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 Carvacrol1

Abstract

Sodium p-Chloro-m-Cresol, p-Chloro-m-Cresol (PCMC), Mixed Cresols, m-Cresol, o-Cresol, p-Cresol, Isopropyl Cresols, Thymol, Chlorothymol, o-Cymen-5-ol, and Carvacrol are substituted phenols used as cosmetic biocides/preservatives and/or fragrance ingredients. Only PCMC, Thymol, and o-Cymen-5-ol are reported to be in current use, with the highest concentration of use at 0.5% for o-Cymen-5-ol in perfumes. The use of PCMC in cosmetics is restricted in Europe and Japan. Cresols can be absorbed through skin, the respiratory tract, and the digestive tract; metabolized by the liver; and excreted by the kidney as glucuronide and sulfate metabolites. Several of these cresols increase the dermal penetration of other agents, including azidothymidine. In acute oral toxicity studies, LD50 values were in the 200 to 5000 mg/kg day-1 range across several species. In short-term studies in rats and mice, an o-Cresol, m-Cresol, p-Cresol or m-Cresol/p-Cresol mixture at 30,000 ppm in the diet produced increases in liver and kidney weights, deficits in liver function, bone marrow hypocellularity, irritation to the gastrointestinal tract and nasal epithelia, and atrophy of female reproductive organs. The no observed effect levels (NOEL) of o-Cresol was 240 mg/kg in mink and 778 mg/kg in ferrets in short-term feeding studies, with no significant dose-related toxicity (excluding body weight parameters). In mice, 0.5% p-Cresol, but neither m-Cresol nor o-Cresol, caused loss of pigmentation. Short-term and subchronic oral toxicity tests performed with various cresols using mice, rats, hamsters, and rabbits resulted in no observed adverse effect levels (NOAELs) for mice of 625 ppm and rats of 50 mg/kg day-1, although the NOEL was 2000 ppm in a chronic study using rats. In rabbits, < or =160 mg/kg PCMC was found to produce irritation and erythema, but no systemic effects. Hamsters dosed with 1.5% p-Cresol in diet for 20 weeks had a greater incidence of mild and moderate forestomach hyperplasia as compared to the control. Acute inhalation toxicity studies using rats yielded LC50 values ranging from >20 mg/m(3) for o-Cresol to >583 mg/m(3) for PCMC. No deaths were recorded in mice given o-Cresol at 50 mg/m(3). Cats exposed (short-term) to 9 to 50 mg/m(3) of o-Cresol developed inflammation and irritation of the upper respiratory tract, pulmonary edema, and hemorrhage and perivascular sclerosis in the lungs. Rats exposed (subchronic) to o-Cresol at 9 mg/m(3) had changes in leukocytes, spinal cord smears, nervous activity, liver function, blood effects, clinical signs, and neurological effects. In guinea pigs, exposure to 9 mg/m(3) produced changes in hemoglobin concentrations and electrocardiograms (EKGs). Rats exposed (subchronic) to 0.05 mg/m(3) Mixed Cresols by inhalation exhibited central nervous system (CNS) excitation, denaturation of lung protein, and decreased weight gain. All cresols appear to be ocular irritants. Numerous sensitization studies have been reported and most positive reactions were seen with higher concentrations of Cresol...

Carvacrol, a Food-Additive, Provides Neuroprotection on Focal Cerebral Ischemia/Reperfusion Injury in Mice

“…Because CAR is widely used as a food additive and its safety is well studied before [39], [40], it has a high potential to be translated from bench research to clinical trials for stroke therapy.…”

Synthesis, Antimicrobial Activity and in silico Studies on Thymol Esters

“…Keeping in view diverse pharmacological activities of thymol [7][8][9][10][11][12][13][14][15][16][17][18][19] and preliminary results on bioactivity of thymyl derivatives 4,5,22,25,[28][29][30]33 we have set the aim of our study. By making a single modification of a phenolic functionality in thymol we have obtained a series of ester compounds (3a-t), performed their structural characterization, in vitro antimicrobial testing and in silico calculation of physico-chemical, pharmacokinetic and toxicological properties.…”

“…9 In addi-Lazarevi} et al: Synthesis, Antimicrobial Activity and in silico ... tion, there is evidence that thymol has antitumor properties. 10 The primary mode of antibacterial action of thymol is not fully known, but is believed to involve outer-and inner membrane disruption, and interaction with membrane proteins and intracellular targets. [11][12][13][14][15][16] The mode of action of thymol against yeast and fungi has been sparsely investigated, though certain studies point to interactions with the cell envelope and intracellular targets.…”

Toxicology and teratology of the active ingredients of professional therapy MuscleCare products during pregnancy and lactation: a systematic review

“… • 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.…”