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Risk profile Sucralfate Page 1 of 27
R I S K P R O F I L E
S u c r a l f a t e
C A S N o. 5 4 1 8 2 - 5 8 - 0
D a t e o f r e p o r t i n g 0 3. 0 6. 2 0 1 3
Content of document
- Identification of substance .................................................................... p. 1
- Uses and origin ................................................................................ p. 2
- Regulation ............................................................................................. p. 4
- Relevant toxicity studies ................................................................... p. 4
- Exposure estimates and critical NOAEL/NOEL .......................................... p. 7
- Other sources of exposure than cosmetic products ............................. p. 8
- Assessment ............................................................................................. p. 10
- Conclusion ............................................................................................. p. 13
- References ............................................................................................. p. 14
- Annexes ............................................................................................. p. 16
1. Identification of substance
Chemical name (IUPAC): (^) Hexadeca--hydroxytetracosahydroxy[ 8 -[1,3,4,6-tetra- O- sulfo--D- fructofuranosyl--D-glucopyranoside tetrakis(hydrogen sulfato)(8- )]]hexadecaaluminum
INCI Aluminum sucrose octasulfate^1
Synonyms The INN name, that is used medicinally, is Sucralfate
CAS No. 54182-58-
EINECS No. 259-018-
Molecular formula C 12 H 30 Al 8 O 51 S 8 .8(H 3 AlO 3 ) 2 (footnote 2) , C 12 H 54 Al 16 O 75 S 8
Chemical structure
(^1) Confusingly, the branch of cosmetic industry has for some obscure reason come to write aluminum
for the element that scientifically is called aluminium. We hereafter used the scientific term. (^2) http://www.chemblink.com/products/54182-58-0.htm
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(x= 8 to 10 and y= 22 to 31)
(Source: wikipedia)
Sucralfate is a sucrose aluminium sulphate complex: a-D-glucopyranoside, β-D-fructofuranosyl-, octakis-(hydrogen sulfate)
Molecular weight (^) 2086.
Contents (if relevant) 1 g tablet of sucralfate contains 20 7 mg of Al.
Physiochemical properties (^) White amorphous powder; soluble in dilute hydrochloric acid & sodium hydroxide solution; practically insoluble in water, ethanol, chloroform.
Al absorption is greater from water than Al hydroxide or sucralfate and from sucralfate suspension than tablet (Krewski et al., 200 7 ;
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In Norway, sucralfate is marketed as “Antepsin”, with the following indications (in Norwegian: “Ulcus duodeni. Ulcus ventriculi. Profylaktisk behandling ved stadig residiverende, eller kroniske duodenalsår. Profylakse mot blødninger pga. stressulcus hos kritisk syke pasienter»).
Sucralfate has also been shown to have antibacterial activity (in relation to healing of e.g. ulcers).
See also: http://en.wikipedia.org/wiki/Sucralfate
Other products
Origin Natural (exo /endo) Synthetic
Sucralfate is an Al salt of a sulfated disaccharide (for molecular structure, see section 1). 1 g of sucralfate contains 20 7 mg of Al.
Mechanism of Action : The protectant and healing effects of sucralfate are exerted through local, rather than systemic, action (see section 4 for toxicity).
Band-aid : Sucralfate mainly serves as a “Band-aid®”, by forming an adherent coating at low pH. At higher pH sucralfate may remain in suspension and improve the gastric environment by adsorbing pepsin, buffering hydrogen ions, increasing bicarbonate secretion etc. Al is poorly absorbed from the intact gastrointestinal tract.
Sucralfate does not affect gastric acid output or enzyme trypsin or pancreatic amylase activity (i.e. is not an antacid).
Sucralfate forms a large complex with proteins (primarily albumin and fibrinogen) that adheres to the ulcer to form a relatively persistent barrier against acid, pepsin, and bile acid penetration, permitting healing to occur (Toxnet[online]).
Sucralfate may decrease the rate of gastric emptying.
Sucralfate may have some cytoprotective effects, possibly by stimulation of prostaglandin E2 and I2.
3. Regulation
Norway (^) Maximum allowed concentration: 2% (skin care products only)^5.
EU No regulation
Rest of the world No regulation
(^4) An ulcer is a sore on the skin or a mucous membrane, accompanied by the disintegration of tissue. Ulcers can
result in complete loss of the epidermis and often portions of the dermis and even subcutaneous fat. Ulcers are (^5) Cf. National Norwegian cosmetics regulation to be lifted 11 July 2013
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4. Relevant toxicity studies
Absorption Skin
GI tractus
Studies on dermal absorption of sucralfate are missing.
It has been reported that significantly burned patients using a 7% sucralfate cream to their skin twice daily did not show detectable serum Al levels in their blood samples (Banati et al. 2001; Burkhart et al., 2009).
Sucralfate is only minimally absorbed from the gastrointestinal tract upon oral intake. Most of the small amounts absorbed - up to 2.2% of a dose in one study using healthy males - are excreted primarily in the urine as intact sulphated disaccharide ((Giesing et al., 1982;Banati et al., 2001; Allain et al., 1990;DrugSafety.com [online]). In rats only 3-5% of an oral dose of 14 C-labelled sucralfate was absorbed during a period of 96 hours (Toxnet [online]; Legemiddelverket[online]). In six volunteer persons, the excretion of labelled sucralfate into urine was 0.5 - 2.2% over a period of four days (Legemiddelverket[online]).
Allain et al. (1990) measured the plasma and urine Al concentrations in healthy subjects after oral administration of sucralfate (a total dose of 4 g/day for 21 days). A small but significant increase in plasma Al concentration and a somewhat greater increase in urinary Al excretion were found. On average, plasma Al increased from about 2 μg/l to more than 5 μg/l, and 24h urine Al increased from less than 5 μg to more than 30 μg. The urinary Al remained higher than normal 5 and 10 days after terminating sucralfate administration. The increases were presumed to reflect gastrointestinal absorption of Al. The results with sucralfate were similar to Al phosphate, another salt that is poorly absorbed from the gastrointestinal tract.
Although studies in normal subjects showed no increases in plasma Al during ingestion of sucralfate (Kinoshita et al., 1982), it has been argued that plasma Al levels are poor indices of Al absorption in normal subjects; i.e. analysis of the levels of aluminum in the urine is much more sensitive than in the blood to determine how much aluminum has been absorbed (Milliner et al., 1984, cited in Robertson et al., 1989).
A case report and study data indicate that sucralfate is a source for Al absorption and can cause Al toxicity in a patient with end-stage renal failure, who was given sucralfate to treat gastritis (Robertson et al., 1989). Recurrent seizures and bone pain developed and the individual was diagnosed as having aluminum-related osteomalacia (softening of the bone with symptoms of weakness, pain, weight loss and bone fracture). A study revealed that the absorption of Al increases during treatment with sucralfate, as seen by an increase in Al in the urine but not in the blood. Also normal volunteers showed similar absorption of Al during ingestion of both sucralfate and Al hydroxide.
Thus, caution should be taken when patients with renal disease are treated with the non-antacid drug sucralfate for ulcers or gastritis; such treatment should be for only short periods of time.
See also: Sucralfate – solubility and absorption (Annex 4).
Distribution Distribution of sucralfate into human body tissues and fluids after systemic absorption has not been determined (Legemiddelverket[online]).
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Repeated dose Mutagenicity /genotoxicity
Carcinogenicity
Reprotoxicity / teratogenicy
Other effects
Mutagenicity studies have not been conducted with sucralfate to date (Toxnet [online]).
Sucralfate has no known carcinogenic risks, as reported in a survey reviewing carcinogenicity in animals and humans of 535 marketed pharmaceuticals. For long-term carcinogenesis assay in mice, results were negative at a dose of 1g/kg/day. (x0.7, in the table of the original publication, denotes the ratio [high animal dose (mg/m^2 )/maximum recommended human dose (mg/m^2 )].) (Brambilla et al., 2012).
Chronic toxicity studies in mice and rats at (oral) doses up to 1 g/kg ( times the usual human dose^7 ) over 24 months showed no evidence of drug-related tumorigenicity.
There is no evidence that sucralfate represents a risk to the fetuses of pregnant women with normal renal function at recommended use levels; i.e. developmental and/or reproductive toxicity, or neurotoxicity; cf. “Sucralfate in Pregnancy and Breastfeeding” (Drugsafety.com[online]).
Teratogenicity studies have been performed in mice, rats, and rabbits at doses up to 50 times (50 * 83 mg = 4150 mg?) the human dose and have revealed no evidence of harm to the fetus due to sucralfate (Toxnet [online]).
In rats, dosages up to 38 times those used in humans caused no impaired fertility Drugsafety.com[online].
Adverse effects related to the Al content of sucralfate The potential foetal toxicity of sucralfate relates to its Al content (AFSSAPS, 2011; JECFA, 2012; VKM, 2013). S ucralfate is a source of bioavailable Al - each 1 g (tablet) of sucralfate contains 207 mg of Al.
JECFA found one study of rats exposed to Al-citrate (one of the more soluble Al compounds) in the drinking water, with reported adverse effects on development and neurotoxicity (JECFA, 2012). Based on the NOAEL of 30 mg/kg bw/day, and applying an uncertainty factor of 100 for inter- and intraspecies variation, a new PTWI of 2 mg/kg bw/week was established, with relevance to all Al compounds in food, including additives (VKM, 2013). For conversion into systemic dose, cf. section 6.
Osteomalacia and encephalopathy : Dialysis patients - impaired renal function: Aluminium is retained by individuals with impaired kidney function, which can lead to osteomalacia (softening of the bone with symptoms of weakness, pain, weight loss and bone fracture) and encephalopathy (an abnormal condition of the structure or function of the tissues of the brain).
Other groups with reduced renal function: Kidney function declines with age. Therefore, elderly people may be at greater risk for developing high Al levels while using sucralfate with other products that contain Al (e.g., antacids).
Premature infants fed by parenteral route may experience increased susceptibility to adverse effects related to chronic high exposure of Al. Commercially available fluids for parenteral nutrition (intravenous
(^7) Human dose: 1/12 of 1000 mg = 83 mg/kg; for a 60 kg person: 83 mg/kg * 60 kg = 5000 mg.
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feeding) used to contain high levels of Al, and should be regulated (AFSSAPS [online]).
5. Exposure estimate and critical NOAEL / NOEL
NOAEL/NOEL critical A NOAEL value for sucralfate in humans has not been established.
Exposure cosmetic products Margin of Safety (MoS) Not estimated for sucralfate - because NOAEL is not available
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remove Al from the body increases the risk of Al toxicity, with more or less subtle signs and symptoms (e.g. weak bones, muscle and bone pain, confusion or other mental changes) that develop over a long period of time. Other sources
Adverse side effects - from uses other than cosmetics
Although Al is implicated in the etiology of Alzheimer and other neuro- degenerative diseases, it has not been established that Al is the cause of dementia. EFSA does not consider exposure to Al via food to constitute a risk for developing Alzheimer’s disease (EFSA, 2011). EFSA also finds no evidence that Al is a human carcinogen at dietary relevant doses.
Sucralfate is well tolerated, with few adverse effects reported. Constipation is the most frequent adverse effect, occurring in approximately 2% of patients (Toxnet [online]; Rx list[online]).
In rare reports describing sucralfate overdose, most patients remained asymptomatic. Adverse effects reported in less than 0.5% of patients include diarrhea, nausea/vomiting, gastric discomfort, indigestion, flatulence, dry mouth, rash, pruritus, headache, dizziness, back pain, drowsiness, and vertigo, which rarely require discontinuation of sucralfate. (Drugs.com [online]; Rx list [online]).
There have been reports of hypersensitivity reactions to sucralfate. These include urticaria (hives), angioedema, respiratory difficulty and rhinitis. A causal relationship has not yet been established (Parkinson[online]).
Sucralfate is used in the management of peptic ulcer. At pH < 4, extensive polymerization occurs and a sticky viscid gel is formed. The French System of Pharmacovigilance has issued advise that caution for adults in intensive care unit being fed by nasogastric tube; sucralfate is contraindicated in premature babies and dysmature newborn babies receiving sucralfate (Guy & Ollagnier, 1999).
Bezoars^8 have been reported in patients treated with sucralfate (Rx list[online]). The majority of patients had underlying medical conditions that may predispose to bezoar formation (such as delayed gastric emptying) or were receiving concomitant enteral tube feedings.
Interactions : Effects on GI absorption of drugs Sucralfate may bind to a number of drugs in the GI tract, e.g. warfarin and possibly other oral anticoagulants, thereby reducing the extent of absorption (Drugs.com[online]; Legemiddelsiden.no[online]). Sucralfate is known to reduce absorption of tetracycline and phenytoin. Because of the potential of sucralfate to alter the absorption of some drugs, sucralfate should be administered separately from other drugs. Instruct patients to administer other drugs at least 2 hours before sucralfate and monitor patients appropriately if alteration in bioavailability of the other drug(s) is critical.
(^8) http://www.rxlist.com/script/main/art.asp?articlekey=
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7. Assessment
General toxicity :
Sucralfate is a non-antacid that is commonly used to treat peptic ulcers and gastritis, but has recently been used as a topical drug for the healing of several types of epithelial wounds such as ulcers, inflammatory dermatitis, mucositis and burn wounds (Masuelli et al., 2010). In cosmetics, sucralfate is used as a skin conditioning agent.
Sucralfate mainly serves as a “Band-aid®”, by forming an adherent coating at low pH. Thus, the action of sucralfate is local rather than systemic as the drug is only minimally absorbed from the gastrointestinal tract. The minute amounts absorbed are primarily excreted in the urine. At higher pH sucralfate may remain in suspension and improve the gastric environment by adsorbing pepsin, buffering hydrogen ions, increasing bicarbonate secretion etc. However, sucralfate does not affect gastric acid output or enzyme activity (i.e. is not an antacid).
Oral ingestion of sucralfate is well tolerated, with few adverse effects reported. Constipation is the most frequent adverse effect, occurring in approx. 2% of patients. There have been (case) reports of hypersensitivity reactions to oral sucralfate, which include urticaria (hives), angioedema, respiratory difficulty and rhinitis. A causal relationship has not yet been established.
There is no evidence that recommended use levels of sucralfate represent a risk to healthy people. However, sucralfate should be avoided in patients with chronic renal failure, because of increased risk of Al toxicity, including osteomalacia and encephalopathy. Sucralfate is not for use in children and its safety for nursing mothers is uncertain due to lack of safety data.
Chemically, sucralfate is a sucrose sulfate complex containing 21% of Al, and potential adverse effects are most likely related to its Al content.
Cosmetics : In cosmetics, sucralfate is used as a skin conditioning agent, especially to help the care of cracked, chapped and peeling lips as well as chapped or cracked hands.
Topically applied sucralfate appears not to be of systemic safety concerns. There have been reports of hypersensitivity reactions to oral sucralfate. These include urticaria (hives), angioedema, respiratory difficulty and rhinitis.
However, potential adverse effects of sucralfate are most likely related to its Al content (21% of Al); i.e. a 2% sucralfate cream (the maximum level according to the current Norwegian regulation) contains 0.42% (2 x 0.21) Al. The risk assessment is based on Al derived from sucralfate takes into account both low and high exposure scenarios in people with normal intact skin and damaged (cracked) skin, respectively. The calculations are shortly outlined and summarized in the table below. For detailed calculations – see Annex 6.
Estimation of systemic aluminium exposure (based on 2% sucralfate cream, containing 21% Al)
Systemic exposure dose (SED) of Al (derived from sucralfate) was calculated according to SCCS's guidelines (SCCS[online], SCCS/1358/10).
Equation: SED = A(mg/kg bw/day) x C(%) x DAp(%), where A = estimated daily exposure; C = concentration of substance, and DAp = dermal absorption.
Two scenarios: low exposure (A), high exposure (B) A. Low exposure (intact skin) : SED, hands (low): 32.70 x (0.02 x 0.21) x 0.00005 = 0.000006867 mg/kg bw/day
Total weekly intake = 0.000007812 mg/kg bw/day x 7 = **0.00 00 55 mg/kg bw/week of Al
0.05 μg/kg bw/week (Dap 1 )**
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Total systemic exposure from cosmetics and food:
Comments:
Normal (intact) skin: The estimated total systemic exposure (SED) of Al from intake of food and cosmetics (hand cream / lipstick) containing 2% sucralfate is 0.34 – 1.50 μg/kg bw/week (adults). This is below the PTWI of 2 μg/kg bw/week established by JECFA (2012).
Damaged (cracked) skin: The estimated total systemic exposure of Al from food and cosmetics containing 2% sucralfate is 1.28 – 17.5 μg/kg bw/week.
Additional contribution from lipstick / lip gloss containing Al (VKM, 2013): VKM estimated SED of 0.22 and 4.3 μg Al /kg bw/week for persons using lipstick/lip gloss daily (other sources than sucralfate), referring to two scenarios with intact and damaged skin, respectively (VKM, 2013).
Additional contribution from lipstick / lip gloss + antiperspirants containing Al (VKM, 2013) When including both the use of lipstick/lip gloss + antiperspirants (for adults), SED values of 31 and 601 μg Al/kg bw/week were estimated for the standard and worst case scenarios, respectively.
Medicinal agents: Estimated Al load is between 8 (0.13 μg/kg bw/day x7 = 1.04 μg/kg bw/week) and 136 μg (2.27 μg/kg bw/day x7 =15.9 μg/kg bw/week) following a 4 g daily oral dose of sucralfate (Aptalispharma.com[online]). (Recommended daily dosage is 2 g for prophylactic use).
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8. Conclusion
Maximum allowed concentration (skin care products only): Lipstick /lip pomade /lip balm: 2% sucralfate Hand cream: 2% sucralfate (intact skin)
Remarks/Warnings : Not to be used on damaged skin. Sucralfate should be avoided in patients with chronic renal failure, because of increased risk of Al toxicity, including osteomalacia and encephalopathy. Sucralfate is not for use in children and its safety for nursing mothers is uncertain due to lack of safety data.
Other comments : For persons with normal intact skin, the estimated total systemic exposure dose of Al from food and cosmetic products containing 2% sucralfate (i.e. hand cream + lipstick) is in the range of 0.34 to 1. μg/kg bw/week , which is below the PTWI of 2 μg/kg bw/week.
Total SED from food and cosmetics, excluding antiperspirants: SED values of 0.22 and 4.3 μg Al/kg bw/week have been estimated for lipstick /lip gloss, i.e. scenarios with intact and damaged skin, respectively (VKM, 2013).
Thus, a total SED of 0.56 (0.34 + 0.22) to 1.72 (1.50 + 0.22) μg/kg bw/week was estimated for systemic exposure of Al from food + cosmetics (with 2% sucralfate) + cosmetics (Al from other sources than sucralfate) in persons with intact skin/lips. This range is still below the PTWI of 2 μg/kg bw/week.
Use of lipstick with 2% sucralfate for cracked lips results in SED in the range of 0.027 to 0.45 μg/kg bw/week (see table above, section 7), i.e. total SED for food and cosmetic products (excluding antiperspirants) just below 2 μg/kg bw/week (= PTWI).
SED for antiperspirants: SED values of 31 and 601 μg Al/kg bw/week from antiperspirants (standard and worst case scenarios, respectively) greatly exceed PTWI (or TWI) alone, without contribution from other sources.
Thus, a recent VKM (2013) risk assessment of Al found that daily use of antiperspirants will substantially reduce the safety margin and may increase the risk of adverse effects, particularly for persons shaving/waxing their armpits often or having impaired skin caused by skin conditions such as eczema. For this scenario the exceedance of TWI/PTWI was 300-940 fold (VKM, 2013).
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Masuelli L, Tumino G, Turriziani M, Modesti A, Bei R (2010) Topical use of sucralfate in epithelial wound healing: clinical evidences and molecular mechanisms of action. Recent Pat Inflamm Allergy Drug Discov. 4(1):25-36. Review.
Pineau A, Guillard O, Fauconneau B, Favreau F, Marty MH, Gaudin A, Vincent CM, Marrauld A, Marty JP (2012) In vitro study of percutaneous absorption of aluminum from antiperspirants through human skin in the Franz™ diffusion cell. J Inorg Biochem 110:21-26.
Richter JE (2005) Review article: the management of heartburn in pregnancy. Aliment Pharmacol Ther. 22(9):749-57.
Robertson JA, Salusky IB, Goodman WG, Norris KC, Coburn JW (1989). Sucralfate, Intestinal Aluminum Absorption, and Aluminum Toxicity in a Patient on Dialysis. Annals of Internal Medicine 111(2):179-181.
VKM (Vitenskapskomiteen for mattrygghet – Norwegian Scientific Committee for food safety) (2013) Risk assessment of the exposure to aluminium through food and the use of cosmetic products in the Norwegian population. Doc. no. 11-504_final (Date: 5.04.2013). ISBN: 978- 82 - 8259 - 088 - 4. Available at: http://www.vkm.no/dav/a729a67e65.pdf (accessed May 23, 2013).
Online:
AFSSAPS (Agence franaise de sécurité sanitaire des produits de santé) (2011). Risk assessment of Al in cosmetics. Available at: http://ansm.sante.fr/var/ansm_site/storage/original/application/ad548a50ee74cc320c788ce8d11ba .pdf (accessed Oct 26, 2012). Translated summary, see Annex 5.
Aptalispharma.com. Sucralfate monograph. Available at: http://www.aptalispharma.com/pdf/Sulcrate- En.pdf (accessed May 14, 2012).
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Legelmiddelsiden.no. Antepsin (= sucralfate). Available at: http://www.legemiddelsiden.no/default.aspx?PageID=179&IOID=62 (accessed May 14, 2013).
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Masuelli L, Tumino G, Turriziani M, Modesti A, Bei R. Topical Use of Sucralfate in Epithelial Wound Healing: Clinical Evidence and Molecular Mechanisms of Action. pp.25-36 (12)
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Rx list. Carafate (i.e. sucralfate). Available at: http://www.rxlist.com/carafate-drug/side-effects- interactions.htm (accessed May 14, 2013)
SCCS (Scientific Committee on Consumer Safety) notes of guidance for the testing of cosmetic ingredients and their safety evaluation (8th revision). Available at: http://ec.europa.eu/health/scientific_committees/consumer_safety/docs/sccs_s_006.pdf (accessed May 03, 2013).
SCCS/1358/10: Basic criteria for the in vitro assessment of dermal absorption of cosmetic ingredients, adopted by the Scientific Committee on Consumer Safety (SCCS) during the 7th plenary meeting on 22 June 2010.
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Annex 2:
Acute toxicity (Toxnet [online])
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Annex 3: Side effects – oral intake sucralfate
http://www.ehealthme.com/print/ds14421663 (accessed May 13, 2013)
