- Research article
- Open Access
Toxicology and teratology of the active ingredients of professional therapy MuscleCare products during pregnancy and lactation: a systematic review
BMC Complementary and Alternative Medicine volume 15, Article number: 40 (2015)
The rates of muscle aches, sprains, and inflammation are significantly increased during pregnancy. However, women are afraid to use systemic analgesics due to perceptions of fetal risks. Thus, topical products are important alternatives to consider for those women. Of interest, Professional Therapy MuscleCare (PTMC) has shown to be effective in alleviating the myofascial pain as reported in a randomized, placebo-controlled double-blinded comparative clinical study of five topical analgesics. However, to date, there is no complete review or long-term safety studies on the safety of these products during pregnancy and lactation. Thus, the aim of this article was to review toxicological, developmental, and reproductive effects associated with the use of PTMC products.
We performed a systematic review on safety of PTMC from all toxicological articles investigating the effects of PTMC’s ingredients. This search was conducted through medical and toxicological databases including, Web of Science, EMBASE, Medline, and Micromedix. Both reported and theoretical adverse effects were extensively reviewed.
Of the 1500 publications reviewed, 100 papers were retrieved and included in the review. Although some ingredients in PTMC products might cause adverse reproductive effects at high systemic doses, these doses are hundreds to thousands fold greater than those systemically available from topical use at the recommended maximum dose (i.e. 10 g/day).
This study provides evidence that, when used as indicated, PTMC is apparently safe for pregnant women and their unborn babies as well as for breastfed infants.
The rates of muscle aches, sprains, and inflammation are significantly increased during pregnancy, often resulting in lower back and neck pain . These pain symptoms tend to increase as pregnancy advances through the first, second, and third trimesters [1-4]. It has been estimated that approximately two-thirds of pregnant women in the United States experience lower back pain, and more than 50% of them receive little or no treatment from their physicians [4,5]. This could be attributed to the fears of fetal risks associated with the use of systemically administered agents such as non-steroidal anti-inflammatory drugs. Therefore, the use of topical analgesics seems attractive for women afraid of adverse effects of oral medications.
Among topical analgesics, the Professional Therapy MuscleCare (PTMC) has been shown to be effective in alleviating muscle pain in a randomized, placebo-controlled double-blind study of five topical analgesics . The line of PTMC products includes an ointment and Roll-on gel containing ingredients that are topically applied to alleviate the pain caused by inflammation, muscle strain/spasm, and arthritis during pregnancy. To date, the safety of PTMC ingredients during pregnancy and lactation has not been reviewed. Thus, the aim of the current article was to review the available evidence related to fetal safety of PTMC ingredients and to create an evidence-based framework for PTMC use during pregnancy and lactation.
Physiological changes during pregnancy and the need for topical analgesics
Pregnancy is associated with continuous physiological changes that lead to higher rates of lower back and neck pains [2-4,7,8]. These changes include weight gain, hormonal changes, and muscle separation in the area of the sacroiliac joint. While the hormone relaxin usually relaxes ligaments in the pelvic area allowing the birth process to take place , this hormone also relaxes ligaments supporting the spine, often leading to severe pain during pregnancy. This situation is exacerbated by separation of muscles secondary to the increased size of the uterine. The emotional stress might also contribute to back spasms in pregnancy . Pain increases as a result of weight gain burdening the muscles from the neck down, often leading to stiffness. Taking into consideration the large number of pregnant women refusing the use of systemic analgesics, there is an urgent need to evaluate the safety of topical analgesics such as PTMC [4,5].
Route of exposure and topical use of PTMC
In this article, we retrieved all existing toxicological information regarding PTMC ingredients in the context of the concentrations of each ingredient within these products. Where available, an attempt has been made to focus on studies employing topical rather than oral exposure, and to highlight studies carried out on humans rather than animals or in vitro cell culture models. However, since PTMC products have not been directly studied in vitro or in vivo, their toxicities need to be extrapolated from studies examining PTMC’s ingredients either alone or in studies using similar ingredients to those found in PTMC products. It is important to bear in mind that compounds in similar creams may be presented at different ratios, which might influence the properties of these products. Thus, when examining each ingredient, it is important to remember that these ingredients were invariably studied at different concentrations in animal studies and, thus, extrapolation of data from other creams to PTMC must be done cautiously. Taking into consideration that the principal source of human exposure to PTMC products is through the skin, these products are strictly intended for external use at recommended maximal dose of 10 g/day. Table 1 summarizes the amounts received by a 70 kg person applying 10 g of PTMC.
A professional librarian with expertise in the areas of systematic reviews carried out literature searches using Web of Science, EMBASE, Medline, and Micromedix. The terms used in systematic search were the names of PTMC ingredients and “reproductive effect” with no language restrictions. Studies were selected based reporting toxicological, developmental, and reproductive effects of PTMC ingredients. We excluded all studies that did not mention safety of these ingredients. Of the 1500 publications reviewed, 100 papers were retrieved and included in the review (Figure 1 Study flowchart).
Results and discussion
Toxicological, developmental, and reproductive effects of PTMC
The PTMC ingredients are mainly classified as anti-inflammatory, analgesics, circulation enhancers, or tissue repair ingredients (Tables 2 and 3). These ingredients were reviewed with respect to general, developmental, and reproductive adverse effects reported in human and/or animal studies (Table 4 summarizes these adverse effects of ingredients of PTMC).
Dimethyl sulfone (Methylsulfonylmethane or MSM)
Several studies showed no adverse reactions when a cream containing dimethyl Sulfone (MSM) was applied topically on a daily basis over four weeks . Treatment of interstitial cystitis with MSM revealed a low rate of adverse effects . Similarly, adverse drug reactions were minimal in a study that evaluated the efficacy of MSM in reduction of symptoms associated with allergic rhinitis . In this study, 15 males and 35 females between the ages of 21 and 60 received 2.6 g of MSM once daily for 30 days and a subset of subjects further received 5.2 g for additional 14 days. Although the recommended dose for dietary supplementation of MSM is 1 to 6 g/day, there are no peer-reviewed studies on its long-term use in humans. MSM was reported to cause low oral toxicity in rats (LD50 was greater than 17 g/kg). A dose of 2 g/kg or long-term administration (1.5 g/kg for 90 days) did not cause adverse events in rats . Although some studies reported that MSM can cross the placenta resulting in higher concentrations in the fetal plasma , to date, there have been no human data on adverse reproductive effects. Oral administration of MSM to pregnant rats at doses of 50 to 1000 mg/kg/day during organogenesis did not induce fetal anomalies. These studies concluded that No Observed Adverse Effect Level (NOAEL) for maternal and developmental toxicity is 1 g/kg/day [15,16].
Poisoning cases after topical use of camphor have been reviewed for adults and children between 1990 and 2003 : 1) A 15-month-old boy who crawled through spilled camphor spirits developed ataxia and generalized convulsions. 2) A 2-month-old girl developed elevated serum transaminase following application of Vicks VapoRub to her chest and neck (4.8% camphor, 3 times a day for 5 days). 3) A 25-month-old boy developed delirium, visual hallucinations, and urinary incontinence after his chest was “soaked” in more than 1 ounce of camphorated oil for 80 hours (6.4 g of camphor). 4) A 9-month-old girl with 20% body surface area burns was treated with a dressing containing 9.6% camphor for 24 hours (estimated exposure to 15 g camphor) and developed severe toxicity including convulsions. 5) A 72-year-old woman developed granulomatous hepatitis following dermal application of five containers of Vicks VapoRub Ointment. After discontinuation of the use, these problems were resolved.
Of importance, several studies have shown that camphor has a low absorption rate (less than 0.1%) from medicated patches containing 46.8 mg camphor in conjunction with 37.4 mg menthol and 74.88 mg methyl salicylate . Orally, the exposure of children (ages of 14 months - 5 years old) to 0.7-1.5 g of camphor was associated with fatal symptoms . Another study has examined the administration of camphor to 80 postpartum women who were injected 195 mg camphor in the first day followed by daily injections of 97 mg over 3 days. In this study, only one patient developed adverse events (nausea and vomiting) . Thus, the US FDA has set a limit of 11% camphor in different products, as ingestion of larger quantities may cause adverse effects such as seizures, confusion, irritability and neuromuscular hyperactivity. The LD50 in mice is 1.3 g/kg.
With respect to reproductive effects, studies showed that camphor can cross the human placenta when ingested orally . Topically, the frequency of birth defects was not greater than baseline among 168 pregnancies where camphor was used in the first trimester as well as among 763 women who used camphor anytime during pregnancy . There was no increase in the incidence of congenital abnormalities when camphor was used at high oral doses in pregnant rats and rabbits (100–1000 mg/kg/day and 50–681 mg/kg/day) [22-24]. Although few reports of camphor poisoning are available, to date, there are no reported adverse fetal effects [20,25-27]. It has been reported that women who used a suppository containing camphor during pregnancy had infants with an increased average birth weight and gestational age .
The FDA has approved methanol as a safe chemical for external use with concentrations up to 16% . Acute dermal toxicity was reported with LD50 of 5 g/kg in rabbits. Orally, the LD50 values were 2.9 g/kg and 3.1 g/kg in rat and mice, respectively. It has been reported that rats given menthol at 200 mg/kg/day for 28 days had increased liver weights and vacuolization of hepatocytes . With respect to reproductive effects, there has been no study examining menthol safety in humans. There were no teratogenic effects seen in the offspring of mice, rats, hamsters, or rabbits receiving doses ranging from 1 to 106 times the accepted daily intake in humans .
Wintergreen oil (Gaultheria procumbens/Methyl salicylate)
Although prolonged skin contact with methyl salicylate may cause dermatitis, methyl salicylate is generally safe in topical formulations . Local necrosis occurred in a 62-year-old man after 1 day use of Bengay (18.3% methyl salicylate and 16% menthol) . The Bengay was applied to the forearms and legs along with periodic heating of the area with a heat pad . There was evidence of tinnitus, diplopia, shortness of breath, mixed metabolic acidosis, and respiratory alkalosis . The lowest lethal oral dose of methyl salicylate was reported in women at 355 mg/kg, in men at 101 mg/kg, and in children at 228 mg/kg. Of importance, a teaspoon or less of wintergreen oil has been implicated in several deaths of children under the age of 6 years . It has been reported that dermal exposure to methyl salicylate was associated with LD50 of 2 g/kg . Both the rate and extent of absorption through the skin are dependent on the exposed area as determined in equine skin . The oral LD50 is 887 mg/kg in rats.
With respect to reproductive effects, administration of methyl salicylate (up to 0.5 mL) in rats during organogenesis increased the rate of abnormalities, particularly of the central nervous system. This dose represents 5 times the lethal adult human dose . It has been reported that pregnant hamsters treated orally or topically with 175 mg/100 g methyl salicylate exhibited central nervous system teratogenicity . However, there is no conclusive evidence that salicylate is teratogenic in humans . When methyl salicylate was given at doses of (200, 250, or 300 mg/kg/day), there was a reported alteration in renal pelvis and urine formation in rats . However, the topical application of methyl salicylate in petroleum-based grease did not cause congenital defects when used at doses up to 6000 mg/kg/day . High doses of methyl salicylate (such as 250 and 500 mg/kg/day) were reported to increase the litter size. However, these doses did not result in congenital abnormalities in mice. The lower doses (100 mg/kg/day) had no observable adverse reproductive effects . Importantly, the doses in these studies were significantly higher than the adult lethal human dose on mg/kg basis. The American Academy of Pediatrics recommended the use of salicylates with caution during breastfeeding .
It has been shown that topical application of a cream containing 0.3% glucosamine sulfate did not cause adverse effects . In large clinical trials, oral glucosamine reduced progression of knee osteoarthritis and prevented joint space narrowing [44,45]. Although glucosamine is widely used in veterinary medicine , no teratogenic effects were reported in mice or rabbits. In a prospective controlled study of 34 pregnant women exposed to glucosamine during the first trimester, there was no increase in risk of major malformations .
Sodium chondroitin sulfate
Several studies failed to report significant adverse events with topical use of a cream containing 0.78% chondroitin sulfate . The use of chondroitin in combination with glucosamine is effective in treatment of knee pain since chondroitin enhances the pain-relieving action of glucosamine [48-50]. It has been reported that chondroitin and glucosamine sulfate attenuate progression of osteoarthritis . Orally, the LD50 was greater than 10 g/kg in mice. However, mice injected with 1 mL of 2% chondroitin on day 9, 10, or 11 of gestation exhibited an increased rate of cleft palate and tail abnormalities in the offspring . To date, there has been no human study on the effects of chondroitin sulfate during pregnancy and lactation.
Eucalyptus leaf oil (Eucalyptus globulus/1, 8-cineole)
Eucalyptus leaf oil is widely used in mouthwashes and cough suppressants. However, to date, there have been no reported deaths caused by topical use of eucalyptus oil. There was only a report of fever and seizure-like motor activity in a 2-year-old boy rubbed with eucalyptus oil . A 6-year-old who was exposed to eucalyptus oil exhibited slurred speech, ataxia, and muscle weakness . There were minor adverse effects in two 76-year-old patients ingesting 600 mg of eucalyptus daily for 7 days . Orally, the LD50 was 2.5 g/kg in rats. There has been no adverse outcome in mice injected on days 6 and 15 of gestation . Also, there has been no evidence of adverse reproductive effects of eucalyptus oil in humans.
Grape seed oil (Vitis vinifera)
Procyanidin B-2, a component of Grape Seed Extract, was found to be safe for topical use based on mutagenic and ocular irritation assays . The proanthocyanidin extract is regarded safe for consumption at 1.4 g/kg/day . There are no safety issues identified in acute and chronic studies of oral and dermal exposure to the proanthocyanidin extract in animal studies . The grape seed extract was also non-mutagenic in mice . Several reports showed that the LD50 for dermal application is greater than 2 g/kg in rats . With subcutaneous injection, the lethal dose of procyanidin B-2 was greater than 2 g/kg . However, to date, there have been no human data on the reproductive effects of grape seed oil.
Vitamin E (Alpha-Tocopherol acetate)
Vitamin E is safe for topical use in different creams aiming to protect the skin against ultraviolet rays . There have been four randomized double-blinded trials involving 566 women at risk of pre-eclampsia who received high doses of vitamin E in the second and third trimesters of pregnancy. In these trials, there was no difference between women exposed to high doses vitamin E and women exposed to placebo in terms of risk for stillbirth, perinatal death, preterm birth, growth restriction, or birth weight [62-65]. Similarly, among 82 infants born to women who received high doses of vitamin E (400 mg/day), there was no increase in malformations or miscarriages [62-65]. Only one infant was born with omphalocele . The frequency of malformations was not increased in the offspring of rats and mice treated with vitamin E at doses hundreds to thousands times of the human doses [67-71].
Thymol is considered safe in topical formulations at a concentration of 0.5% . However, thymol was toxic to mucous membranes as well as to the kidneys, liver, and central nervous system . The oral LD50 was 980 mg/kg in rats, 640 mg/kg in mice, and 880 mg/kg in guinea pigs. Thymol was not associated with increased incidence of birth defects based on 52 pregnancies exposed in the first trimester of pregnancy . Although thymol was used previously as part of an abortifacient paste to induce the abortion [73-75], only one fatality was reported with the paste use .
Sea cucumber extract (SCE)
It has been reported that topical exposure of gingival tissue to sea cucumber extract (SCE) over three months was safe . Also, the use of SCE as an oral daily supplement for six months was not associated with any adverse effects. Although SCE has been shown to have potent anti-tumor effects in vitro [78-81], to date, there has been no evidence on safety of SCE during pregnancy and lactation.
Aloe Barbadensis leaf juice
Aloe is considered safe in topical formulations since hypersensitivity reaction is relatively rare . Although the aloe is used in adults, it is not recommended for children under age of 12 years . The aloe is used orally to relieve constipation and adverse effects were reported only in rare cases . A 56-year-old woman developed hypothyroidism after high doses of aloe taken for 11 months . The thyroid function tests had normalized 16 months after discontinuation of treatment . Another 73-year-old woman developed acute hepatitis after ingesting aloe powder every 2 to 3 days for 5 years . The liver function tests and biopsies were consistent with findings of drug-induced acute hepatitis and completely resolved after discontinuation of aloe use . Similarly, a 24-year-old male developed acute drug-induced hepatitis after 3 weeks of daily use of oral aloe extract where the clinical symptoms resolved 7 days after the aloe was discontinued . Thus, aloe is not recommended orally during pregnancy and/or lactation . Teratogenic effects have been reported when aloe was given at high oral doses to rats . However, there is no contraindication for topical use during pregnancy and/or lactation.
Peppermint oil is commonly used and may cause skin irritation due to the presence of menthone . There are no specific therapeutic or toxic dose rages for oral use. The enteric-coated capsules of the oil have been used to treat irritable bowel syndrome at doses of 0.2 to 0.4 mL three times daily without adverse events [90,91]. Also, the average daily dose of 6 to 8 drops of the oil caused no adverse effects . According to the world health organization (WHO), peppermint oil is considered a safe additive at doses up to 4 mg/kg. The oral LD50 is 2490 mg/kg in mice and 2426 mg/kg in rats. The peppermint oil has also been used to induce menstruation and it is not recommended at high oral doses during pregnancy . Although there is insufficient evidence on safety of the oil during lactation, it has been suggested that amount of the oil in OTC products is likely to be safe for breastfed infants .
Boswellia and ilex
Boswellia is frequently used in topical formulations to treat osteoarthritis. However, dermatitis was reported in 4 of 62 patients who used topical preparations containing boswellia [92,93]. The boswellia is recommended for oral use at 400 mg three times daily for arthritis and 300 mg three times daily for asthma [94,95]. The common oral adverse effects are nausea, abdominal fullness, and epigastric pain . Both acute and chronic toxicity studies were conducted in mice, rats, and monkeys. In these studies there was no mortality in rats and mice that received doses up to 2 g/kg. Similarly, there were no changes in behavior, clinical, biochemical, or pathological data with oral daily use of boswellia in rats and monkeys . With respect to reproductive effects, there is insufficient evidence on safety of boswellia during pregnancy and lactation. Similar to boswellia, there is insufficient scientific evidence on safety of ilex during pregnancy and lactation.
Magnesium (Magnesium chloride)
Magnesium is commonly used in topical preparations as well as a dietary supplement in doses raging from 54 to 483 mg/day . It is often used to treat hypomagnesemia intravenously as 4 g in 250 mL D5W and up to a maximum rate of 3 mL/min . However, magnesium chloride is not recommended for oral ingestion in patients with renal impairment . The FDA has listed magnesium chloride as pregnancy category A, which means “Adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of a risk in later trimesters)” .
Synthesis of findings and conclusions
Pregnant women frequently hesitate to use systemic analgesics for treatment of pregnancy-related pain due to strong perception of teratogenic risks. Among the available topical analgesics, PTMC products are used to alleviate muscle and joint pains. Although some active ingredients in PTMC are relatively toxins when used orally at high doses, these doses are thousands of times larger than those available systemically after topical use at the recommended maximum dose (i.e. 10 g/day). Thus, this review provides evidence that, when used as indicated, PTMC is apparently safe for pregnant women and their unborn babies as well as for lactating women.
Professional therapy MuscleCare
Sea cucumber extract
Unite state food and drug administration
Over the counter
Lethal dose required to kill 50% of the animals
Foti T, Davids JR, Bagley A. A biomechanical analysis of gait during pregnancy. J Bone Joint Surg Am. 2000;82(5):625–32.
Kalus SM, Kornman LH, Quinlivan JA. Managing back pain in pregnancy using a support garment: a randomised trial. BJOG. 2008;115(1):68–75.
Mogren I. Perceived health, sick leave, psychosocial situation, and sexual life in women with low-back pain and pelvic pain during pregnancy. Acta Obstet Gynecol Scand. 2006;85(6):647–56.
Skaggs CD, Prather H, Gross G, George JW, Thompson PA, Nelson DM. Back and pelvic pain in an underserved United States pregnant population: a preliminary descriptive survey. J Manipulative Physiol Ther. 2007;30(2):130–4.
Greenwood CJ, Stainton MC. Back pain/discomfort in pregnancy: invisible and forgotten. J Perinat Educ. 2001;10(1):1–12.
Avrahami D, Hammond A, Higgins C, Vernon H. A randomized, placebo-controlled double-blinded comparative clinical study of five over-the-counter non-pharmacological topical analgesics for myofascial pain: single session findings. Chiropr Man Therap. 2012;20:7.
Vermani E, Mittal R, Weeks A. Pelvic girdle pain and low back pain in pregnancy: a review. Pain Pract. 2010;10(1):60–71.
Vleeming A, Albert HB, Ostgaard HC, Sturesson B, Stuge B. European guidelines for the diagnosis and treatment of pelvic girdle pain. Eur Spine J. 2008;17(6):794–819.
MacLennan AH, Nicolson R, Green RC, Bath M. Serum relaxin and pelvic pain of pregnancy. Lancet. 1986;2(8501):243–5.
Cardwell MS. Stress: pregnancy considerations. Obstet Gynecol Surv. 2013;68(2):119–29.
Childs SJ. Dimethyl sulfone (DMSO2) in the treatment of interstitial cystitis. Urol Clin North Am. 1994;21(1):85–8.
Barrager E, Veltmann Jr JR, Schauss AG, Schiller RN. A multicentered, open-label trial on the safety and efficacy of methylsulfonylmethane in the treatment of seasonal allergic rhinitis. J Altern Complement Med. 2002;8(2):167–73.
Horvath K, Noker PE, Somfai-Relle S, Glavits R, Financsek I, Schauss AG. Toxicity of methylsulfonylmethane in rats. Food Chem Toxicol. 2002;40(10):1459–62.
Garrettson LK, Procknal JA, Levy G. Fetal acquisition and neonatal elimination of a large amount of salicylate. Study of a neonate whose mother regularly took therapeutic doses of aspirin during pregnancy. Clin Pharmacol Ther. 1975;17(1):98–103.
Magnuson BA, Appleton J, Ryan B, Matulka RA. Oral developmental toxicity study of methylsulfonylmethane in rats. Food Chem Toxicol. 2007;45(6):977–84.
Magnuson BA, Appleton J, Ames GB. Pharmacokinetics and distribution of [35S]methylsulfonylmethane following oral administration to rats. J Agric Food Chem. 2007;55(3):1033–8.
Manoguerra AS, Erdman AR, Wax PM, Nelson LS, Caravati EM, Cobaugh DJ, et al. Camphor poisoning: an evidence-based practice guideline for out-of-hospital management. Clin Toxicol (Phila). 2006;44(4):357–70.
Martin D, Valdez J, Boren J, Mayersohn M. Dermal absorption of camphor, menthol, and methyl salicylate in humans. J Clin Pharmacol. 2004;44(10):1151–7.
Love JN, Sammon M, Smereck J. Are one or two dangerous? Camphor exposure in toddlers. J Emerg Med. 2004;27(1):49–54.
Weiss J, Catalano P. Camphorated oil intoxication during pregnancy. Pediatrics. 1973;52(5):713–4.
Heinonen OP, Slone D, Shapiro S. Birth defects and drugs in pregnancy. Littleton, Mass: Publishing Sciences Group Inc; 1977.
Leuschner J. Reproductive toxicity studies of D-camphor in rats and rabbits. Drug Res. 1997;47(2):124–8.
NTP (National Toxicology Program). Developmental toxicity evaluation of d-camphor (CAS No. 464-49-3) administered by gavage to Sprague-Dawley (CD®) rats on gestational days 6 through 15. Abstract for TER91018. 1992. Final study report and appendix. http://ntp.niehs.nih.gov/testing/types/dev/abstracts/pages/ter91018/index.html. Accessed on 21 Sept 2014.
NTP (National Toxicology Program). Developmental toxicity evaluation of d-camphor (CAS No. 464-49-3) administered by gavage to New Zealand White (NZW) rabbits on gestational days 6 through 19. Abstract for TER91019. 1992. Final study report and appendix. http://ntp.niehs.nih.gov/testing/types/dev/abstracts/pages/ter91019/index.html. Accessed on 21 Sept 2014.
Blackmon WP, Curry HB. Camphor poisoning; report of case occurring during pregnancy. JFMA. 1957;43(10):999–1000.
Jacobziner H, Raybin HW. Camphor poisoning. Arch Pediatr Adolesc Med. 1962;79:28–30.
Riggs J, Hamilton R, Homel S, McCabe J. Camphorated oil intoxication in pregnancy; report of a case. Obstet Gynecol. 1965;25:255–8.
Czeizel AE, Toth M. Birth weight, gestational age and medications during pregnancy. Int J Gynaecol Obstet. 1998;60(3):245–9.
Patel T, Ishiuji Y, Yosipovitch G. Menthol: a refreshing look at this ancient compound. J Am Acad Dermatol. 2007;57(5):873–8.
Thorup I, Wurtzen G, Carstensen J, Olsen P. Short term toxicity study in rats dosed with pulegone and menthol. Toxicol Lett. 1983;19(3):207–10.
Food & Drug Research Labs Inc. Teratologic evaluation of FDA 71–57 (menthol natural Brazilian). 1973. http://www.inchem.org/documents/jecfa/jecmono/v042je04.htm. Accessed on 21 Sept 2014.
Cosmetic Ingredient Review Expert Panel. Safety assessment of Salicylic Acid, Butyloctyl Salicylate, Calcium Salicylate, C12-15 Alkyl Salicylate, Capryloyl Salicylic Acid, Hexyldodecyl Salicylate, Isocetyl Salicylate, Isodecyl Salicylate, Magnesium Salicylate, MEA-Salicylate, Ethylhexyl Salicylate, Potassium Salicylate, Methyl Salicylate, Myristyl Salicylate, Sodium Salicylate, TEA-Salicylate, and Tridecyl Salicylate. Int J Toxicol. 2003;22 Suppl 3:1–108.
Heng MC. Local necrosis and interstitial nephritis due to topical methyl salicylate and menthol. Cutis. 1987;39(5):442–4.
Davis JE. Are one or two dangerous? Methyl salicylate exposure in toddlers. J Emerg Med. 2007;32(1):63–9.
Mills PC, Cross SE. Regional differences in the in vitro penetration of methylsalicylate through equine skin. Vet J. 2007;173(1):57–61.
Warkany J, Takacs E. Experimental production of congenital malformations in rats by salicylate poisoning. Am J Pathol. 1959;35(2):315–31.
Overman DO, White JA. Comparative teratogenic effects of methyl salicylate applied orally or topically to hamsters. Teratology. 1983;28(3):421–6.
Briggs GG, Freeman RK, Yaffe SJMD. Drugs in pregnancy and lactation for PDA: a reference guide to fetal and neonatal risk. Baltimore, MD: Lippincott Williams & Wilkins; 2002.
Daston GP, Rehnberg BF, Carver B, Rogers EH, Kavlock RJ. Functional teratogens of the rat kidney. I. Colchicine, dinoseb, and methyl salicylate. Fundam Appl Toxicol. 1988;11(3):381–400.
Infurna R, Beyer B, Twitty L, Koehler G, Daughtrey W. Evaluation of the dermal absorption and teratogenic potential of methyl salicylate in a petroleum based grease (Abstract). Teratology. 1990;41:566.
Lamb J. Reproductive toxicology. Methyl salicylate. Environ Health Perspect. 1997;105 Suppl 1:323–4.
Morra P, Bartle WR, Walker SE, Lee SN, Bowles SK, Reeves RA. Serum concentrations of salicylic acid following topically applied salicylate derivatives. Ann Pharmacother. 1996;30(9):935–40.
Cohen M, Wolfe R, Mai T, Lewis D. A randomized, double blind, placebo controlled trial of a topical cream containing glucosamine sulfate, chondroitin sulfate, and camphor for osteoarthritis of the knee. J Rheumatol. 2003;30(3):523–8.
Pavelka K, Gatterova J, Olejarova M, Machacek S, Giacovelli G, Rovati LC. Glucosamine sulfate use and delay of progression of knee osteoarthritis: a 3-year, randomized, placebo-controlled, double-blind study. Arch Intern Med. 2002;162(18):2113–23.
Reginster JY, Deroisy R, Rovati LC, Lee RL, Lejeune E, Bruyere O, et al. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet. 2001;357(9252):251–6.
Nolen RS. Facing crackdown, dietary supplement companies promise changes. J Am Vet Med Assoc. 2002;221(4):479. –81, 83.
Sivojelezova A, Koren G, Einarson A. Glucosamine use in pregnancy: an evaluation of pregnancy outcome. J Womens Health (Larchmt). 2007;16(3):345–8.
Distler J, Anguelouch A. Evidence-based practice: review of clinical evidence on the efficacy of glucosamine and chondroitin in the treatment of osteoarthritis. J Am Acad Nurse Pract. 2006;18(10):487–93.
Das A, Hammad TA. Efficacy of a combination of FCHG49 glucosamine hydrochloride, TRH122 low molecular weight sodium chondroitin sulfate and manganese ascorbate in the management of knee osteoarthritis. Osteoarthritis Cartilage. 2000;8(5):343–50.
Deal CL, Moskowitz RW. Nutraceuticals as therapeutic agents in osteoarthritis. The role of glucosamine, chondroitin sulfate, and collagen hydrolysate. Rheum Dis Clin North Am. 1999;25(2):379–95.
Bruyere O, Reginster JY. Glucosamine and chondroitin sulfate as therapeutic agents for knee and hip osteoarthritis. Drugs Aging. 2007;24(7):573–80.
Kamei T. Teratogenic effect of excessive chondroitin sulfate in the DON strain of mice. Med Biol. 1995;60:126–9.
Dreisinger N, Zane D, Etwaru K. A poisoning of topical importance. Pediatr Emerg Care. 2006;22(12):827–9.
Darben T, Cominos B, Lee CT. Topical eucalyptus oil poisoning. Australas J Dermatol. 1998;39(4):265–7.
Kehrl W, Sonnemann U, Dethlefsen U. Therapy for acute nonpurulent rhinosinusitis with cineole: results of a double-blind, randomized, placebo-controlled trial. Laryngoscope. 2004;114(4):738–42.
Pages N, Fournier G, Lee-Luyer F, Marques MC. Eucalyptus globus in mice. Plan Med Phyto. 1990;24:21–6.
Takahashi T, Yokoo Y, Inoue T, Ishii A. Toxicological studies on procyanidin B-2 for external application as a hair growing agent. Food Chem Toxicol. 1999;37(5):545–52.
Yamakoshi J, Saito M, Kataoka S, Kikuchi M. Safety evaluation of proanthocyanidin-rich extract from grape seeds. Food Chem Toxicol. 2002;40(5):599–607.
Ray S, Bagchi D, Lim PM, Bagchi M, Gross SM, Kothari SC, et al. Acute and long-term safety evaluation of a novel IH636 grape seed proanthocyanidin extract. Res Commun Mol Pathol Pharmacol. 2001;109(3–4):165–97.
Erexson GL. Lack of in vivo clastogenic activity of grape seed and grape skin extracts in a mouse micronucleus assay. Food Chem Toxicol. 2003;41(3):347–50.
Thiele JJ, Ekanayake-Mudiyanselage S. Vitamin E in human skin: organ-specific physiology and considerations for its use in dermatology. Mol Aspects Med. 2007;28(5–6):646–67.
Salles AMR, Galvao TF, Silva MT, Motta LCD, Pereira MG. Antioxidants for preventing preeclampsia: a systematic review. ScientificWorldJournal. 2012;20:10–2.
Chappell LC, Seed PT, Briley AL, Kelly FJ, Lee R, Hunt BJ, et al. Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: a randomised trial. Lancet. 1999;354(9181):810–6.
Beazley D, Ahokas R, Livingston J, Griggs M, Sibai BM. Vitamin C and E supplementation in women at high risk for preeclampsia: a double-blind, placebo-controlled trial. Am J Obstet Gynecol. 2005;192(2):520–1.
Gulmezoglu AM, Hofmeyr GJ, Oosthuisen MM. Antioxidants in the treatment of severe pre-eclampsia: an explanatory randomised controlled trial. BJOG. 1997;104(6):689–96.
Boskovic R, Gargaun L, Oren D, Djulus J, Koren G. Pregnancy outcome following high doses of Vitamin E supplementation. Reprod Toxicol. 2005;20(1):85–8.
Siman CM, Eriksson UJ. Vitamin E decreases the occurrence of malformations in the offspring of diabetic rats. Diabetes. 1997;46(6):1054–61.
Al Deeb S, Al Moutaery K, Arshaduddin M, Tariq M. Vitamin E decreases valproic acid induced neural tube defects in mice. Neurosci Lett. 2000;292(3):179–82.
Hassoun EA, Walter AC, Alsharif NZ, Stohs SJ. Modulation of TCDD-induced fetotoxicity and oxidative stress in embryonic and placental tissues of C57BL/6 J mice by vitamin E succinate and ellagic acid. Toxicology. 1997;124(1):27–37.
Kappus H, Diplock AT. Tolerance and safety of vitamin E: a toxicological position report. Free Radic Biol Med. 1992;13(1):55–74.
Wentzel P, Eriksson UJ. Ethanol-induced fetal dysmorphogenesis in the mouse is diminished by high antioxidative capacity of the mother. Toxicol Sci. 2006;92(2):416–22.
Andersen A. Final report on the safety assessment of sodium p-chloro-m-cresol, p-chloro-m-cresol, chlorothymol, mixed cresols, m-cresol, o-cresol, p-cresol, isopropyl cresols, thymol, o-cymen-5-ol, and carvacrol. Int J Toxicol. 2006;25 Suppl 1:29–127.
Keemer EB. Looking back at Luenbach: 296 non-hospital abortions. J Natl Med Assoc. 1970;62(4):291–3.
Sood SV. Termination of pregnancy by the intrauterine insertion of Utus paste. BMJ. 1971;2(5757):315–7.
Walker AH. Termination of pregnancy using utus paste. J R Soc Med. 1969;62(8):832.
Thomas TA, Galizia EJ, Wensley RT. Termination of pregnancy with Utus paste: report of a fatal case. BMJ. 1975;1(5954):375–6.
Taiyeb-Ali TB, Zainuddin SL, Swaminathan D, Yaacob H. Efficacy of ‘Gamadent’ toothpaste on the healing of gingival tissues: a preliminary report. J Oral Sci. 2003;45(3):153–9.
Tian F, Zhu CH, Zhang XW, Xie X, Xin XL, Yi YH, et al. Philinopside E, a new sulfated saponin from sea cucumber, blocks the interaction between kinase insert domain-containing receptor (KDR) and alphavbeta3 integrin via binding to the extracellular domain of KDR. Mol Pharmacol. 2007;72(3):545–52.
Tong Y, Zhang X, Tian F, Yi Y, Xu Q, Li L, et al. Philinopside A, a novel marine-derived compound possessing dual anti-angiogenic and anti-tumor effects. Int J Cancer. 2005;114(6):843–53.
Zhang SY, Yi YH, Tang HF. Bioactive triterpene glycosides from the sea cucumber Holothuria fuscocinerea. J Nat Prod. 2006;69(10):1492–5.
Zhang SY, Yi YH, Tang HF, Li L, Sun P, Wu J. Two new bioactive triterpene glycosides from the sea cucumber Pseudocolochirus violaceus. J Asian Nat Prod Res. 2006;8(1–2):1–8.
Morrow DM, Rapaport MJ, Strick RA. Hypersensitivity to aloe. Arch Dermatol. 1980;116(9):1064–5.
American Botanical Council. Therapeutic Guide to Herbal Medicines. 1998. http://cms.herbalgram.org. Accessed 21 Sept 2014.
Pigatto PD, Guzzi G. Aloe linked to thyroid dysfunction. Arch Med Res. 2005;36(5):608.
Bottenberg MM, Wall GC, Harvey RL, Habib S. Oral aloe vera-induced hepatitis. Ann Pharmacother. 2007;41(10):1740–3.
Kanat O, Ozet A, Ataergin S. Aloe vera-induced acute toxic hepatitis in a healthy young man. Eur J Inter Med. 2006;17(8):589.
Suzuki I, Saito H, Inoue S, Migita S, Takahashi T. Purification and characterization of two lectins from Aloe arborescens Mill. J Biochem. 1979;85(1):163–71.
Nath D, Sethi N, Singh RK, Jain AK. Commonly used Indian abortifacient plants with special reference to their teratologic effects in rats. J Ethnopharmacol. 1992;36(2):147–54.
Parys BT. Chemical burns resulting from contact with peppermint oil mar: a case report. Burns Incl Therm Inj. 1983;9(5):374–5.
Kligler B, Chaudhary S. Peppermint oil. Am Fam Physician. 2007;75(7):1027–30.
Rees WD, Evans BK, Rhodes J. Treating irritable bowel syndrome with peppermint oil. BMJ. 1979;2(6194):835–6.
Kulkarni R, Patki P, Jog V, Gandage S, Patwardhan B. Treatment of osteoarthritis with a herbomineral formulation: a double-blind, placebo-controlled, cross-over study. J Ethnopharmacol. 1991;33(1):91–5.
Kulkarni R, Patki P, Jog V, Patwardban B. Efficacy of an Ayurvedic formulation in rheumatoid arthritis: a double-blind, placebo-controlled, cross-over study. Indian J Pharmacol. 1992;24(2):98.
Werbach MR, Murray MT. Botanical influences on illness: a sourcebook of clinical research. Tarzana, CA: Third Line Press Inc; 1994.
Gupta I, Gupta V, Parihar A, Gupta S, Ludtke R, Safayhi H, et al. Effects of Boswellia serrata gum resin in patients with bronchial asthma: results of a double-blind, placebo-controlled, 6-week clinical study. Eur J Med Res. 1998;3(11):511–4.
Gupta I, Parihar A, Malhotra P, Singh GB, Ludtke R, Safayhi H, et al. Effects of Boswellia serrata gum resin in patients with ulcerative colitis. Eur J Med Res. 1997;2(1):37–43.
Singh GB, Bani S, Singh S. Toxicity and safety evaluation of boswellic acids. Phytomedicine. 1996;3(1):87–90.
Olin B, editor. Facts and Comparisons(R). St. Louis, MO: Wolters Kluwer Health Inc; 1996.
Claris Lifesciences Limited. Product-Information: Magnesium chloride hexahydrate IV solution. 2003. http://www.dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=50173. Accessed 21 Sep 2014.
Briggs GG, Freeman RK, Yaffe SJMD. Drugs in pregnancy and lactation. Baltimore, MD: Lippincott Williams & Wilkins; 1998.
A.M.S.A. is clinical pharmacologist/toxicologist at KSU and active member of Motherisk, Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, University of Toronto. A.M.S.A. is the recipient of the active scholarship from the Ministry of higher education and KSU, College of pharmacy, Riyadh, Saudi Arabia. We are grateful for the Deanship of Scientific Research, King Saud University (KSU), Riyadh, Saudi Arabia for supporting A.M.S.A. This study was supported by a grant from the Ontario Centers of Excellence, the Government of Ontario.
The authors declare that they have no competing interests.
This manuscript has not been published and is not under consideration for publication elsewhere.
Participated in paper design: AMSA and GK. Conducted review: AMSA, CF, and GK. Wrote or contributed to the writing of the manuscript: AMSA and GK. All authors read and approved the final manuscript.
About this article
Cite this article
Alsaad, A.M., Fox, C. & Koren, G. Toxicology and teratology of the active ingredients of professional therapy MuscleCare products during pregnancy and lactation: a systematic review. BMC Complement Altern Med 15, 40 (2015). https://doi.org/10.1186/s12906-015-0585-8