GHS Classification Results by the Japanese Government

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GENERAL INFORMATION
Item Information
CAS RN 210631-68-8
Chemical Name [3-(4,5-Dihydroisoxazol-3-yl)-2-methyl-4-(methylsulfonyl)phenyl](5-hydroxy-1-methyl-1H-pyrazol-4-yl)methanone; Topramezone
Substance ID R02-A-055-METI
Classification year (FY) FY2020
Ministry who conducted the classification Ministry of Economy, Trade and Industry (METI)
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 Not classified (Not applicable)
-
-
- - There are no chemical groups present in the molecule associated with explosive or self-reactive properties.
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 Classification not possible
-
-
- - The substance is an organic compound containing oxygen (but not fluorine or chlorine), which is chemically bonded to the element other than carbon or hydrogen (S). However, the classification is not possible due to no data.
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
-
-
- - 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), (2).

[Evidence Data]
(1) LD50 for rats (females): > 2,000 mg/kg (GLP) (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013))
(2) LD50 for rats: > 2,000 mg/kg (GLP) (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013))
1 Acute toxicity (Dermal) Not classified
-
-
- - [Rationale for the Classification]
It was classified as "Not classified" from two test results in (1), (2).

[Evidence Data]
(1) LD50 for rats: > 2,000 mg/kg (GLP) (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013))
(2) LD50 for rats: > 2,000 mg/kg (GLP) (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013))
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) Not classified
-
-
- - [Rationale for the Classification]
It was classified as "Not classified" from (1).

[Evidence Data]
(1) LC50 for rats (4 hours): > 5.05 mg/L (GLP) (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013))
2 Skin corrosion/irritation Not classified
-
-
- - [Rationale for the Classification]
It was classified as "Not classified" from (1), (2).

[Evidence Data]
(1) It is reported that in a skin irritation test with rabbits (n = 3) (GLP, semi-occlusive, 4-hour application, 3-day observation), slight erythema was observed in 2 animals at 24 hours after the removal of patches, but all skin reactions disappeared within 72 hours (erythema/eschar score: 0.7/0.3/0, edema score: 0/0/0) (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013)).
(2) It is reported that in a skin irritation test with rabbits (n = 3) (GLP, semi-occlusive, 4-hour application, 3-day observation), slight erythema was seen in 2 animals at 1 hour after the removal of patches, but all skin reactions disappeared within 72 hours (erythema/eschar score: 0/0/0.7, edema score: 0/0/0) (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013)).
3 Serious eye damage/eye irritation Not classified
-
-
- - [Rationale for the Classification]
It was classified as "Not classified" from (1), (2).

[Evidence Data]
(1) It is reported that in an eye irritation test with rabbits (n = 3) (GLP, 7-day observation), all the animals showed focal or circular hyperemia in the scleral blood vessels by 72 hours, and it disappeared within 72 hours in 1 and within 7 days in 2 animals (corneal opacity score: 0/0/0, iritis score: 0/0/0, conjunctival redness score: 1.3/2/1, chemosis score: 0/0.3/0) (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013)).
(2) It is reported that in an eye irritation test with rabbits (n = 3) (GLP, 7-day observation), moderate conjunctival redness in all the animals and slight chemosis in 2 were observed after 24 hours, but eye reactions disappeared within 7 days (corneal opacity score: 0/0/0, iritis score: 0/0/0, conjunctival redness score: 1.3/1.7/1.7, chemosis score: 0.7/0.7/0.3) (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013)).
4 Respiratory sensitization Classification not possible
-
-
- - [Rationale for the Classification]
Classification not possible due to lack of data.
4 Skin sensitization Not classified
-
-
- - [Rationale for the Classification]
It was classified as "Not classified" from (1), (2).

[Evidence Data]
(1) It is reported that in a maximization test with guinea pigs (n = 20) (GLP, intradermal administration: 5% solution), a positive rate was 0% (0/20) at both 24, 48 hours after a challenge (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013)).
(2) It is reported that in a maximization test with guinea pigs (n = 20) (GLP, intradermal administration: 5% solution), a positive rate was 0% (0/20) at both 24, 48 hours after a challenge (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013)).
5 Germ cell mutagenicity Not classified
-
-
- - [Rationale for the Classification]
Based on (1) to (5), it was classified as "Not classified."

[Evidence Data]
(1) In a micronucleus test using the bone marrow from mice, negative results were reported (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013)).
(2) It was reported that in bacterial reverse mutation tests (GLP), this substance was weakly positive in one of the four tests and negative in the other three (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013)).
(3) It was reported that in a chromosomal aberration test using Chinese hamster lung cells (V79) (GLP), this substance was positive (S9+) in one of the two tests and weakly positive (S9+) in the other test (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013)).
(4) It was reported that in a gene mutation test using Chinese hamster ovary cells (GLP), negative results were reported (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013)).
(5) Based on adequate results of in vitro and in vivo tests, this substance was not considered to have a genotoxic potential (Australian Pesticides and Veterinary Medicines Authority (2019)).
6 Carcinogenicity Not classified
-
-
- - [Rationale for the Classification]
Based on (1) to (4), it was classified as "Not classified."

[Evidence Data]
(1) As for the classification results by domestic and international organizations, EPA classified this substance in NL (Not Likely to be Carcinogenic to Humans) (EPA Annual Cancer Report 2018 (Accessed September 2020): Classification in 2005).
(2) It was reported that in a two-year combined chronic toxicity/carcinogenicity study with rats dosed by feeding, an increase in the incidence of thyroid follicular cell adenoma was observed in males and females at the highest dose (6,000 ppm) (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013)).
(3) In an 18-month carcinogenicity study with mice dosed by feeding, there was no treatment-related increase in the incidence of tumors and no carcinogenicity was observed (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013)).
(4) According to the report by the Australian Government, the test results on the effects of this substance on the thyroid function were inconclusive as the evidence for a TSH-mediated tumor induction mechanism (decreased serum T4 levels and elevated serum TSH levels). Thyroid tumors that occur as a result of alterations to thyroid hormone levels are generally not considered to be relevant to human subjects. It was described that this substance was unlikely to pose a carcinogenic risk to human subjects (Australian Pesticides and Veterinary Medicines Authority (2019)).
7 Reproductive toxicity Category 1B


Danger
H360 P308+P313
P201
P202
P280
P405
P501
[Rationale for the Classification]
Based on (1) to (5), it was classified in Category 1B. In (1) and (2), organ malformations (unilateral kidney/ureter agenesis) and an increase in the incidence of skeletal malformations observed in rabbit pups at doses that did not elicit maternal toxicity were not dose-related, but in (3), the EFSA evaluated that the effects were teratogenic. In (4), skeletal variations were observed in pups of rabbits at doses that did not elicit maternal toxicity. In (5), the EPA suggested that there was a concern that the maternal exposure of this substance might cause developmental neurotoxicity to the offspring.

[Evidence Data]
(1) It was reported that in a developmental toxicity study with rabbits dosed by gavage (GLP, gestation days 7 to 28), at doses where no general toxicity was observed in parental animals, lower fetal body weight, unilateral kidney/ureter agenesis, skeletal malformations (an increase in the incidence of short ribs: not dose-related) and skeletal variations (extra sterna, extra ribs) were observed in pups (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013)).
(2) It was reported that in a developmental toxicity study with rabbits dosed by gavage (GLP, gestation days 7 to 28), at doses where no general toxicity was observed in parental animals, unilateral kidney/ureter agenesis was observed in pups. The incidence of malformations was the highest at a low dose and the lowest at a high dose (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013)).
(3) In a two-generation reproduction test with rats, at doses where general toxicity effects appeared in parental animals, an increase in the deaths of litters and insufficient maternal care of dams were observed. In a three-generation reproduction test with mice, no reproductive or offspring toxicity was observed. Developmental toxicity was extensively investigated in rats, mice, and rabbits. No developmental effect was observed in mice, and an increase in skeletal variations was observed in rats at doses where no apparent maternal toxicity was reported. On the other hand, severe malformations (unilateral agenesis of the kidney/ureter) were observed in rabbits at lower dose levels that did not elicit maternal toxicity. These effects were considered to indicate that this substance should be classified in a developmental toxicant Category 1B (EFSA (2014)).
(4) It was reported that in a developmental toxicity study with rabbits dosed by gavage (GLP, gestation days 6 to 28), skeletal variations, such as extra ribs, an increase in thoracic vertebrae and a decrease in lumbar vertebrae, were observed in pups at 5 mg/kg/day where no general toxicity was observed in parental animals (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013)).
(5) According to the EPA evaluation, in a developmental neurotoxicity study with rats, offspring neurobehavioral and neuropathological changes were observed in the presence of limited maternal toxicity (corneal opacity) and it suggested that there was a concern that maternal exposure to this substance might cause developmental neurotoxicity to the next generation (US Federal Register (2017)).

[Reference Data, etc.]
(6) It was reported that in a two-generation reproduction toxicity study with rats dosed by feeding (GLP), at doses where general toxicity effects (such as a decrease in body weight and effects on eyes and kidney) were observed in parental animals, an increase in the deaths of pups, abnormalities in eyes, decreases in kidney/spleen weight and lower body weight etc. were observed in the offspring (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013)).
(7) It was reported that in a three-generation reproduction test with mice dosed by feeding (GLP), no reproductive toxicity was observed (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013)).
(8) It was reported that in a developmental toxicity study with rats dosed by gavage (GLP, gestation days 6 to 19), at doses where no general toxicity effect was observed in parental animals, an increase in extra ribs and skeletal variations and lower fetal weight were observed in pups (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013)).
8 Specific target organ toxicity - Single exposure Not classified
-
-
- - [Rationale for the Classification]
Based on (1) to (6), it was classified as "Not classified."

[Evidence Data]
(1) It was reported that in an acute oral toxicity test with rats (females) (GLP), no symptom was observed at 2,000 mg/kg (within the range for Category 2), and at the necropsy, no abnormality was observed in live animals (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013)).
(2) It was reported that in an acute oral toxicity test with rats (GLP), no symptom was observed at 2,000 mg/kg (within the range for Category 2) and at the necropsy, no abnormality was observed in either male or female live animals (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013)).
(3) It was reported that in an acute neurotoxicity test with rats by oral administration (GLP), no systemic toxicity and no neurotoxicity were observed at 2,000 mg/kg/day (within the range for Category 2) (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013)).
(4) It was reported that in an acute dermal toxicity test with rats (GLP), no systemic symptom appeared in either males or females at 2,000 mg/kg (within the range for Category 2) but erythema was observed at the treated areas (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013)).
(5) It was reported that in another acute dermal toxicity test with rats (GLP), no systemic symptom appeared in either males or females at 2,000 mg/kg (within the range for Category 2) but very slight erythema was observed at the treated area in one female animal one day after the treatment (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013)).
(6) It was reported that in an acute (dust) inhalation toxicity test with rats (for 4 hours, GLP), hyperpnea, crouching posture, piloerection, and staining of hair coat were observed in both males and females after exposure at 5.05 mg/L (in the range corresponding to "Not classified") (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013)).
9 Specific target organ toxicity - Repeated exposure Category 1 (visual organs, thyroid, pancreas)


Danger
H372 P260
P264
P270
P314
P501
[Rationale for the Classification]
Based on (1) to (4), the target organs were considered to be the visual organs, thyroid, and pancreas, and effects were observed within the dosage range for Category 1, therefore, it was classified in Category 1 (visual organs, thyroid, pancreas).

[Evidence Data]
(1) It was reported that in a repeated dose 90-day oral toxicity study with rats dosed by feeding (GLP), effects on the eyes (such as corneal opacity, striated scars on the lens and neovascularization), pancreas effects (diffuse degeneration of exocrine part) and thyroid effects (flaky colloid in the follicles) were observed at or above 60 ppm (4.2 mg/kg/day (males), 5.0 mg/kg/day (females), within the range for Category 1); and chronic keratitis was observed at or above 600 ppm (43.8 mg/kg/day (males), 50.9 mg/kg/day (females), within the range for Category 2) (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013)).
(2) It was reported that in a repeated dose 90-day oral toxicity study with rats dosed by feeding (GLP), flaky colloid in the thyroid follicular cells (males) and an increase in relative liver weight (males) were observed at 15 ppm (1.1 mg/kg/day (males), 1.3 mg/kg/day (females), within the range for Category 1); and diffuse degeneration of an exocrine part of the pancreas and an increase in relative liver weight (females) were observed at 30 ppm (2.1 mg/kg/day (males), 2.5 mg/kg/day (females), within the range for Category 1) (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013)).
(3) It was reported that in a one-year combined chronic toxicity/carcinogenicity study with rats dosed by feeding (GLP), effects on the eyes (corneal opacity, pannus, chronic keratitis) and thyroid effects (an increase in follicular cell hypertrophy and localized follicular cell hyperplasia (males)) were observed at 60 ppm (3.9 mg/kg/day (males), 5.3 mg/kg/day (females), within the range for Category 1); and an increase in diffuse degeneration of acinar cells of the pancreas (males) and localized thyroid follicular cell hyperplasia (females) were observed at 600 ppm (42.0 mg/kg/day (males), 53.2 mg/kg/day (females), within the range for Category 2) (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013)).
(4) It was reported that in a two-year combined chronic toxicity/carcinogenicity study with rats dosed by feeding (GLP), effects on the eyes (corneal opacity, chronic keratitis), diffuse lesions of the pancreas, and thyroid effects (diffuse follicular cell hypertrophy (males), localized follicular cell hyperplasia (females)) were observed at 60 ppm (3.6 mg/kg/day (males), 4.7 mg/kg/day (females), within the range for Category 1); and localized thyroid follicular cell hyperplasia (males) was observed at or above 600 ppm (36.4 mg/kg/day (males), 50.8 mg/kg/day (females), within the range for Category 2) (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013)).

[Reference Data, etc.]
(5) It was reported that in a repeated dose 90-day oral toxicity study with mice dosed by feeding (GLP), an increase in relative liver weight (females) was observed at or above 1,000 ppm (288.0 mg/kg/day (males), 406.0 mg/kg/day (females), in the range corresponding to "Not classified") (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013)).
(6) It was reported that in a repeated dose 90-day oral toxicity study with dogs dosed by feeding (GLP), light brown feces, reddish brown urine (two males), and reduced food efficiency and reduced body weight gain (males) were observed at 25,000 ppm (535 mg/kg/day (males), 624 mg/kg/day (females), in the range corresponding to "Not classified") (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013)).
(7) It was reported that in a one-year chronic toxicity study with dogs dosed by feeding (GLP), an increase in absolute kidney weight (males) was observed in males at 3,000 ppm and in females at or above 2,800 ppm (81 mg/kg/day (males), 92 mg/kg/day (females), within the range for Category 2); and severe lesions of the kidney and the urinary bladder, such as urinary bladder mucosal hemorrhage, cystitis, suppurative/necrotic pyelonephritis, suppurative inflammation of the renal cortex, and necrotic lesions in the inner zone of the renal medulla, were observed in males at 9,000 ppm and in females at or above 7,800 ppm (248 mg/kg/day (males), 287 mg/kg/day (females), in the range corresponding to "Not classified") (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013)).
(8) It was reported that in a one-year chronic toxicity study with dogs dosed by feeding (GLP), no specific target organ toxicity was observed at 500 ppm (15.3 mg/kg/day (males), 15.4 mg/kg/day (females), within the range for Category 2) (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013)).
(9) It was reported that in an 18-month combined chronic toxicity/carcinogenicity study with mice dosed by feeding (GLP), an increase in relative kidney weight and an increase in relative liver weight (males) were observed at 80 ppm (19 mg/kg/day (males), 26 mg/kg/day (females), within the range for Category 2); and an increase in relative testis/epididymis weight and centrilobular hepatocyte hypertrophy (males) and an increase in relative liver weight (females) were observed at 800 ppm (194 mg/kg/day (males), 256 mg/kg/day (females), in the range corresponding to "Not classified") (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013)).
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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