Study

Subject

Outcome parameters

Results

Pulmonary toxicity

Wei et al (2021) (26)

A549

Determination of cytotoxicity of PHMG (0–32 μg/ml) and study of the expression of IL-8¹ and IL-6.

PHMG (≤ 2 μg/ml) had little effect on cell proliferation, cytotoxicity was observed at >4 μg/ml at 6 and 24 h, and IL-8 and IL-6 expression was also increased.

Lee et al (2022) (27)

HPAEpiC

Long-term exposure concentration of PHMG-P that is not surface reactive at 24, 48, and 72 h and determination of the carcinogenic effect of PHMG-P.

CV using 2 μg/ml PHMG-P after 72 h was ~90%. Exposure to 1 μg/ml PHMG-P for 10 days caused changes in 2 protein-coding genes and 5 non-coding genes and for 27–35 days - 24 protein-coding and 5 non-coding genes.

Choi et al (2022) (28)

BEAS-2B

A549

Effect of PHMG-P (2.5 μg/ml, 1 h) on SG² formation under stress conditions.

PHMG-P under stress and infection conditions increased the formation of SG, induced the expression of fibrotic genes, and caused cell death due to DNA³ damage.

Jin et al (2020) (29)

BEAS-2B

Determination of CV⁴ under conditions of exposure to PHMG-P (1–16 μg/ml for 4–24 h).

Exposure to >4 μg/mL PHMG-P reduced CV by >50% at 24 h and also increased LDH⁵ release by 3-fold, promoting epithelial barrier breakdown.

Jung et al (2014) (30)

A549

IMR-90

BEAS-2B

Determination of the cytotoxic effect of PHMG and its mediated changes in gene expression in A549 cells.

PHMG (5 μg/ml) reduced the viability of IMR-90 and BEAS-2B cells by more than 90% after 24 h, while the viability of A549 cells exceeded 60%.

Song et al (2019) (31)

A549

MRC-5

THP-1

Determine the toxic effects of PHMG-P by assessing cell survival rates as a function of dose (0.25–20 μg/mL) and time (24, 48, and 72 h).

Exposure of A549 and MRC-5 to PHMG-P (5 μg/ml) reduced CV by 44.7% and 64.9% at 24 h, by 19% and 25.8% at 48 h, and by 11.2% and 12.7% at 72 h, respectively, while THP-1 was 86.9% at 24 h, 73.8% at 48 h, and 69.4% at 72 h in THP-1 cells.

Hepatic toxicity

Kim et al (2013) (32)

THP-1

Studying the hepatotoxicity of PHMG-P by assessing the number of SA-β-gal-positive cells⁶.

By the 13th passage, cells treated with PHMG (0.03%) showed an 8-fold increase in the number of SA-β-gal-positive cells compared to the control, indicating the effect of acute aging of liver tissue.

Kim et al (2019) (33)

HepG2

Study of hepatotoxicity under the influence of PHMG-P for 24, 48, and 72 h based on CV.

The IC₅₀⁷ values after 24, 48, and 72 h of incubation with PHMG-P in HepG2 cells were 7.612, 5.822, and 5.840 μg/mL, respectively.

Skin toxicity

Yang et al (2021) (34)

THP-1

Skin sensitization potential of PHMG by MIT⁸ assessment by h-CLAT⁹.

The MIT for PHMG was 0.87 μg/mL, a strong sensitizer.

Oral toxicity

Vitt et al (2017) (35)

HGF¹⁰

Cytotoxic effect of PHMG-P (0.005% and 0.00009%) by measuring the number of vital cells at a clinically relevant exposure time (1-30 min) and for 24 h. Determination of the immunomodulatory effect of PHMG-P by assessing the levels of PGE2¹¹, IL-6, IL-8, and MMP-1¹².

Exposure to PHMG-P (0.005%) for 1–30 min resulted in loss of CV within 5 min. Exposure to PHMG-P (0.00009%) for 24 h resulted in loss of fibroblast viability. The addition of PHMG-P together with IL-1b significantly reduced PGE2 levels (p<0.001) as well as the production of IL-6, IL-8, and MMP-1 by fibroblasts (p<0.05) at all concentrations tested.

Ocular toxicity

Park et al (2019) (36)

RHClE¹³

Study the ophthalmic toxicity of PHMG by tissue viability assay.

Aqueous solutions of PHMG (≤0.13%) had no irritant effect.

Note: ¹IL – interleukin; ²SG – stress granule; ³DNA - deoxyribonucleic acid; ⁴CV – cell viability; ⁵LDH - lactate dehydrogenase; ⁶SA-β-gal - senescence-associated β-galactosidase; ⁷IC₅₀ - half maximal inhibitory concentration; ⁸MIT - minimal induction threshold; ⁹h-CLAT - human cell line activation test; ¹⁰HGF - human gingival fibroblasts; ¹¹PGE2 - prostaglandin E2; ¹²MMP-1 - matrix metalloproteinase-1; ¹³RHClE - reconstructed human cornea-like epithelium.

Study

Subject

Outcome parameters

Results

Acute / Subchronic toxicity

Kovalenko et al. (2011) (37)

M¹⁴

Acute toxicity study of PHMG-H (0.05-0.1%) intragastrically.

The detected LD₅₀²¹ of PHMG-H was 1434 mg/kg. The substance was low toxic.

Kim, H. R. et al. (2015) (38)

ME¹⁵

RAW264.7

To study the inflammatory effect induced by PHMG-P at concentrations from 0.14 mg/ml to 35.10 mg/ml for 6 and 24 h.

PHMG-P caused dose-dependent cytotoxicity LC₅₀²² of 11.15-0.99 mg/ml at 6 and 24 h, respectively. PHMG-P induced pro-inflammatory cytokines including IL-1β, IL-6 and IL-8.

Asiedu-Gyekye, I. J. et al. (2014) (39)

RSD¹⁶

Study of the possible effects of subchronic toxicity of PHMG-H administered intragastrically.

The detected LD₅₀ of PHMG-H was 600 mg/kg.

Dias, F. G. G. et al. (2021) (40)

RW¹⁷

Assessment of acute oral toxicity of 0.5% PHMG-H solution.

PHMG-H 5% is classified as Acute Toxicity Category 5 (LD₅₀ > 2000–5000 mg/kg).

Lee, Y. H. et al. (2020) (41)

RF344¹⁸

Assess subacute inhalation toxicity of PHMG-H (1, 5, or 25 mg/m³ over 6 h per day, 5 days per week for two weeks).

NOAEL²³ PHMG-H < 1 mg/m³.

Skin toxicity

Kovalenko et al. (2011) (37)

GP¹⁹

Study of the sensitizing properties of PHMG-H (1% and 3%) when applied to the skin twice a day.

The drug did not have a cumulative, sensitizing or irritating effect at the indicated concentrations.

Dias, F. G. G. et al. (2021) (40)

RW, M

Evaluation of possible side effects of cutaneous PHMG-H 0.5%.

PHMG-H reduced the area of ​​skin lesions and increased the number of fibroblasts, with no side effects. At a concentration of 5%, PHMG-H exhibited neither genotoxicity nor cytotoxicity at doses up to 1500 mg/kg by micronucleus assay.

Oral toxicity

Sklyanova et al. (2006) (42)

R²⁰

To determine the toxicity of PHMG-P injection (0.25%) in a histomorphological study when exposed to cheek tissue.

PHMG-P (0.25%) caused aseptic inflammation at the injection site. The least irritating effect on cheek tissue and subcutaneous connective tissue was produced by 1.0 ml of injection.

Pulmonary toxicity

Jeong S.H. et al (2024) (43)

R

To study the severity of lung injury resulting from intratracheal instillation of PHMG-P (0.2, 1.0, and 5.0 mg/kg).

The severity of lung damage, as well as the number, size and malignancy of tumors, increased as the dose of PHMG-P was increased. Bronchiolar-alveolar hyperplasia developed in all groups.

Song, J. et al. (2022) (44)

M

Study of the lung injury process of PHMG-P when administered intravenously (0.9 or 7.2 mg/kg) or intratracheally (0.9 mg/kg).

PHMG-P promoted the production of pro-inflammatory cytokines and also caused fibrotic changes in the lungs when administered intratracheally (0.9 mg/kg).

Li, X. Et al. (2021) (45)

M C57BL/6J

Study of the mechanism of PHMG-induced (0.05, 0.1, 1, and 2 mg/ml) pulmonary fibrosis based on increased surface tension mediated by pulmonary surfactant inhibition.

PHMG-H induced pulmonary fibrosis along with increased surface tension.

Lee, J. D. et al (2020) (46)

RW

Determination of pulmonary toxicity caused by intratracheal PHMG-P (single dose 1.5 mg/kg or 0.1 mg/kg, 2 times a week, for 4 weeks).

Upon single administration, PHMG-P induced alveolar macrophage aggregation and granulomatous inflammation. Pulmonary fibrosis, chronic inflammation, bronchiole-alveolar fibrosis, and squamous cell metaplasia were observed in the repeated administration group.

Lee, Y. H. et al. (2019) (47)

Males RF344

Assessment of oxidative stress in the lungs induced by inhaled exposure to PHMG-H (0.13, 0.40 or 1.20 mg/m³ 6 h per day, 5 days per week for 13 weeks).

The number of oxidative stress markers in the bronchial epithelium of rats increased in a dose-dependent manner. At 1.20 mg/m³ an increase in respiratory rate and a decrease in body weight were observed. At 0.13 mg/m³, no deviations in the lung structure were observed.

Lee, Y. H. et al. (2020) (41)

RF344

Subacute inhalation toxicity study of PHMG-H (1, 5, or 25 mg/m³ for 6 h per day, 5 days per week for 2 weeks).

The severity of lung damage increased in a dose-dependent manner. Exposure to PHMG-H (5 and 25 mg/m³) caused squamous metaplasia of the bronchial and bronchiolar epithelium, as well as alveolar emphysema and necrosis with inflammation. Lymphoid hyperplasia of broncho-associated lymphoid tissue was observed in rats exposed to 1, 5, and 25 mg/m³. Alveolar macrophage aggregation was observed in male rats exposed to 0, 1, 5, and 25 mg/m³ and female rats exposed to 1 and 25 mg/m³.

Park, S. et al. (2014) (48)

RSD

Assessment of lung injury resulting from nasal inhalation of PHMG-P (1.6 mg/m³) aerosol 6 h per day, 5 days per week, for 4 weeks.

PHMG-P (1.6 mg/m³) caused typical bronchiolocentric destruction with inflammation and fibrosis.

Cardiac toxicity

Choi, J. H. et al. (2024) (49)

RSD

Study of platelet procoagulant activity induced by PHMG-P (2.5 μg/ml)

PHMG-P causes procoagulant platelet activation, which may contribute to prothrombotic risk and cardiovascular disease.

Ocular toxicity

Lee, H., et al. (2021) (50)

Rabbit cornea cells

Study of the adverse ocular effects of PHMG-H (1, 5, 10 and 25 μg/ml for 24, 48, 72 and 96 h).

PHMG-H can cause fibrosis. IC₅₀²⁴ of PHMG-H at 24, 48, 72 and 96 h: 20.8 µg/ml, 13.8 µg/ml, 8.5 µg/ml and 6.2 µg/ml, respectively. PHMG-H induced cyclooxygenase-2 at 25 μg/ml and hemeoxygenase-1 at all concentrations.

Hepatic toxicity

Choi, Y. J. et al (2022) (51)

M

Study of the effect of PHMG (0, 60 and 200 μg/kg) on ​​the pathophysiology and metabolism of the liver when administered intratracheally 3 times a week, 12 times in total.

PHMG significantly reduced liver cholesterol levels. mRNA-seq²⁵ analysis revealed changes in the expression of genes associated with cholesterol biosynthesis and metabolism to bile acids.

Asiedu-Gyekye, I. J. et al. (2014) (39)

RSD

To study the possible subchronic toxicity effects of PHMG-H (0.006 mg/kg, 0.012 mg/kg, and 0.036 mg/kg) administered intragastrically.

In 10% of animals at all doses, local areas of mild pericentral degeneration of hepatocytes were observed in the liver tissue.

Kim, M. et al (2022) (52)

M C57/BL6 male

To study the pathophysiology of liver fibrosis induced by intraperitoneal administration of PHMG-P (0.03% and 0.1%) twice a week for 5 weeks.

Diffuse fibrotic lesions of the liver were revealed without affecting the lungs. PHMG-P induces liver fibrosis in the pericentral, periportal, and capsular regions.

Dias, F. G. G. et al. (2021) (40)

RW

Investigate the potential for liver injury when 0.5% PHMG-H topical solution is administered orally by gavage.

Alanine aminotransferase/aspartate aminotransferase and urea/creatinine did not differ significantly from the control group.

Hematological toxicity

Sung HJ et al. (2022) (53)

RSD males

Study of possible disorders of hematopoietic function 20 weeks after intratracheal instillation of PHMG-P (1-5 mg/kg).

PHMG-P affects hematopoiesis involved in monocyte differentiation and platelet production.

Asiedu-Gyekye, I. J. et al. (2014) (39)

RSD

(males and females)

Study of hematological parameters during intragastric administration of PHMG-H (0.006 mg/kg, 0.012 mg/kg, and 0.036 mg/kg).

PHMG-H did not have any harmful effects on the hematopoietic system of animals.

Lee, J. et al. (2021) (54)

Females RSD

Study of hematological parameters in pregnant female rats by inhalation of PHMG-P aerosol (0.14, 1.60, and 3.20 mg/m³).

PHMG-P (3.20 mg/m³) increased the total number of red blood cells, hematocrit, hemoglobin and neutrophils, decreased the number of reticulocytes, lymphocytes, eosinophils, basophils, decreased alanine aminotransferase, alkaline phosphatase, total bilirubin, total cholesterol, sodium, phospholipids, and chloride. PHMG-P (1.60 mg/m³) also increased the total number of red blood cells, hematocrit, and hemoglobin, and a decrease in alkaline phosphatase and chloride was observed.

Lee, Y. H. et al. (2020) (41)

RF344 (males and females)

Study of hematological parameters as part of a study of subacute toxicity of PHMG-H in the form of an aerosol (1 mg/m³, 5 mg/m³, or 25 mg/m³ for 6 h a day, 5 days a week for two weeks).

PHMG-H (1, 5, and 25 mg/m³) increased the total number of red blood cells, hematocrit, and hemoglobin. Hemoglobin increased significantly at 25 mg/m³. Reticulocytes were significantly reduced at 5 and 25 mg/m³. Platelets decreased at 25 mg/m³. Monocytes and neutrophils increased at 25 mg/m³. Lymphocytes were reduced in males at 25 mg/m³, and in females at 5 and 25 mg/m³. Eosinophils were significantly reduced in females at 25 mg/m³. Alanine aminotransferase increased in males at 25 mg/m³, and in females at 5 and 25 mg/m³. Aspartate aminotransferase increased significantly in all at 25 mg/m³.

Reproductive toxicity

Lee, J. et al. (2022) (55)

R

To study the postnatal development of offspring after exposure to PHMG-P (0, 0.14, 1.60, and 3.20 mg/m³).

PHMG-P (1.60 and 3.20 mg/m³) increased perinatal mortality and decreased the viability index; F1 offspring had lower birth weight. Pregnant rats had severe systemic toxicity and a prolonged gestation period.

Lee, J. et al (2019) (56)

RSD

To study the toxic effects of orally administered PHMG-P (0, 13, 40, and 120 mg/kg)

PHMG-P (120 mg/kg) exhibited toxicity including depressed behavior, thinness, decreased body weight, decreased food intake, and decreased body weight of F1 offspring. NOAEL was 40 mg/kg/day.

Nephrotoxicity

Asiedu-Gyekye, I. J. et al. (2014) (39)

RSD

To study the possible subchronic toxicity effects of PHMG-H (0.006 mg/kg, 0.012 mg/kg, and 0.036 mg/kg) administered intragastrically.

At 0.006 mg/kg and 0.036 mg/kg, 20% of animals showed mild degrees of hydropic changes in the proximal tubules.

Note: ¹⁴M – mice; ¹⁵ME - Mice macrophage; ¹⁶RSD – Rats Sprague-Dawley; ¹⁷RW – Rats Wistar; ¹⁸RF344 – Rats F344; ¹⁹GP - guinea pig; ²⁰R – Rats; ²¹LD₅₀ - median lethal dose;  ²²LC₅₀ –  median lethal concentration; ²³NOAEL - No-observed-adverse-effect level; ²⁴IC₅₀ - half maximal inhibitory concentration; ²⁵mRNA-seq - messenger ribonucleic acid sequencing.

Study

Subject

Outcome parameters

Results

Pulmonary toxicity

Ryu et al (2019) (57)

Patients with lung damage (n=453), control group (n=700).

Assessment of inhalation exposure to HD²⁶.

In 259 (57.2%) patients with ILD²⁷, it developed within one year of HD use, where the average level of inhaled PHMG was 145.1 µg/m³.

Lamichhane et al (2019) (58)

Patients with IIP (n=244), control group (n=244).

Frequency distribution of characteristics associated with HD exposure.

The use of HD-containing PHMG was associated with a higher risk of lung damage compared to those who used other disinfectants.

Lee et al (2021) (59)

Patients (n=362).

Study of asthma induced by PHMG-based HD exposure using data from a panel study of South Korean children.

Asthma associated with PHMG exposure was characterized by decreased lung function, less positive bronchial hyperresponsiveness scores, and different plasma protein distribution.

Park et al (2014) (60)

Patients with lung damage (n=38).

Assessing PHMG-based HD exposure through medical record review.

Three pregnant women and six preschool-aged children died as a result of lung damage. Another six pregnant women and 22 preschool-aged children experienced non-lethal lung injury. Three adult male office workers did not suffer fatal lung damage.

Ju et al (2021) (61)

Patients with fatal injuries (n=1413)

Analysis of the distribution of causes of death among applicants according to medical records.

43.0% of the affected individuals had more than one case of ILD identified. Among the causes of mortality in the deceased, respiratory organ diseases accounted for 54.4%. Among those who died from respiratory diseases, ILD were the most common cause of death (65.5%).

Hepatic toxicity

Kim et al (2023) (62)

Patients (n=3) who used HD.

To examine the likelihood of developing toxic hepatitis due to the inhalation of HD-containing PHMG by analyzing patients' medical records.

Patients exhibited an increase in aspartate aminotransferase and alanine aminotransferase levels up to 2000-4000 IU/L. One fatality was recorded, while two patients were discharged after treatment. Hepatotoxicity due to inhalation was not confirmed.

Makarov et al (2009) (63)

Blood serum of patients (n=40) with toxic hepatitis and healthy volunteers (n=50).

Determining the impact of consuming alcohol surrogates containing PHMG-H on the lipid profile of blood.

Patients differed from healthy volunteers by a twofold decrease in the relative content of total phospholipids, free fatty acids, cholesterol esters, and phosphatidylcholine, but had higher levels of free cholesterol and total lysophospholipids. The overall lipid levels in patients were three times higher than the norm. The development of toxic hepatitis has been confirmed.

Ostapenko et al (2011) (22)

Patients with poisoning from surrogate alcohol (n=579).

Study of the clinical presentation and outcomes of poisoning with surrogate alcohol containing PHMG-H.

Jaundice was observed in 99.7%, with detected foci of cholestasis, fibrosis progressing to cirrhosis and inflammatory infiltration. The development of cholestatic hepatitis has been confirmed.

Skin Toxicity

Pummi et al (2012) (64)

Patient with skin sensitization (n=1) and previously observed dermatitis.

Assessing the risk of skin sensitization from a PHMG-containing antiseptic.

Sensitization developed within 1-2 months with frequent use of a non-alcoholic disinfectant containing PHMG at concentrations of 0.1-1%.

Oral Toxicity

Vitt et al (2019) (65)

Patients with severe chronic periodontitis (n=19).

Evaluation of side effects of irrigation with antiseptic PHMG-P (1%) in periodontal treatment.

No adverse effects were observed with PHMG-P (1%) during the study.

Note: ²⁶HD - humidifier disinfectants; ²⁷ILD - interstitial lung diseases.