NITE - Chemical Management Field

GHS Classification Results by the Japanese Government

GENERAL INFORMATION

Item	Information
CAS RN	79-57-2
Chemical Name	Oxytetracycline
Substance ID	R02-A-025-METI, MOE
Classification year (FY)	FY2020
Ministry who conducted the classification	Ministry of Economy, Trade and Industry (METI)/Ministry of the Environment (MOE)
New/Revised	New
Classification result in other fiscal year
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)
Model SDS by MHLW (External link)
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.
2	Flammable gases	Not classified (Not applicable)	- -	-	-	Solid (GHS definition)
3	Aerosols	Not classified (Not applicable)	- -	-	-	Not aerosol products.
4	Oxidizing gases	Not classified (Not applicable)	- -	-	-	Solid (GHS definition)
5	Gases under pressure	Not classified (Not applicable)	- -	-	-	Solid (GHS definition)
6	Flammable liquids	Not classified (Not applicable)	- -	-	-	Solid (GHS definition)
7	Flammable solids	Classification not possible	- -	-	-	No data available.
8	Self-reactive substances and mixtures	Classification not possible	- -	-	-	There is a chemical group associated with self-reactive properties (ethylene group) present in the molecule, but the classification is not possible due to no data.
9	Pyrophoric liquids	Not classified (Not applicable)	- -	-	-	Solid (GHS definition)
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).
13	Oxidizing liquids	Not classified (Not applicable)	- -	-	-	Solid (GHS definition)
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.
15	Organic peroxides	Not classified (Not applicable)	- -	-	-	Organic compounds containing no bivalent -O-O- structure in the molecule.
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.

HEALTH HAZARDS

Hazard class		Classification	Pictogram Signal word	Hazard statement (code)	Precautionary statement (code)	Rationale for the classification
1	Acute toxicity (Oral)	Not classified	- -	-	-	[Rationale for the Classification] It was classified as "Not classified" from (1). [Evidence Data] (1) LD50 for rats: about 9,000 mg/kg (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2016))
1	Acute toxicity (Dermal)	Not classified	- -	-	-	[Rationale for the Classification] It was classified as "Not classified" from (1). [Evidence Data] (1) LD50 for rats: > 5,000 mg/kg (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2016))
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). [Evidence Data] (1) It is reported that in a skin irritation test with rabbits (n = 6) (GLP, semi-occlusive, 4-hour application, 3-day observation), no eye irritation was seen (erythema/eschar score: 0/0/0/0/0/0, edema score: 0/0/0/0/0/0) (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2018)).
3	Serious eye damage/eye irritation	Not classified	- -	-	-	[Rationale for the Classification] It was classified as "Not classified" from (1). [Evidence Data] (1) It is reported that in an eye irritation test with rabbits (n = 9) (GLP, 72-hour observation), the mean score after 24/48/72 hours was 0 for corneal opacity, 0 for iritis, 0 for conjunctival redness, and 0 for chemosis in the washed eye group (3 animals), and the mean score after 24/48/72 hours was 0.06 for corneal opacity, 0.06 for iritis, 0.44 for conjunctival redness, and 0.28 for chemosis in the unwashed eye group (6 animals). These effects were fully reversible within 72 hours (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2018)).
4	Respiratory sensitization	Classification not possible	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.
4	Skin sensitization	Category 1A	Warning	H317	P302+P352 P333+P313 P362+P364 P261 P272 P280 P321 P501	[Rationale for the Classification] It was classified in Category 1A from (1) - (3). [Evidence Data] (1) It is reported that in a patch test in 10 subjects in the group sensitized with 3% of this substance and 31 subjects in the negative control group, strong reactions in 7 and weak reactions in 2 were observed in the sensitized group, and no reactions were found in 30 in the control group and 1 in the sensitized group (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2016)). (2) It is very rare, but skin symptoms such as morbilliform rashes, urticaria, and generalized dermatitis may occur as hypersensitive reactions, and angioedema and anaphylaxis may develop (EPA Pesticide RED (2006)). (3) It is reported that in a maximization test with guinea pigs (n = 20) (GLP, intradermal administration: 0.5% solution), all the animals showed erythema at both 24 and 48 hours after the removal of the challenge patches, and a positive rate was 100% (20/20) (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2016), A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2018)).
5	Germ cell mutagenicity	Not classified	- -	-	-	[Rationale for the Classification] Based on (1) to (6), it was classified as "Not classified." [Evidence Data] (1) In a micronucleus test with mice, positive results were obtained, but it was considered that this substance had no significant genotoxicity to living organisms (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2016)). (2) In a micronucleus test using bone marrow cells from mice, the substance was negative (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2016)). (3) In a bacterial reverse mutation test, the substance was negative (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2016)). (4) In an in vitro mammalian cell chromosome aberration test, the substance was negative (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2016)). (5) In a sister chromatid exchange test, the substance was negative (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2016)). (6) In a gene mutation test using mouse lymphoma cells, the substance was positive (+S9) or negative (-S9) (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2016)).
6	Carcinogenicity	Not classified	- -	-	-	[Rationale for the Classification] Based on the classification results by other organizations of (1) and the test results of (2) to (4), it was classified as "Not classified." [Evidence Data] (1) As for the classification results for carcinogenicity by domestic and international organizations, EPA classified oxytetracycline calcium (CAS RN 7179-50-2) in Group D (Not Classifiable as to Human Carcinogenicity) (EPA Annual Cancer Report (2018): Classification in 2016). (2) In a 103-week carcinogenicity study for oxytetracycline hydrochloride (OTC-HCl: CAS RN 2058-46-0) with rats dosed by feeding, a dose-related increase in the incidence of pheochromocytoma of the adrenal gland in males and an increase in the incidence of adenomas of the pituitary gland in females were observed, which were considered to be equivocal evidence of carcinogenicity for both male rats and female rats (NTP TR315 (1987)). However, since the survival rate of males in the control group was low, it was considered that the incidence of benign tumors of the adrenal gland was not of significance. Concerning pituitary adenoma observed in females, the incidence of hyperplasia was lower than that of the control group. Therefore, it was considered that this substance was not carcinogenic (Risk Assessment Report (Food Safety Commission of Japan, 2016)). (3) In a 24-month carcinogenicity study for OTC-HCl with a different strain of male rats dosed by feeding, no carcinogenicity was observed (Risk Assessment Report (Food Safety Commission of Japan, 2016)). (4) In a 103-week carcinogenicity study for OTC-HCl with mice dosed by feeding, no evidence of carcinogenicity was observed in male mice and female mice. Therefore, it was considered that this substance was not carcinogenic (NTP TR315 (1987), Risk Assessment Report (Food Safety Commission of Japan, 2016)).
7	Reproductive toxicity	Category 1A, Additional category for effects on or via lactation	Danger	H360	P308+P313 P201 P202 P280 P405 P501	[Rationale for the Classification] Based on (1) to (3), it was classified in Category 1A, and the effects of lactation were added. [Evidence Data] (1) Infants of mothers treated with OTC during pregnancy may develop a brown discoloration of the teeth. It was also reported that OTC might be deposited in the skeleton of fetuses or children resulting in bone growth reduction, which was readily reversible when the period of exposure to OTC was short (EPA Pesticide RED (2006), Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2016)). (2) Tetracyclines pass through the placenta and are excreted in breast milk. It was also reported that use of tetracyclines by pregnant women (during the last half of pregnancy) was not recommended because it might cause permanent discoloration of teeth, enamel hypoplasia, inhibition of skeletal growth, photosensitivity reactions, and oral or vaginal candidiasis in the fetuses or infants (HSDB (Accessed May 2020)). (3) It was reported that in a developmental toxicity study with rats dosed by gavage (gestation days 1 to 21), reduced ossification of the forelimbs and an increase in embryo resorption were observed in the fetuses at 48 to 480 mg/kg/day (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2016)).
8	Specific target organ toxicity - Single exposure	Category 1 (gastrointestinal tract)	Danger	H370	P308+P311 P260 P264 P270 P321 P405 P501	[Rationale for the Classification] Based on (1), it was classified in Category 1 (gastrointestinal tract). [Evidence Data] (1) Tetracyclines (TC) antibiotics including this substance cause various degrees of gastrointestinal irritation. Such effects commonly occur after oral administration. Gastrointestinal dysfunction (epigastric burning and distress, abdominal discomfort, nausea, vomiting and diarrhea) may occur. Various hypersensitive skin reactions such as morbilliform rashes, urticaria, and generalized dermatitis may occur, although they are extremely rare, and angioedema and anaphylaxis may develop (EPA Pesticide RED (2006), Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2016), JECFA (1998), HSDB (Accessed Aug. 2020) [Reference Data, etc.] (2) Concerning oxytetracycline hydrochloride (OTC-HCl: CAS RN 2058-46-0), there are descriptions about symptoms of shock (such as hypotension, pallor and abnormal pulses), central nervous symptoms (such as tremors and convulsion) as serious side effects (frequencies are not clear). Also, there are descriptions that it may cause sensitization and administration shall be stopped if any signs (such as itching and reddening) appear (IF (2009) of OXYTETRA DENTAL CONE, dental intercalator, 5mg, Showa Yakuhin Kako Co., Ltd.). (3) It was reported that in an acute oral toxicity test with rats dosed by feeding, reduced spontaneous activity was observed at or above 5,208 mg/kg (in the range corresponding to "Not classified") and salivation, diarrhea, ataxia, and death after convulsion were observed at 6,250 mg/kg (in the range corresponding to "Not classified") (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2016)). (4) It was reported that in an acute oral toxicity test with mice dosed by feeding, reduced spontaneous activity, salivation, diarrhea, ataxia, and clonic convulsion were observed at 9,000 mg/kg (in the range corresponding to "Not classified") (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2016)).
9	Specific target organ toxicity - Repeated exposure	Category 1 (blood system, liver, bone, teeth)	Danger	H372	P260 P264 P270 P314 P501	[Rationale for the Classification] Based on (1), it was classified in Category 1 (blood system, liver, bone/tooth). [Evidence Data] (1) There are reports that prolonged administration of tetracyclines antibiotics including this substance to humans may cause blood disorders (leukocytosis, atypical lymphocytes, toxic granulation of granulocytes, thrombocytopenia purpura, delayed blood coagulation), liver injury, onycholysis, pigmentation of the nails, and brown discoloration of the teeth in children under 7 years of age. Infants of mothers treated with tetracyclines antibiotics during pregnancy may develop brown discoloration of the teeth and inhibition of growth. However, it was reported that these symptoms were readily reversible when the period of exposure to OTC was short (EPA Pesticide RED (2006), Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2016), JECFA (1990)). [Reference Data, etc.] (2) This substance produces hepatic toxicity in many of the patients parenterally dosed at or above 2 g/day, and the effects may also occur after oral administration only at a high dosage. In pregnant women, especially serious TC-induced hepatic damage may occur. It was reported that jaundice, azotemia, acidosis, and irreversible shock might be caused (HSDB (Accessed Aug. 2020)). (3) It was reported that in a 24-month oral administration test for oxytetracycline hydrochloride (OTC-HCl: CAS RN 2058-46-0) with rats dosed by feeding, no effects were observed at 3,000 ppm (150 mg/kg/day (a converted value equivalent to this substance: 139.1 mg/kg/day), in the range corresponding to "Not classified") (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2016), JECFA (1990)) (4) It was reported that in a 12-month oral administration test for oxytetracycline hydrochloride (OTC-HCl: CAS RN 2058-46-0) with dogs dosed by feeding, degeneration of seminiferous epithelia in the seminiferous tubules was observed at 10,000 ppm (250 mg/kg/day (a converted value equivalent to this substance: 232 mg/kg/day), in the range corresponding to "Not classified") (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2016), JECFA (1990)).
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)	Category 1	Warning	H400	P273 P391 P501	It was classified in Category 1 from 72-hour ErC50 = 0.111 mg/L for algae (Raphidocelis subcapitata) (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2018)).
11	Hazardous to the aquatic environment Long term (Chronic)	Category 1	Warning	H410	P273 P391 P501	If chronic toxicity data are used, then it is classified as "Not classified" because it is not rapidly degradable (BIOWIN) and due to 72-hour NOErC = 50 mg/L for algae (Desmodesmus subspicatus) (REACH registration dossier, 2021). If acute toxicity data are used for a trophic level for which chronic toxicity data are not obtained, then it is classified in Category 1 because it is not rapidly degradable (BIOWIN) and due to 48-hour EC50 = 0.843 mg/L for crustacea (Daphnia magna) (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2018)). By drawing a comparison between the above results, it was classified in Category 1.
12	Hazardous to the ozone layer	Classification not possible	- -	-	-	This substance is not listed in the Annexes to the Montreal Protocol.

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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