . Kaolin dust concentrations and pneumoconiosis at a kaolin mine . Thorax . 1984 ; 39 ( 6 ): 436-441 .
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