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GHS Classification Results by the Japanese Government

GENERAL INFORMATION

Item	Information
CAS RN	22373-78-0
Chemical Name	Monensin, monosodium salt
Substance ID	R02-B-120-MHLW
Classification year (FY)	FY2020
Ministry who conducted the classification	Ministry of Health, Labour and Welfare (MHLW)
New/Revised	Revised
Classification result in other fiscal year	FY2006
Download of Excel format	Excel file

REFERENCE INFORMATION

Item	Information
Guidance used for the classification (External link)	GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0))
UN GHS document (External link)	UN GHS document
Definitions/Abbreviations (Excel file)	Definitions/Abbreviations
Model Label by MHLW (External link)	MHLW Website (in Japanese Only)
Model SDS by MHLW (External link)	MHLW Website (in Japanese Only)
OECD/eChemPortal (External link)	eChemPortal

PHYSICAL HAZARDS

Hazard class		Classification	Pictogram Signal word	Hazard statement (code)	Precautionary statement (code)	Rationale for the classification
1	Explosives	Not classified (Not applicable)	- -	-	-	There are no chemical groups associated with explosive properties present in the molecule. It was classified as "Not classified."
2	Flammable gases	Not classified (Not applicable)	- -	-	-	Solid (GHS definition). It was classified as "Not classified."
3	Aerosols	Not classified (Not applicable)	- -	-	-	Not aerosol products. It was classified as "Not classified."
4	Oxidizing gases	Not classified (Not applicable)	- -	-	-	Solid (GHS definition). It was classified as "Not classified."
5	Gases under pressure	Not classified (Not applicable)	- -	-	-	Solid (GHS definition). It was classified as "Not classified."
6	Flammable liquids	Not classified (Not applicable)	- -	-	-	Solid (GHS definition). It was classified as "Not classified."
7	Flammable solids	Classification not possible	- -	-	-	No data available.
8	Self-reactive substances and mixtures	Not classified (Not applicable)	- -	-	-	There are no chemical groups present in the molecule associated with explosive or self-reactive properties. It was classified as "Not classified."
9	Pyrophoric liquids	Not classified (Not applicable)	- -	-	-	Solid (GHS definition). It was classified as "Not classified."
10	Pyrophoric solids	Classification not possible	- -	-	-	No data available.
11	Self-heating substances and mixtures	Classification not possible	- -	-	-	No data available.
12	Substances and mixtures which, in contact with water, emit flammable gases	Not classified (Not applicable)	- -	-	-	The chemical structure of the substance does not contain metals or metalloids (B, Si, P, Ge, As, Se, Sn, Sb, Te, Bi, Po, At). It was classified as "Not classified."
13	Oxidizing liquids	Not classified (Not applicable)	- -	-	-	Solid (GHS definition). It was classified as "Not classified."
14	Oxidizing solids	Not classified (Not applicable)	- -	-	-	The substance is an organic compound containing oxygen (but not fluorine or chlorine) which is chemically bonded only to carbon or hydrogen. It was classified as "Not classified."
15	Organic peroxides	Not classified (Not applicable)	- -	-	-	Organic compounds containing no bivalent -O-O- structure in the molecule. It was classified as "Not classified."
16	Corrosive to metals	Classification not possible	- -	-	-	Classification is not possible because test methods applicable to solid substances are not available.
17	Desensitized explosives	Not classified (Not applicable)	- -	-	-	There are no chemical groups associated with explosive properties present in the molecule. It was classified as "Not classified."

HEALTH HAZARDS

Hazard class		Classification	Pictogram Signal word	Hazard statement (code)	Precautionary statement (code)	Rationale for the classification
1	Acute toxicity (Oral)	Category 2	Danger	H300	P301+P310 P264 P270 P321 P330 P405 P501	[Rationale for the Classification] It was classified in Category 2 from (1) - (6). [Evidence Data] (1) LD50 for rats (mycelial): females: 22 mg/kg, males: 40 mg/kg (Risk Assessment Report (Veterinary Medicinal Products and Feed Additives) (Food Safety Commission of Japan, 2015)) (2) LD50 for rats (mycelial): females: 24 mg/kg (Risk Assessment Report (Veterinary Medicinal Products and Feed Additives) (Food Safety Commission of Japan, 2015)) (3) LD50 for rats (mycelial): females: 205.1 mg/kg, males: 290.4 mg/kg (Risk Assessment Report (Veterinary Medicinal Products and Feed Additives) (Food Safety Commission of Japan, 2015)) (4) LD50 for rats (crystalline): females: 238.0 mg/kg, males: 318.0 mg/kg (Risk Assessment Report (Veterinary Medicinal Products and Feed Additives) (Food Safety Commission of Japan, 2015)) (5) LD50 for rats: 21.7-50 mg/kg (EU EMEA (2007)) (6) LD50 for rats: females: 86-130 mg/kg, males: 340-860 mg/kg (EU EFSA (2005)) [Reference Data, etc.] (7) Sensitivity was different between species, but toxic signs were similar in all animals tested and were death, anorexia, decreased locomotor activity, skeletal muscle weakness, ataxic gait, diarrhea, and reduced weight gain. Overall, females were more sensitive than males. There was no significant difference in toxicity effects between the morphology of monensin (crystalline or mycelial) (Risk Assessment Report (Veterinary Medicinal Products and Feed Additives) (Food Safety Commission of Japan, 2015)). (8) LD50 for mice (mycelial): males: 70 mg/kg, females: 96 mg/kg (Risk Assessment Report (Veterinary Medicinal Products and Feed Additives) (Food Safety Commission of Japan, 2015)) (9) LD50 for mice (mycelial): females: 230.1 mg/kg, males: 302.0 mg/kg (Risk Assessment Report (Veterinary Medicinal Products and Feed Additives) (Food Safety Commission of Japan, 2015)) (10) LD50 for mice (crystalline): females: 330.0 mg/kg, males: 368.0 mg/kg (Risk Assessment Report (Veterinary Medicinal Products and Feed Additives) (Food Safety Commission of Japan, 2015)) (11) LD50 for mice (crystalline): males: 350.0 mg/kg (Risk Assessment Report (Veterinary Medicinal Products and Feed Additives) (Food Safety Commission of Japan, 2015))
1	Acute toxicity (Dermal)	Category 3	Danger	H311	P302+P352 P361+P364 P280 P312 P321 P405 P501	[Rationale for the Classification] It was classified in Category 3 from (1). Besides, the classification result was changed from the previous classification by using a new information source. [Evidence Data] (1) LD50 for rats: females: 550 mg/kg, males: 700 mg/kg (EU EFSA (2005))
1	Acute toxicity (Inhalation: Gases)	Not classified	- -	-	-	[Rationale for the Classification] Solid (GHS definition). It was classified as "Not classified."
1	Acute toxicity (Inhalation: Vapours)	Classification not possible	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.
1	Acute toxicity (Inhalation: Dusts and mists)	Classification not possible	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.
2	Skin corrosion/irritation	Not classified	- -	-	-	[Rationale for the Classification] It was classified as "Not classified" from (1). The classification result was changed due to new data obtained. [Evidence Data] (1) In a skin irritation test with rabbits, no irritation was seen for this substance itself and a 20% preparation of this substance (EU EFSA (2005)). [Reference Data, etc.] (2) In a test in which mycelial monensin (monensin activity 13.4%, 10.6 mg as this substance) was applied to the skin of rabbits (n = 3) at 500 mg/kg (single dose), no irritation was found except for slight erythema seen in one animal (EU EFSA (2004), HSDB (Access on June 2020)). (3) In a test by 24-hour occlusive application of 2,000 mg of granular monensin (9.9% formulation) to the skin of rabbits (n = 3), cracking and crusting of the skin were observed and were returned to normal, but one animal died (EU EFSA (2004)).
3	Serious eye damage/eye irritation	Not classified	- -	-	-	[Rationale for the Classification] It was classified as "Not classified" from (1), (2). [Evidence Data] (1) In an eye irritation test with rabbits on this substance itself and a 20% preparation of this substance, no irritation was seen for the substance, but acute edema and mild erythema of the conjunctiva were observed for a 20% preparation, which was reported as a slight irritant (EU EFSA (2005)). (2) In an eye irritation test with rabbits on this substance itself and 50% and 10% solutions of this substance, there was no or slight irritation for 50% and 10% solutions, and irritation was seen for the substance but disappeared after 48 hours (Risk Assessment Report (Veterinary Medicinal Products and Feed Additives) (Food Safety Commission of Japan, 2015)). [Reference Data, etc.] (3) In an eye irritation test with rabbits (n = 3) in which mycelial monensin (monensin activity 13.4%, 10.6 mg as this substance) was applied, severe corneal opacity, iris hyperemia, conjunctival inflammation, and edema were observed within 24 hours, and there was no healing, and 2/3 animals died (EU EFSA (2004)). (4) In an eye irritation test with rabbits (n = 3) in which dried mycelial monensin (59 mg) was applied, corneal opacity, marked iritis, and moderate conjunctivitis developed within 1 hour, 1/3 animal exhibited staphyloma with corneal perforation after 7 days, and as healing occurred, extensive neovascularization was seen (EU EFSA (2004), JECFA FAS 61 (2009), Risk Assessment Report (Veterinary Medicinal Products and Feed Additives) (Food Safety Commission of Japan, 2015), HSDB (Access on June 2020)). (5) In an eye irritation test in which a formulation (53 mg) containing this substance was applied to rabbits, mild corneal opacity, marked iritis, and moderate conjunctivitis were observed within 1 hour after application, well-defined to severe corneal opacity and severe conjunctivitis developed within 2 hours after application, and the corneal opacity was not reversible (EU EFSA (2004), JECFA FAS 61 (2009), Risk Assessment Report (Veterinary Medicinal Products and Feed Additives) (Food Safety Commission of Japan, 2015), HSDB (Access on June 2020)).
4	Respiratory sensitization	Classification not possible	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.
4	Skin sensitization	Category 1B	Warning	H317	P302+P352 P333+P313 P362+P364 P261 P272 P280 P321 P501	[Rationale for the Classification] It was classified in Category 1B from (1), (2). [Evidence Data] (1) In a mouse local lymph node assay (LLNA) on this substance (93.8% monensin) according to OECD TG 429, a positive response was seen from 50 mg/mL (5%) (EU EFSA (2004), JECFA FAS 61 (2009)). (2) In a mouse local lymph node assay (LLNA) on a formulation containing this substance according to OECD TG 429, a positive response was found (EU EFSA (2004)). [Reference Data, etc.] (3) In a skin sensitization test with guinea pigs (maximization test), both the substance and a 20% preparation of this substance were reported to be negative for sensitization (EU EFSA (2005)). (4) In a skin sensitization test with guinea pigs (modified Buehler test) on mycelial monensin, no sensitization was observed (EU EFSA (2004), JECFA FAS 61 (2009), Risk Assessment Report (Veterinary Medicinal Products and Feed Additives) (Food Safety Commission of Japan, 2015), HSDB (Access on June 2020)).
5	Germ cell mutagenicity	Not classified	- -	-	-	[Rationale for the Classification] It was classified as "Not classified" from (1), (2). Information was added, and the classification was changed. [Evidence Data] (1) As for in vivo, it was reported to be negative in a micronucleus test by oral administration to mice (Risk Assessment Report (Veterinary Medicinal Products and Feed Additives) (Food Safety Commission of Japan, 2015), JECFA FAS 61 (2009), EU EFSA (2005)). (2) As for in vitro, it was reported to be negative in a bacterial reverse mutation test, a chromosomal aberration test and a gene mutation test using cultured mammalian cells (same as the above).
6	Carcinogenicity	Not classified	- -	-	-	[Rationale for the Classification] There were no classification results by domestic and international organizations. There were no available reports in humans. Because either carcinogenicity tests on this substance in (1) and (2) or a carcinogenicity test on free acid of this substance in (3) revealed no treatment-related increases in tumor incidences were seen, this substance was classified as "Not classified." An investigation was conducted by using a new information source, and the classification result was changed. [Evidence Data] (1) In a combined chronic toxicity/carcinogenicity test by 2-year diet administration of this substance to male and female rats, malignant and benign tumors were observed in the control and treatment groups, but no relation was found between the treatment and the kind and severity of tumors (Risk Assessment Report (Veterinary Medicinal Products and Feed Additives) (Food Safety Commission of Japan, 2015)). (2) In a combined chronic toxicity/carcinogenicity test by intrauterine exposure to monensin (CAS RN 17090-79-8) followed by 2-year diet administration of this substance to male and female rats, no differences in the onset time and prevalence of malignant and benign tumors were observed between the treated and control groups, and no carcinogenicity was seen (Risk Assessment Report (Veterinary Medicinal Products and Feed Additives) (Food Safety Commission of Japan, 2015)). (3) In a combined chronic toxicity/carcinogenicity test by 2-year diet administration of monensin (CAS RN 17090-79-8: mycelial) to male and female mice, no carcinogenicity was seen (Risk Assessment Report (Veterinary Medicinal Products and Feed Additives) (Food Safety Commission of Japan, 2015)).
7	Reproductive toxicity	Not classified	- -	-	-	[Rationale for the Classification] It was classified using the data on this substance (1) to (4), and the data on the free acid of this substance (5) and (6). In a two-generation reproductive study by an administration of this substance to rats in (1), lower litter size at birth, etc. were observed at a dose at which parental toxicity was observed, however, since no effect on fertility was observed in a three-generation reproductive study by an administration of mycelial monensin and crystalline monensin to rats in (5) and (6), these effects were considered to be negated. Based on (2) to (4), it was considered that there was no effect on fetal development. Therefore, it was classified as “Not classified.” [Evidence Data] (1) In a two-generation reproductive study by an administration of this substance to rats by feeding, lower litter size at birth and lower body weight of liveborn pups were observed, and effects on body weight gain of offspring were also observed at a dose (12.5 mg/kg/day) at which parental toxicity (reduced body weight gain, a decrease in food consumption, and wasting and hunchback position in females during lactation) was observed (Risk Assessment Report (Veterinary Medicinal Products and Feed Additive) (Food Safety Commission of Japan, 2015)). (2) In a developmental toxicity study by an administration of this substance to female rats by feeding during the rearing period and on days 0 to 20 of gestation, no effect was observed (Risk Assessment Report (Veterinary Medicinal Products and Feed Additive) (Food Safety Commission of Japan, 2015)). (3) In a developmental toxicity study by an administration of this substance to female rabbits dosed by gavage on days 6 to 18 of gestation, no effect was observed (Risk Assessment Report (Veterinary Medicinal Products and Feed Additive) (Food Safety Commission of Japan, 2015)). (4) In a developmental toxicity study by an administration of this substance to female rabbits dosed by gavage on days 6 to 28 of gestation, an increase in fetal deaths was observed at a dose (3 mg/kg/day) at which maternal toxicity (reduced body weight, worsening of general condition, 1 dead animal, 1 animal sacrificed in extremis, abortion in about half of dams) was observed. Since this dose level was highly toxic to the dams, it was concluded that it was not appropriate to examine developmental effects. No effect on fetuses was observed at doses (0.1 and 0.3 mg/kg/day) at which no maternal toxicity was observed (Risk Assessment Report (Veterinary Medicinal Products and Feed Additive) (Food Safety Commission of Japan, 2015)). (5) In a three-generation reproductive study by an administration of mycelial monensin (CAS RN 17090-79-8) to rats by feeding (0, 1.6, 2.5, and 4 mg/kg/day), there was a decrease in body weight gain in all generations of all treated groups, but no effect on fertility, embryotoxicity, or teratogenicity was observed (Risk Assessment Report (Veterinary Medicinal Products and Feed Additive) (Food Safety Commission of Japan, 2015)). (6) In a three-generation reproductive study by an administration of crystalline monensin to rats by feeding, no changes were reported at up to the maximum dose (1.43 to 2.3 mg/kg/day), and no teratogenicity was observed (Risk Assessment Report (Veterinary Medicinal Products and Feed Additive) (Food Safety Commission of Japan, 2015)).
8	Specific target organ toxicity - Single exposure	Category 1 (skeletal muscle, heart)	Danger	H370	P308+P311 P260 P264 P270 P321 P405 P501	[Rationale for the Classification] Based on (1) and (2), it was classified in Category 1 (skeletal muscle, heart). Since effects on the kidney were considered to be secondary effects of rhabdomyolysis, they were not adopted as target organ toxicity. A new information source was used and the classification results were changed from the previous classification. [Evidence Data] (1) There were reports on two cases: one case in which a 17-year-old boy ingested this substance (the dose level was unknown), and the other case in which a 16-year-old boy ingested monensin (CAS RN 17090-79-8) (about 500 mg). In both cases, initial symptoms were nausea, anorexia, abdominal pains, etc., and lower-extremity muscle weakness and severe pains, blackish brown urine, leukocytosis, and an increase in erythrocyte sedimentation rate were also observed. In both cases, rhabdomyolysis occurred due to this substance, which caused acute renal failure, and in one case, heart failure occurred. It was stated that the main target of excessive ingestion of this substance in humans was considered to be the skeletal muscle and cardiac muscle (Risk Assessment Report (Veterinary Medicinal Products and Feed Additive) (Food Safety Commission of Japan, 2015)). (2) In an acute oral toxicity test using this substance, although the susceptibility varied greatly among species such as rats, mice, dogs, and monkeys, signs of toxicity were shown to be similar in all animals tested and comprised of death, anorexia, reduced locomotor activity, skeletal muscle weakness, ataxia, diarrhea, and reduced body weight gain. Female animals were more susceptible than males. There was no significant difference in the toxic effects of monensin (crystalline or mycelial) depending on its form (Risk Assessment Report (Veterinary Medicinal Products and Feed Additive) (Food Safety Commission of Japan, 2015), EU EMEA (2007)). The minimum LD50 values in an oral administration to rats and mice were 22 to 40 mg/kg for rats and 70 to 96 mg/kg for mice (Risk Assessment Report (Veterinary Medicinal Products and Feed Additive) (Food Safety Commission of Japan, 2015)), and the above symptoms were considered to occur within the dose range for Category 1. [Reference Data, etc.] (3) A 17-year-old male died from acute rhabdomyolysis with renal failure after intentionally ingesting combined formulation (premix) of monensin (EU EMEA (2007)). (4) A patient who ingested monensin developed severe rhabdomyolysis followed by acute renal failure, heart failure, and death (HSDB (Access on June 2020)).
9	Specific target organ toxicity - Repeated exposure	Category 1 (heart, skeletal muscle, blood system)	Danger	H372	P260 P264 P270 P314 P501	[Rationale for the Classification] Based on (1) to (4), it was classified in Category 1 (heart, skeletal muscle, blood system). As a result of a review based on the new information, the classification results were changed from the previous classification. [Evidence Data] (1) As a result of a 3-month administration of this substance (mycelial) to mice by feeding, slight diffuse vacuolation of the myocardial fiber in 1 male at 5.6 mg/kg/day (within the range for Category 1); a decrease in leukocyte count in females at or above 5.6 mg/kg/day (within the range for Category 1); decreases in leukocyte count and lymphocyte percentage and an increase in neutrophils in males at 11.2 mg/kg/day (within the range for Category 2); decreases in erythrocyte count, hemoglobin, and hematocrit levels in males and females, and an increase in serum CPK in males at or above 22.5 mg/kg/day (within the range for Category 2); and slight diffuse vacuolation of the myocardial fiber in males and females (8 males, 2 females), and an increase in serum CPK in females at 45 mg/kg/day (within the range for Category 2) were observed (Risk Assessment Report (Veterinary Medicinal Products and Feed Additive) (Food Safety Commission of Japan, 2015)). (2) As a result of a 90-day administration of this substance (mycelial) to rats by feeding, deaths (males: 40%; females: 80%), decreases in food consumption and feed efficiency, muscle inflammation of the skeletal muscle, changes in the cardiac muscle with diffuse degeneration and histiocyte infiltration, and degeneration of the diaphragm muscle fiber in males and females, and decreases in hematocrit value and leukocyte count in males (the statistical analysis for females of the same group could not be performed because the number of live animals was small) were observed at 500 ppm (39 to 47 mg/kg/day, within the range for Category 2) (Risk Assessment Report (Veterinary Medicinal Products and Feed Additive) (Food Safety Commission of Japan, 2015)). (3) As a result of a 90-day oral administration of this substance (mycelial) to dogs, sacrifice and deaths (1 animal was sacrificed in a 15 mg/kg/day group, 2 animals died in a 50 mg/kg/day group; and degeneration of the muscle fiber, myocardial damage with infiltration of macrophages, and congestion of the internal organs in the animals that died), vomiting, low body weight, muscle weakness, ataxia, arrhythmia, convulsions and mydriasis, and changes in the striated muscle such as diffuse degeneration of the muscle fiber and infiltration of the histiocytes were observed in males at or above 15 mg/kg/day (within the range for Category 2); and changes in the striated muscle such as diffuse degeneration of the muscle fiber and infiltration of the histiocytes were observed in females at 50 mg/kg/day (within the range for Category 2) (Risk Assessment Report (Veterinary Medicinal Products and Feed Additive) (Food Safety Commission of Japan, 2015)). (4) As a result of a 13-week administration of this substance to dogs by feeding, findings of myodegeneration in males and females at or above 83 ppm (2.1 mg/kg/day, within the range for Category 1), hypoactivity in females on day 11 of administration of 167 ppm (4.2 mg/kg/day, within the range for Category 1) (recovered as a result of discontinuation of the administration until day 18 of administration), and hypoactivity and ataxia in males and females at 250 ppm (6.3 mg/kg/day, within the range for Category 1) were observed (Risk Assessment Report (Veterinary Medicinal Products and Feed Additive) (Food Safety Commission of Japan, 2015)). [Reference Data, etc.] (5) It was reported that, as a result of a 52-week administration of this substance to rats by feeding, vacuolation of the hepatocytes (accumulation of lipoprotein) in females at 1.36 mg/kg/day, and a death in 1 female at 4.59 mg/kg/day were observed (Risk Assessment Report (Veterinary Medicinal Products and Feed Additive) (Food Safety Commission of Japan, 2015)). (6) It was reported that, as a result of two 2-year combined chronic toxicity/carcinogenicity studies with rats using this substance (crystalline), no effect of administration was observed except for transient body weight loss (Risk Assessment Report (Veterinary Medicinal Products and Feed Additive) (Food Safety Commission of Japan, 2015)).
10	Aspiration hazard	Classification not possible	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.

ENVIRONMENTAL HAZARDS

Hazard class		Classification	Pictogram Signal word	Hazard statement (code)	Precautionary statement (code)	Rationale for the classification
11	Hazardous to the aquatic environment Short term (Acute)	-	- -	-	-	-
11	Hazardous to the aquatic environment Long term (Chronic)	-	- -	-	-	-
12	Hazardous to the ozone layer	-	- -	-	-	-

NOTE:

GHS Classification Result by the Japanese Government is intended to provide a reference for preparing a GHS label or SDS for users. To include the same classification result in a label or SDS for Japan is NOT mandatory.
Users can cite or copy this classification result when preparing a GHS label or SDS. Please be aware, however, that the responsibility for a label or SDS prepared by citing or copying this classification result lies with users.
This GHS classification was conducted based on the information sources and the guidance for classification and judgement which are described in the GHS Classification Guidance for the Japanese Government etc. Using other literature, test results etc. as evidence and including different content from this classification result in a label or SDS are allowed.
Hazard statement and precautionary statement will show by hovering the mouse cursor over a code in the column of "Hazard statement" and "Precautionary statement," respectively. In the excel file, both the codes and statements are provided.
A blank or "-" in the column of "Classification" denotes that a classification for the hazard class was not conducted in the year.
An asterisk “*” in the column of “Classification” denotes that “Not classified (or No applicable)” and/or “Classification not possible” is applicable. Details are described in the column of “Rationale for the classification”. If no English translation is available for “Rationale for the classification,” please refer to the Japanese version of the results.

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