NITE - Chemical Management Field

GHS Classification Results by the Japanese Government

GENERAL INFORMATION

Item	Information
CAS RN	1861-40-1
Chemical Name	N-Butyl-2,6-dinitro-N-ethyl-4-trifluoromethylaniline; Benfluralin
Substance ID	R02-A-058-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	Classification not possible	- -	-	-	There is a chemical group associated with explosive properties (nitro group) present in the molecule, and the oxygen balance is -143, higher than the criteria: -200, but the classification is not possible due to no data.
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. Besides, there is information that it is combustible (GESTIS (accessed Sep. 2020)).
8	Self-reactive substances and mixtures	Classification not possible	- -	-	-	There is a chemical group associated with explosive properties (nitro 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	- -	-	-	Classification is not possible because test methods applicable to solid (melting point <= 140 deg C) substances are not 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 fluorine and oxygen (but not chlorine), and the oxygen is chemically bonded to the element other than carbon or hydrogen (N). 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	- -	-	-	Classification is not possible because test methods applicable to solid substances are not available.
17	Desensitized explosives	Classification not possible	- -	-	-	There is a chemical group associated with explosive properties (nitro group) present in the molecule, but the classification is not possible due to no data.

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) - (3). [Evidence Data] (1) LD50 for rats: > 10,000 mg/kg (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2010), EPA Pesticides RED (2004)) (2) LD50 for rats (males): > 5,000 mg/kg (OECD TG 401, GLP) (CLH Report (2019), EPA Pesticides RED (2004)) (3) LD50 for rats (females): > 5,000 mg/kg (OECD TG 401, GLP) (CLH Report (2019), EPA Pesticides RED (2004))
1	Acute toxicity (Dermal)	Not classified	- -	-	-	[Rationale for the Classification] It was classified as "Not classified" from three test results in (1) - (3). [Evidence Data] (1) LD50 for rabbits: > 5,000 mg/kg (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2010), EPA Pesticides RED (2004)) (2) LD50 for rabbits: > 5,000 mg/kg (OECD TG 402, GLP) (CLH Report (2019)) (3) LD50 for rabbits: > 5,000 mg/kg (OECD TG 402, GLP) (CLH Report (2019))
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] The classification is not possible because effects are unknown at a dose near the upper limit for Category 4 from (1) - (3). [Evidence Data] (1) LC50 for rats: > 2.3 mg/L (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2010), EPA Pesticides RED (2004)) (2) LC50 for rats (males): > 2.16 mg/L (OECD TG 403, GLP) (CLH Report (2019)) (3) LC50 for rats (females): > 2.16 mg/L (OECD TG 403, GLP) (CLH Report (2019))
2	Skin corrosion/irritation	Category 2	Warning	H315	P302+P352 P332+P313 P362+P364 P264 P280 P321	[Rationale for the Classification] It was classified in Category 2 from (1) - (3). [Evidence Data] (1) It is reported that in a skin irritation test with rabbits (n = 6) (OECD TG 404, GLP, semi-occlusive, 4-hour application, 14-day observation), erythema persisted for 15 days in 3 animals (erythema/eschar score: 1/2/1.7/2/2/2, edema score: 1/1/1/1/1/1.3) (CLH Report (2019)). (2) It is reported that in a skin irritation test with rabbits (n = 6) (OECD TG 404, GLP, 4-hour application, 9-day observation), scaliness was observed in 5 animals after 9 days (erythema/eschar score: 0/0/0.3/0.7/0.7/0.3, edema score: 0.7/0.3/1/2/0.3/1.3) (CLH Report (2019)). (3) Moderate irritation was seen in a skin irritation test with rabbits (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2019), EPA Pesticides RED (2004)).
3	Serious eye damage/eye irritation	Category 2A	Warning	H319	P305+P351+P338 P337+P313 P264 P280	[Rationale for the Classification] It was classified in Category 2A from (1). [Evidence Data] (1) It is reported that in an eye irritation test with rabbits (n = 6) (OECD TG 405, GLP, 14-day observation), eye irritation reactions that were seen largely resolved within 7 days and completely disappeared after 14 days (corneal opacity score: 1/1/1/1/1/1.3, iritis score: 0/1/0.7/0.7/0.3/1, conjunctival redness score: 2.3/2/2/2.3/2.7/2.7, chemosis score: 2/1.3/3/2/2.3/4) (CLH Report (2019)).
4	Respiratory sensitization	Classification not possible	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.
4	Skin sensitization	Category 1	Warning	H317	P302+P352 P333+P313 P362+P364 P261 P272 P280 P321 P501	[Rationale for the Classification] It was classified in Category 1 from (1), (2). Besides, (1) supports Category 1B, (2) supports Category 1A, and it was classified in Category 1 without sub-categorization. [Evidence Data] (1) It is reported that in a maximization test with guinea pigs (n = 20) (OECD TG 406, GLP, intradermal administration: 5% solution), a sensitization rate was 95% (CLH Report (2019)). (2) It is reported that in a modified Buehler test with guinea pigs (n = 12) (OECD TG 406, GLP, topical administration: 5% solution), a sensitization rate was 75% (CLH Report (2019)).
5	Germ cell mutagenicity	Not classified	- -	-	-	[Rationale for the Classification] Based on (1) to (7), it was classified as "Not classified." [Evidence Data] (1) It was reported that in a micronucleus test using the bone marrow cells of mice (dosed by gavage), equivocal results were reported (CLH Report (2019), Annexes to the CLH Report (2019)). (2) In two micronucleus tests using the bone marrow cells of rats (dosed twice by gavage), negative results were reported (CLH Report (2019), Annexes to the CLH Report (2019)). (3) In a sister chromatid exchange test with hamsters (single oral dose), negative results were reported (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2010)). (4) In bacterial reverse mutation tests, three negative results were reported (CLH Report (2019), Annexes to the CLH Report (2019)). (5) In gene mutation tests using the mouse lymphoma cells, three negative results were reported (CLH Report (2019), Annexes to the CLH Report (2019)). (6) In micronucleus tests using the human lymphocytes, two negative results were reported (CLH Report (2019), Annexes to the CLH Report (2019)). (7) It was reported that in a chromosomal aberration test using the Chinese hamster ovary cells (CHO), negative results were reported (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2010)).
6	Carcinogenicity	Category 2	Warning	H351	P308+P313 P201 P202 P280 P405 P501	[Rationale for the Classification] Based on (1) to (3), it was classified in Category 2. [Evidence Data] (1) As for the classification results by domestic and international organizations, the EPA classified this substance in S (Suggestive Evidence of Carcinogenicity, but not Sufficient to Assess Human Carcinogenic Potential) (EPA Annual Cancer Report 2018 (Accessed September 2020): Classification in 2001). (2) In a two-year combined chronic toxicity/carcinogenicity study with rats dosed by feeding (OECD TG 453, GLP), an increase in the incidence of hepatocellular adenoma (males) and an increase in the total incidence of adenoma and carcinoma in thyroid follicular cells (males and females) were observed at or above 2,500 ppm (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2010), CLH Report (2019)). (3) In a two-year combined chronic toxicity/carcinogenicity study with mice dosed by feeding (OECD TG 451, GLP), an increase in the total incidence of hepatocellular adenoma and carcinoma was observed in females at 1,500 ppm (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2010)). According to the CLH Report (2019), based on the analysis of the background data, increases in the incidence of hepatocellular adenoma (1,500 ppm) and hepatocellular carcinoma (50, 300 and 1,500 ppm) were observed in females. On the other hand, a high number of liver tumors was observed in male mice at 1,500 ppm, but no statistically significant difference was obtained due to a high number of hepatocellular tumors in the control group. [Reference Data, etc.] (4) From the results of carcinogenicity studies, it was concluded that liver and thyroid tumors were observed in rats and liver tumors were observed in mice. The development mechanism of these tumors has been revealed to some extent, but non-relevance of extrapolation to humans was not clearly demonstrated. Therefore, according to the classification criteria, it was considered to be classified in Category 2 (EFSA (2019)). (5) It should be noted that in the carcinogenicity study with mice in (3), the batch of this substance used as a test specimen contained, as impurity, a higher level of EBNA (ethyl-butyl-nitrosamine: CAS RN 4549-44-4), which was a structural analog of known carcinogens, than the batch used in the mutagenicity/genotoxicity assessment of this substance (CLH Report (2019)).
7	Reproductive toxicity	Not classified	- -	-	-	[Rationale for the Classification] Based on (1) to (3), it was classified as "Not classified." [Evidence Data] (1) In a two-generation reproductive study with rats dosed by feeding, at doses where noticeable general toxicity effects (death (one female of F0 and of F1, or 2/30 cases), reduced body weight gain, a reduction in food consumption, liver and kidney lesions (such as hepatocellular hypertrophy, chronic nephropathy and pyelonephritis) were observed in parental animals, a reduction in litter size in F0 and F1 dams; an increase in the duration of gestation, a decrease in the number of live pups per litter on post-natal day 4, and reduced weaning rate in F1 females; and lower birth weight and lower body weight in the period from post-natal day 4 until weaning in F1 pups were observed. It was reported that no effect on fertility was observed (CLH Report (2019), Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2010)). (2) It was reported that in a developmental toxicity study with rats dosed by gavage (gestation days 6 to 15), at a dose where reduced body weight gain was observed in dams, an increase in the incidence of slight skeletal variations (variations of the vertebrae/sternebrae) in fetuses was observed, but no teratogenicity was observed (CLH Report (2019), Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2010)). (3) It was reported that in a developmental toxicity study with rabbits dosed by gavage (gestation days 6 to 18), there was no effect in fetuses at doses where reduced body weight gain and a reduction in food consumption were observed in dams, while an increase in the incidence of skeletal variations (skull bones) was observed at a high dose where death and abortion were observed in dams (CLH Report (2019), Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2010)). [Reference Data, etc.] (4) In a two-generation reproductive study with rats, several dose-dependent cases where there was no visible milk in the stomach in pups were observed. Based on this finding and the result of an ADME study in cows showing that this substance and metabolites were secreted in milk, the CLP classification proposer considered that this substance could be transferred via milk and caused growth inhibition via breast milk in pups as an adverse effect and proposed an additional classification for effects on or via lactation (CLH Report (2019)).
8	Specific target organ toxicity - Single exposure	Category 3 (Respiratory tract irritation)	Warning	H335	P304+P340 P403+P233 P261 P271 P312 P405 P501	[Rationale for the Classification] Based on (1), it was classified in Category 3 (respiratory tract irritation). [Evidence Data] (1) It was reported that in an acute (dust) inhalation toxicity test with rats (OECD TG 403, GLP), temporary hypoactivity, and body weight loss were observed at 1.12 mg/L (within the range for Category 2); and death (in 2/5 males and 1/5 females, and necropsy revealed hepatic and pulmonary congestion), dyspnea, hypoactivity, and body weight loss were observed at 2.16 mg/L (within the range for Category 2) (CLH Report (2019), EU EFSA (2019)). [Reference Data, etc.] (2) In an acute oral toxicity test with rats dosed by gavage (OECD TG 401, GLP), hypoactivity, perineal soiling with urine and lacrimation were observed after administration at 5,000 mg/kg (in the range corresponding to "Not classified") but all animals appeared symptom-free at the end of the 14-day observation period. At necropsy, no treatment-related abnormality was observed. It was reported that 2/5 females died due to a gavage error (CLH Report (2019)). (3) It was reported that in an acute dermal toxicity test with rabbits dosed by gavage (OECD TG 402, GLP), desquamation and signs of skin irritation (moderate to severe erythema and edema) were observed at 5,000 mg/kg (in the range corresponding to "Not classified"), which cleared in all animals within 28 days. No other treatment-related effect was observed (CLH Report (2019)). (4) It was reported that in an acute dermal toxicity test with rabbits (OECD TG 402, GLP), slight erythema and edema, burns and fissures (males), and scale formation and scabs were observed at 5,000 mg/kg (in the range corresponding to "Not classified") (CLH Report (2019)).
9	Specific target organ toxicity - Repeated exposure	Category 1 (liver, kidney)	Danger	H372	P260 P264 P270 P314 P501	[Rationale for the Classification] Based on (1) to (5), it was classified in Category 1 (liver, kidney). Concerning the kidney, although alpha 2mu-globulin nephropathy observed in (1) was generally specific to male rats, kidney effects were also observed in female rats. Therefore, the kidney was adopted as a target organ. [Evidence Data] (1) It was reported that in a 90-day repeated oral dose toxicity test in rodents using rats dosed by feeding (OECD TG 408, GLP), chronic nephropathy (the finding in males was caused by the accumulation of alpha 2mu-globulin), pigmentation of renal cortical tubular epithelial cells (females) and increases in absolute and relative liver/kidney weight (females) were observed at 250 ppm (17 mg/kg/day (males), 20 mg/kg/day (females), within the range for Category 2); and an increase in urinary AST (males), kidney effects (formation of hyaline droplets, regeneration of renal cortical tubular epithelial cells) (males) and hypertrophy of the liver (males) were observed at 500 ppm (25 mg/kg/day, within the range for Category 2) (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2010), CLH Report (2019)). (2) It was reported that in a 90-day repeated oral dose toxicity test with dogs dosed by gavage (OECD TG 409, GLP), vomit having the same color as that of the specimen (females) was observed at 5 mg/kg/day (within the range for Category 1); spleen effects (hemosiderin pigmentation) and vomit having the same color as that of the specimen (males) were observed at 25 mg/kg/day (within the range for Category 2); and liver effects (hepatocellular hypertrophy, increases in absolute and relative weight (males), hemosiderin pigmentation) were observed at 125 mg/kg/day (in the range corresponding to "Not classified") (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2010), CLH Report (2019)). (3) It was reported that in a chronic toxicity study with dogs dosed by gavage (OECD TG 452, GLP), liver effects (an increase in relative weight), an increase in ALT (females) and liver effects (pigmentation of sinusoidal cells) (females) were observed at 25 mg/kg/day (within the range for Category 2); and an increase in ALT (males) and liver effects (pigmentation of sinusoidal cells) (males) were observed at 125 mg/kg/day (in the range corresponding to "Not classified") (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2010), CLH Report (2019)). (4) It was reported that in a combined chronic toxicity/carcinogenicity study with rats dosed by feeding (OECD TG 453, GLP), kidney effects (formation of hyaline droplets, pelvis calculus), karyomegaly of tubular epithelial cells (males), hyperplasia of transitional epithelium (males), and liver effects (hepatocellular hypertrophy, hepatocellular pigmentation) (females) were observed at 100 ppm (5.4 mg/kg/day (males), 6.8 mg/kg/day (females), within the range for Category 1); and hematological effects (decreases in RBC, Hb and Ht, an increase in PLT, increases in BUN, Cre, TP, Alb and Glob), liver effects (increases in absolute and relative weight and chronic inflammation, hepatocellular hypertrophy (males), hepatocellular pigmentation (males), single cell necrosis in the liver (males)), chronic nephropathy, urinary bladder epithelial hyperplasia, degeneration of the sciatic nerve and femoral muscle, and chronic inflammation of the lungs were observed at 2,500 ppm (136 mg/kg/day (males), 168 mg/kg/day (females), in the range corresponding to "Not classified") (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2010), CLH Report (2019)). (5) It was reported that in a combined chronic toxicity/carcinogenicity study with mice dosed by feeding (OECD TG 451, GLP), urinary system disorder and liver nodules (females) were observed at 300 ppm (36.4 mg/kg/day (males), 41.8 mg/kg/day (females), within the range for Category 2); and bright yellow urine, liver effects (increases in absolute and relative weight, multifocal hepatocellular hyperplasia (females)) and increases in ALT and ALP (females) were observed at 1,500 ppm (185 mg/kg/day (males), 224 mg/kg/day (females), in the range corresponding to "Not classified") (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2010), CLH Report (2019)). [Reference Data, etc.] (6) After short- and long-term administrations in rats, dogs, and mice, this substance showed target organ toxicity in the liver. It was reported that in rats, the red blood cells and kidneys were affected upon a short-term exposure as well as the thyroid upon a long-term exposure, and in dogs, in addition to the above, the red blood cells were also affected (EFSA (2019)).
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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