Table 4 Summary of general and reproductive effects of PTMC products

Methylsulfonylmethane

Human

• Topically, there are no adverse reactions.

• Till date, no data.

[11-16]

• There are no studies on long-term use.

Animal

• Orally, it has low toxicity.

• Do not induce structural or fetal anomalies.

• Long-term use did not cause adverse events.

Camphor

Human

• Topically, poisonings were reported in children and adults.

• Topically, the frequency of birth defects was less.

[17-28]

• Orally, it caused fatal symptoms in children.

• Orally, cross the human placenta, however, till date, there are no adverse fetal effects.

Animal

• The oral LD₅₀ = 1.3 g/kg in mice.

• Orally, there are no congenital abnormalities in rats and rabbit.

Menthol

Human

• Topically, it is safe.

• Till date, no data.

[29-31]

Animal

• Topically, acute dermal toxicity was reported with LD₅₀ = 5 g/kg in rabbit.

• There is no teratogenic effect in mice, rats, hamsters, or rabbits.

• Orally, toxicity was reported at LD₅₀ = 2.9 g/kg and 3.1 g/kg in rat and mice, respectively.

Wintergreen Oil

Human

• In cosmetics, methyl salicylate is safe, however, might cause local necrosis.

• Till date, no data.

[32-42]

• There are some reports for tinnitus, diplopia, shortness of breath, and respiratory alkalosis.

Animal

• Topically, sub-chronic exposure might lead to kidney damage in rats.

• It is associated with increased risk of abnormalities.

Glucosamine Sulfate

Human

• Topically, it did not cause toxicity or adverse effects.

• There is no increase in risk of malformations.

[43-47]

Animal

• Topically, it is considered safe.

• Teratogenic effects were not reported in mice or rabbits exposed to glucosamine.

Sodium Chondroitin Sulfate

Human

• Topically, there are no adverse events.

• Till date, no data

[43,48-52]

• It interferes with progression of osteoarthritis.

Animal

• The oral LD₅₀ for mice is greater than 10 g/kg.

• There is increased risk of cleft palate and tail abnormalities in mice.

• Orally, there are no adverse effects in mice and rabbits.

Eucalyptus Leaf Oil)

Human

• Topically, it is safe.

• Till date, no data.

[53-56]

• A report of fever and seizure-like motor activity -in slurred speech, ataxia, and muscle weakness were reported in children.

• Orally, there are minor side effects.

Animal

The oral LD₅₀ = 2.5 g/kg in rats.

• There are no adverse outcomes in mice.

Grape Seed Oil

Human

• Topically, it is safe.

• Till date, no data.

[57-60]

Animal

• There are no safety issues associated with acute and chronic safety studies rats

• The grape seed extract was non-mutagenic in mice.

• Several reports showed that LD₅₀ for dermal application is greater than 2 g/kg in rats.

Vitamine E

Human

• Topically, it is safe.

• There are no risks of stillbirth, perinatal death, preterm birth, intrauterine growth restriction, or mean birth weight.

[61-66]

• High doses were associated with reduction in birth weight.

Animal

• Topically, it is safe.

• Malformation was not greater than expected in offspring of rats and mice.

[67-71]

Thymol

Human

• Topically, it is safe.

• It is not associated with increased risks of birth defects.

[21,72-76]

• It is toxic to mucous membranes and to kidneys, liver, and central nervous system.

Animal

• Topically, it is safe.

• Might cause adverse reproductive effects.

Sea Cucumber Extract

Human

• Topically, it is safe

• Till date, no data.

[77-81]

Animal

• Topically, it is safe.

• Till date, no data.

Aloe Barbadensis Leaf Juice

Human

• Topically, it is safe, however, not recommended for children under age of 12 years.

• Orally, it is not recommended in pregnancy or lactation.

[82-88]

• Orally, there are adverse effects in rare cases.

Animal

• Topically, it is safe.

• Teratogenic effects have been reported with high oral doses in rats.

Peppermint Oil

Human

• Topically, it caused skin irritation with frequent use of oil.

• It induces menstruation and, thus, it is not recommended at high oral doses during pregnancy.

[83,89-91]

• Orally, enteric-coated capsules were not associated with adverse reactions.

• There is insufficient evidence to determine the safety of peppermint oil during lactation.

Animal

• The oral LD₅₀ was reported at 2490 mg/kg in mice and at 2426 mg/kg in rats.

• Orally, the LD₅₀ was 2490 mg/kg in mice and 2426 mg/kg in rats.

• The peppermint oil was used to induce menstruation and it is not recommended at high oral doses in pregnancy.

Boswelli, and Magnesium chloride

Human

• Topically, boswelli is associated with dermatitis.

• Orally, there is lack of evidence on safe use of boswelli during pregnancy and lactation.

[92-99]

• Orally, boswelli is associated with gastrointestinal effects including, nausea, abdominal fullness, and epigastria.

• Similarly, magnesium chloride studies failed to demonstrate risks of birth defects to the fetus.

• Orally, magnesium chloride is not recommended for patients with renal impairment.

• Both magnesium and ilex are safe for topical use.

Animal

• Topically, boswelli is safe in mice, rats and monkeys.

• There is lack of evidence on safe use during pregnancy and lactation.

• Orally, boswelli was not associated with mortality in rat and mice.

• In rat and monkey, there was no change in behavior, clinical, biochemical, or pathological data when boswelli was used orally.