Kojik asit

EU 1223/2009 Annex III — SCCS görüşü: Opinion on Kojic acid

EU 1223/2009 Annex III — SCCS görüşü: scientific opinion on Kojic acid

EU 1223/2009 Annex III — SCCS görüşü: preliminary version of 26-27 October 2021

EU 1223/2009 Annex III — SCCS görüşü: final version of 15-16 March 2022

EU 1223/2009 Annex III — SCCS görüşü: Corrigendum of 10 June 2022

Acute Toxicity Studies In acute mouse studies with Kojic Acid, oral, subcutaneous, and intraperitoneal LD50 values were 5.1, 2.7, and 2.6 g/kg bw, respectively.2 In rats, the LD50 values were greater than 2 g/kg bw in oral and dermal studies, and 2.6 and 2.4 g/kg bw in subcutaneous and intraperitoneal studies, respectively. Short-Term Toxicity Studies Dermal A 4-wk dermal study in rats found that exposure at up to 1000 mg/kg/d Kojic Acid lowered lymphocyte counts at 300 and 1000 mg/kg/d and decreased absolute and relative spleen weights at 1000 mg/kg/d.2 The no-observable-effect level (NOEL) for this study was 100 mg/kg/d. The dermal toxicity of Kojic Acid was assessed in a 30-d study in New Zealand White rabbits.3,4 Groups of 5 males and 5 females received 0, 13, 130, or 1300 mg/kg bw/d (0, 0.65, 6.5, or 65% w/v) Kojic Acid in 1% aqueous methylcellulose on abraded skin daily (2 ml/kg/d). Treatment sites were covered for 6 h each day with gauze before being removed with warm water. Animals were observed daily for clinical signs and mortality, and body weight and feed consumption were recorded weekly. Blood samples for hematological and biochemical parameters were taken prior to the start of treatment and in the control and in the highest dose group prior to study end. The rabbits were killed after the end of the treatment prior and underwent necropsy and histopathology. All rabbits had slight dermal reactions, but effects were more persistent in the animals that were treated with Kojic Acid. Erythematous papules and abscesses were observed in several rabbits. Two animals had an infection of Staphylococcus aureus. One female of the 13 mg/kg bw/d group and 1 male of the 130 mg/kg bw/d group were found dead  Distributed for Comment Only -- Do Not Cite or Quote … [kırpıldı — bölüm toplam 6683 karakter]

Oral Several oral studies of Kojic Acid, with doses tested up to 900 mg/kg/d in mice, 1000 mg/kg/d in rats and 500 mg/kg/d in rabbits, found the substance was not a developmental or reproductive toxicant.2

Kojic Acid (tested at up to 10,000 µg/plate) was genotoxic in Salmonella typhimurium and Escherichia coli in several Ames studies performed with and without metabolic activation.2 Genotoxicity was observed to Kojic Acid in Chinese hamster ovary (CHO) assays for sister chromatid exchanges and chromosomal aberrations (up to 6 mg/ml, with or without metabolic activation) assay, but genotoxicity was not observed in cell mutation assays in mouse lymphoma L5178 TK+/- cells (up to 1421 µg/ml, with or without metabolic activation) or in Chinese hamster V79 cells (up to 3000 µg/ml). Kojic Acid was a weak clastogen without metabolic activation in a chromosome aberration assay in Chinese hamster V79 cells when tested at  Distributed for Comment Only -- Do Not Cite or Quote up to1420 µg/ml, with and without metabolic activation, but the effects observed may have been related to cytotoxicity. In in vivo mammalian tests, Kojic Acid was not genotoxic in micronucleus tests in mice that received up to 4000 mg/kg bw intraperitoneally, a dominant lethal test in mice (up to 700 mg/kg orally), an unscheduled DNA synthesis test in rats (up to 1500 mg/kg orally), a comet assay in rats (up to 2000 mg/kg orally), or DNA adduct assays (up to 2% in diet). In an oral micronucleus study in both mice (3- and 9-wk old) and rats (9-wk old) with up to 1000 mg/kg Kojic Acid, mean values of micronucleated hepatocytes in 9-wk old mice were increased in a dose-dependent manner, with a significant increase over the negative control at 1000 mg/kg; however, this effect was not observed in 3-wk old mice or in the rats. Kojic Acid was a weak photo-mutagen in a photo-reverse mutation assay in S. typhimurium and E. coli when tested at up to 5000 µg/ml, and in a chromosomal aberration study with light irradiation in Chinese hamster lung cells when tested at up to 1.4 ml/ml. … [kırpıldı — bölüm toplam 2857 karakter]

The International Agency for Research on Cancer (IARC) concluded that Kojic Acid is a group 3 carcinogen—not classifiable to human carcinogenicity.2 Tumorigenic potential of Kojic Acid was observed in the liver, but not in the thyroid follicular epithelial cells in mice that were fed a diet containing up to 3% Kojic Acid for 26 wk; however, up to 1% Kojic Acid was not tumorigenic to mice in a 78-wk dietary study. In a 55-wk rat dietary study of 0.5 or 2% Kojic Acid, the no- observable-adverse-effect level (NOAEL) was determined to be below 0.5%. Changes in the liver, thyroid glands, and adrenal glands, including diffuse follicular cell hyperplasia in the thyroid glands in both treatment groups and adenomas and/or carcinomas in the 2% group, were observed. Tumor Promotion and/or Tumor Initiation Kojic Acid did not possess initiation or promotion potential for skin carcinogenesis in mice.2 Several studies on mice and rat liver found Kojic Acid to have carcinogenesis-promoting potential but not an initiation potential. More robust summaries of these data may be found in Table 4. Thyroid Effects Studies on the effect of Kojic Acid on rodent thyroids found the chemical inhibits iodine uptake and organification in the thyroid, which causes a proliferative effect.2 More robust summaries of these data may be found in Table 5. In the original safety assessment on Kojic Acid, the only thyroid carcinogenesis data available were those pertaining to rodents. The Panel noted that it had been reported that rodent thyroid glands, especially in male rats, have greater sensitivity to chemical substances and physiologic perturbations than human thyroid glands. This difference was attributed to several factors, including shorter plasma half-life of T4 in rodents and differences in transport and binding of proteins for … [kırpıldı — bölüm toplam 11026 karakter]

Kojic Acid at 1 and 3% was a mild dermal irritant in rabbits.2 In guinea pigs, 30% Kojic Acid was not a dermal sensitizer. No sensitization was observed in human repeat insult patch tests (HRIPTs) of a cream product containing 1% Kojic Acid (54 subjects tested) or a formulation containing 2% Kojic Acid (218 subjects tested). Dermal Depigmentation The depigmenting effects of Kojic Acid were studied in a black guinea pig study.2 Kojic Acid at 0.1 ml was applied at concentrations of 1 and 4% (w/v) in a 1:4 mixture of dimethyl sulfoxide and ethanol to the shaved dorsal area (4 x 4 cm2 or 4 x 3 cm2) of 4 JY-4 black guinea pigs. The vehicle alone was also tested. The test substance was applied once a day, 6 d/wk, for 5 successive weeks. After the application period had ended, the animals were killed and skin samples were prepared for examination. The depigmentation action was evaluated by macroscopic observation and spectrophotometric colorimetry. Optical and electron microscopy of epidermal melanocytes were also performed for morphological examination. The mechanism for which skin whitening occurs was also investigated by measuring oxygen consumption and the relation of free radicals to melanin synthesizing enzyme tyrosinase. The skin whitening action of Kojic Acid was very weak when compared to phenylhydroquinone: the results of the macroscopic evaluation of phenylhydroquinone at 1 and 4% were “+” and “++”, respectively, while these results were “-” and “+ ~ ±” in the 1 and 4% Kojic Acid, respectively. The 4% Kojic Acid test group, however, showed no statistically significant difference from the vehicle group in the colorimetric value. A white substance that was thought to be crystals of the applied Kojic Acid may have been causing the whitening rather than an actual depigmenting action. With repeated … [kırpıldı — bölüm toplam 2684 karakter]

IARC Grup 3 — Kanserojenliği sınıflandırılamıyor. Mevcut kanıt bir sınıflandırma yapmaya yetmiyor. 'Güvenli' DEMEK DEĞİLDİR; 'yeterli veri yok' demektir. (Monograf cilt: 79). Sınır: IARC TEHLİKE sınıflandırması yapar, RİSK değil — 'bir koşulda kansere yol açabilir' der, 'kozmetikteki kullanım seviyesinde kanser yapar' DEMEZ. Maruziyet yolu ve dozu ayrıca değerlendirilmelidir. Veri 01/2021 anlık görüntüsüdür.

EPA ToxValDB kanser değerlendirmesi: 3 - Not classifiable as to its carcinogenicity to humans. Sınır: bu bir derleme kayıttır; doz, tür ve maruziyet yolu birlikte değerlendirilmelidir.

EPA ToxValDB genotoksisite: positive — pozitif rapor: 5, negatif: 4, Ames: positive, mikronükleus: positive. Sınır: bu bir derleme kayıttır; doz, tür ve maruziyet yolu birlikte değerlendirilmelidir.