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GHS Classification Results by the Japanese Government

GENERAL INFORMATION

Item	Information
CAS RN	29232-93-7
Chemical Name	O-2-(Diethylamino)-6-methylpyrimidin-4-yl O,O-dimethyl phosphorothioate (synonym: Pirimiphos-methy)
Substance ID	R03-B-019-METI, MOE
Classification year (FY)	FY2021
Ministry who conducted the classification	Ministry of Economy, Trade and Industry (METI)/Ministry of the Environment (MOE)
New/Revised	Revised
Classification result in other fiscal year	FY2008
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.
2	Flammable gases	Not classified (Not applicable)	- -	-	-	Liquid (GHS definition)
3	Aerosols	Not classified (Not applicable)	- -	-	-	Not aerosol products.
4	Oxidizing gases	Not classified (Not applicable)	- -	-	-	Liquid (GHS definition)
5	Gases under pressure	Not classified (Not applicable)	- -	-	-	Liquid (GHS definition)
6	Flammable liquids	Classification not possible	- -	-	-	No data available. Besides, there is information that some may burn but none ignite readily (CAMEO Chemicals in PubChem (Accessed June 2021)).
7	Flammable solids	Not classified (Not applicable)	- -	-	-	Liquid (GHS definition)
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	Classification not possible	- -	-	-	No data available.
10	Pyrophoric solids	Not classified (Not applicable)	- -	-	-	Liquid (GHS definition)
11	Self-heating substances and mixtures	Classification not possible	- -	-	-	Test methods applicable to liquid substances are not available.
12	Substances and mixtures which, in contact with water, emit flammable gases	Not classified	- -	-	-	It contains a metalloid (P), but it is estimated that it does not react vigorously with water from data obtained: water solubility of 8.6 mg/L (GESTIS (Accessed June 2021)).
13	Oxidizing liquids	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 (P). However, the classification is not possible due to no data.
14	Oxidizing solids	Not classified (Not applicable)	- -	-	-	Liquid (GHS definition)
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	- -	-	-	No data 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)	Category 4	Warning	H302	P301+P312 P264 P270 P330 P501	[Rationale for the Classification] Based on (1) to (6), it was classified in Category 4. [Evidence Data] (1) LD50 for rats: 1,414 mg/kg (OECD TG 401, GLP) (CLH Report (2017), EFSA (2005)) (2) LD50 for rats: between 1,667 to 2,050 mg/kg (JMPR (2006)) (3) LD50 for rats: 2,050 mg/kg (EHC 63 (1986)) (4) LD50 for rats: 2,400 mg/kg (EPA Pesticides RED (2006)) (5) LD50 for rats: 1,250 mg/kg (HSDB in PubChem (Accessed July 2021)) (6) LD50 for rats: 1,861 mg/kg (JMPR (1992))
1	Acute toxicity (Dermal)	Not classified	- -	-	-	[Rationale for the Classification] Based on (1) and (2), it was classified as "Not classified." [Evidence Data] (1) LD50 for rats: > 2,000 mg/kg (EFSA (2005)) (2) LD50 for rabbits: > 2,000 mg/kg (EHC 63 (1986))
1	Acute toxicity (Inhalation: Gases)	Not classified	- -	-	-	[Rationale for the Classification] Liquid (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] Based on (1) and (2), it was classified as "Not classified." Also, the exposure concentration was higher than the saturated vapor pressure concentration (< 0.01 mg/L) and it was judged as being in a mist state. [Evidence Data] (1) LC50 (4 hours) for rats: > 4.7 mg/L (EFSA (2005), EPA Pesticides RED (2006)) (2) LC50 (4 hours) for rats: > 5.04 mg/L (Haz-Map in PubChem (Accessed July 2021))
2	Skin corrosion/irritation	Category 2	Warning	H315	P302+P352 P332+P313 P362+P364 P264 P280 P321	[Rationale for the Classification] Based on (1), it was classified in Category 2 in accordance with the GHS Classification Guidance for the Japanese Government. Also, based on the new findings, classification results were changed. [Evidence Data] (1) This substance was a moderate irritant substance (EPA Pesticides (2006)). [Reference Data, etc.] (2) It was reported that, in a skin irritation test with rabbits, slight irritation was observed (HSDB (Accessed Aug. 2021)). (3) This substance was a slight irritant substance (EFSA (2005)).
3	Serious eye damage/eye irritation	Category 2	Warning	H319	P305+P351+P338 P337+P313 P264 P280	[Rationale for the Classification] Based on (1), it was classified in Category 2 in accordance with the GHS Classification Guidance for the Japanese Government. [Evidence Data] (1) This substance was an eye irritant substance (EPA Pesticides (2006)). [Reference Data, etc.] (2) It was reported that, in an eye irritation test with rabbits, slight eye irritation was observed (HSDB (Accessed Aug. 2021)). (3) This substance was a slightly eye irritant substance (EFSA (2005)).
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] Based on (1) to (3), it was classified as "Not classified." Also, based on the new findings, classification results were changed. [Evidence Data] (1) This substance was not a skin sensitizing substance (EPA Pesticides (2006)). (2) It was reported that, in a Maximization test with guinea pigs, mild sensitization reaction was observed (EFSA (2005)). (3) It was reported that, in a test with guinea pigs, no skin sensitization was observed (HSDB (Accessed Aug. 2021)).
5	Germ cell mutagenicity	Not classified	- -	-	-	[Rationale for the Classification] Based on (1) and (2), it was classified as "Not classified." [Evidence Data] (1) As for in vivo, the results of a micronucleus assay using the bone marrow cells of mice, an unscheduled DNA synthesis test using hepatocytes of rats, and a dominant lethal study using mice were all negative (CLH Report (2017), EFSA (2005)). (2) As for in vitro, the results of a bacterial reverse mutation test, a mammalian cell (mouse lymphoma cells L5178Y) gene mutation assay, and a chromosomal aberration test using the human lymphocytes were all negative (CLH Report (2017)).
6	Carcinogenicity	Not classified	- -	-	-	[Rationale for the Classification] Based on (1) to (3), it was classified as "Not classified." [Evidence Data] (1) In a 2-year combined chronic toxicity/carcinogenicity study with rats dosed by feeding (non-GLP), marginally increased incidences of pancreatic and brain tumors were observed mainly in the highest-dose group (300 ppm: equivalent to 12.6 mg/kg/day) (CLH Report (2017), EFSA (2005)). However, it was judged that these tumors were not related to treatment but occurred spontaneously. The rationale for the judgment was that the increase in the incidence was minimal and that any pre-neoplastic lesions or any other toxicological findings in the pancreas and brain tissues were not observed, and therefore, these organs were difficult to be considered as target organs. There was no mechanistic basis for tumor formation, raising into question the biological plausibility of the findings. Furthermore, it was found to be non-genotoxic and the test results with mice treated at higher doses in (2) were negative (CLH Report (2017)). (2) In a 78-week carcinogenicity study with mice dosed by feeding (OECD TG451, GLP), at doses up to 300 ppm (equivalent to 57 mg/kg/day), no increase in the incidence of tumors was observed in either males or females (CLH Report (2017), EFSA (2005)). (3) Based on (1) and (2), the RAC of the ECHA agreed to the classification proposal that this substance should not be classified for carcinogenicity in light of the CLP classification criteria (ECHA RAC (2018)). [Reference Data, etc.] (4) As for the classification results by domestic and international evaluation organizations, the EPA classified this substance as CBD (Cannot Be Determined) (EPA OPP Annual Cancer Report 2020 (Accessed July 2021): Classification in 1999). (5) With regard to pancreatic tumors in rats, there was an increased incidence of islet cell adenoma in males and one male of the top dose group was found to have pancreatic islet cell carcinoma. Both findings were within historical control data provided and were considered a natural occurrence in aged rats, unrelated to treatment. In addition, there were no pre-neoplastic lesions and no pancreatic tumors observed in female rats and mice. Therefore, the pancreatic tumors observed in male rats were not considered to be treatment-related (CLH Report (2017)). (6) With regard to brain tumors in rats, two male rats of the mild and high dose groups were found to have benign meningioma (versus each 1 in controls and the low dose groups). The tumor incidences were only marginally above the concurrent control and were within the historical control data range, and therefore, not considered as sufficient evidence of a carcinogenic response. In females, 1 rat in the top dose group was found to have a brain ependymoma (not seen in concurrent controls or other treated animals). However, this was within the historical control data range, and therefore, not considered to be treatment-related (CLH Report (2017)).
7	Reproductive toxicity	Not classified	- -	-	-	[Rationale for the Classification] Based on (1) to (6), it was classified as "Not classified." Besides, in (1), reduced mating rate and pregnancy rate were noted in pups, but the extent of reduction was unknown. In (2), which was newly conducted later, no reproductive and developmental toxicity was observed in the high-dose groups, and in the two-generation reproduction toxicity study and developmental toxicity studies in (3) to (6), no reproductive toxicity was observed, either. [Evidence Data] (1) In a three-generation reproduction toxicity study with rats dosed by feeding, at doses at which no general toxicity effects were observed in parental animals (20 ppm and 200 ppm, a four-generation study at 20 ppm), reduced mating rate and dose-related reduction of pregnancy rates were noted in F1 or F2 pups (JMPR (1992)). (2) It was reported that, in another three-generation reproduction toxicity study with rats dosed by feeding up to high dose (100 ppm) at which reduced plasma and erythrocyte cholinesterase (ChE) activities (> 20%) were observed in parental animals, no reproductive and developmental toxicity effects were observed (JMPR (1992)). (3) It was reported that, in two-generation reproduction toxicity study with rats by oral administration, no reproductive toxicity was observed (EFSA (2005)). (4) It was reported that, in a developmental toxicity study (days 1-20 of gestation) with rats dosed by feeding, no developmental toxicity was observed (JMPR (1992)). (5) It was reported that, in a developmental toxicity study (days 7-16 of gestation) with rats dosed by gavage, only minor effects (slight delayed ossification) were observed in offspring at the highest dose at which general toxic effects (reduced body weight gain and reduced food consumption) were observed in parent animals (JMPR (1992)). (6) It was reported that, in one of two developmental toxicity studies with rabbits dosed by gavage (days 1 to 28 of gestation), an increase in litter size and associated decreased mean weight of pups from a litter were observed at a dose (16 mg/kg/day) at which general toxicity effects (reduced erythrocyte and plasma ChE activities) were observed in parental animals (JMPR (1992)). It was reported that, in another test, shifted pelvic position was observed in pups at a dose (48 mg/kg/day) at which general toxicity effects (reduced erythrocyte and brain ChE activity) were observed in parental animals. However, this finding was judged as a borderline effect and a skeletal variation, not a malformation (EFSA (2005)).
8	Specific target organ toxicity - Single exposure	Category 1 (nervous system)	Danger	H370	P308+P311 P260 P264 P270 P321 P405 P501	[Rationale for the Classification] Based on (1) to (5), it was classified in Category 1 (nervous system). Also, based on the new findings, classification results were changed. [Evidence Data] (1) This substance can cause cholinesterase inhibition in humans. It was reported that, if it caused cholinesterase inhibition, it could overstimulate the nervous system causing nausea, dizziness, and confusion, and at very high exposures due to accidents, etc., respiratory paralysis and death (HSDB in PubChem (Accessed July 2021)). (2) It was reported that, in an acute neurotoxicity test with rats, dose-related decreases in erythrocyte and brain acetylcholinesterase activities were observed at or above 150 mg/kg (within the range for Category 1) (JMPR Report (2006)). (3) It was reported that, in an acute neurotoxicity study with rats, the primary effect observed was inhibition of cholinesterase activity in both brain and erythrocytes, and the NOAEL was determined to be 15 mg/kg (EFSA (2005)). (4) It was reported that, in an acute oral toxicity test with rats (OECD TG 401, GLP), piloerection, urine staining, tip toe gait, salivation, and upward curvature of the spine were seen with a dose-related increase in severity at or above 500 mg/kg (within the range for Category 2) (CLH Report (2017)). (5) It was reported that, in an acute neurotoxicity test with rats, effects on erythrocyte, plasma, and brain cholinesterase were observed and the LOAEL was determined to be 15 mg/kg (EPA Pesticides RED (2006)).
9	Specific target organ toxicity - Repeated exposure	Category 1 (nervous system)	Danger	H372	P260 P264 P270 P314 P501	[Rationale for the Classification] In (1) to (9), effects on plasma, erythrocyte, and brain cholinesterase activities were observed within the range for Category 1. In addition, in (5), effects on the liver were observed within the range for Category 2, while in (6), which was a longer-term test using the same species, no effect was observed. Based on the above, it was classified in Category 1 (nervous system). Besides, in a test with humans, since the dosage was limited in (10) and (11), no toxicological findings were observed. [Evidence Data] 1) It was reported that, in a repeated dose 28-day oral toxicity study with rats dosed by feeding, inhibition of plasma and brain cholinesterase activities was observed at or above 250 ppm (converted guidance value: 3.89 mg/kg/day, within the range for Category 1); an increase in serum ALP was observed at or above 500 ppm (converted guidance value: 7.78 mg/kg/day, within the range for Category 1); and a slight increase in liver weight and an increase in serum transaminase were observed at 1,000 ppm (converted guidance value: 15.6 mg/kg/day, within the range for Category 2) (JMPR (1992)). (2) It was reported that, in a repeated dose 28-day oral toxicity study with rats dosed by feeding, inhibition of plasma cholinesterase activity (>20%) and brain cholinesterase activity (>10%) was observed at 50 ppm (converted guidance value: 0.778 mg/kg/day, within the range for Category 1) (JMPR (1992), CLH Report (2017)). (3) It was reported that, in a repeated dose 4-week oral toxicity study with rats dosed by gavage (5 days/week), prolonged blood coagulation time and prothrombin time, and a decrease in platelet count were observed at or above 50 mg/kg/day (converted guidance value: 11.1 mg/kg/day, within the range for Category 2) (JMPR (1992)). (4) It was reported that, in a repeated dose 90-day oral toxicity study with rats dosed by feeding, depressed plasma cholinesterase activity, reduced body weight gain (females) and a slight decrease in food consumption (females) were observed at 80 ppm (4 mg/kg/day, within the range for Category 1) and depressed erythrocyte and brain cholinesterase activities were observed at 360 ppm (18 mg/kg/day, within the range for Category 2) (JMPR (1992), CLH Report (2017)). (5) It was reported that, in a repeated dose 13-week oral toxicity study with dogs dosed by gavage, inhibition of plasma and erythrocyte cholinesterase activities and decreased food consumption (females) were observed at or above 2 mg/kg/day (within the range for Category 1); bile duct hyperplasia (males) was observed at 10 mg/kg/day (within the range for Category 1); liquid stool and reduced body weight gain (females) were observed at or above 10 mg/kg/day; and reduced body weight gain (males), decreased food consumption (males), bile duct hyperplasia and portal cirrhosis (males), and higher ALAT and SAP were observed at 25 mg/kg/day (within the range for Category 2) (JMPR (1992)). (6) It was reported that, in a 2-year chronic toxicity study with dogs, inhibition of brain cholinesterase activity was observed at or above 0.5 mg/kg/day (within the range for Category 1); inhibition of erythrocyte cholinesterase activity was observed at 2 mg/kg/day (within the range for Category 1); and inhibition of plasma cholinesterase activity, reduced body weight gain, decreased food consumption, increased absolute and relative liver weight, and a slight increase in ALAT were observed at 10 mg/kg/day (within the range for Category 1) (JMPR (1992), CLH Report (2017)). (7) It was reported that, in an 80-week oral administration study with mice dosed by feeding, reduced erythrocyte and plasma cholinesterase activities were observed at 500 ppm (25 mg/kg/day, within the range for Category 2) (JMPR (1992)). (8) It was reported that, in a 2-year combined chronic toxicity/carcinogenicity study with rats, reduced brain cholinesterase activity (males) and reduced plasma cholinesterase activity (females) were observed at 50 ppm (2.5 mg/kg/day, within the range for Category 1), and reduced plasma, erythrocyte, and brain cholinesterase activities and mild anemia (females) were observed at 300 ppm (15 mg/kg/day, within the range for Category 2) (JMPR (1992)). (9) It was reported that, in a repeated dose 21-day dermal administration test with rabbits (6 hours/day), reduced erythrocyte cholinesterase activity (females) was observed at 40 mg/kg/day (converted guidance value: 9.33 mg/kg/day, within the range for Category 1) and reduced erythrocyte cholinesterase activity was observed at 400 mg/kg/day (converted guidance value: 93.3 mg/kg/day, within the range for Category 2) (CLH Report (2017)). [Reference Data, etc.] (10) It was reported that, after 5 normal men orally ingested this substance at 0.25 mg/kg/day for 28 days, inhibition of plasma cholinesterase activity (21.5%) was observed in one man on day 28, and in comparison to pre-ingestion, a slight decrease in erythrocyte cholinesterase activity was observed in 4/5 men in the last 2 weeks. However, it was reported that there was no significant difference in the mean value of the group at any point in time, and the variability was within the range of normal test subjects who did not ingest it (JMPR (1992)). (11) This substance was administered by capsule to 3 men and 4 women at 0.25 mg/kg/day for 56 days. It was reported that there were no abnormalities in liver functions (plasma AST, ALT, ALP, GT), blood test data (Hb, PCV, MCHC, total white blood cell count and differential white blood count, platelet count, ESR (erythrocyte sedimentation rate)), or erythrocyte ChE activity (JMPR (1992)).
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 48-hour EC50 = 0.000314 mg a.i./L for crustacea (Daphnia magna) (EU CLP CLH, 2017, Document for registration standards for agricultural chemicals set by the Minister of Environment to prevent harm to animals and plants in areas of public waters, 2018). The classification result was changed from the previous classification by using new information (a.i.: active ingredient).
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 in Category 1 due to being not rapidly degradable (BIOWIN) and 21-day NOEC = 0.00005 mg/L for crustacea (Daphnia magna) (EU CLP CLH, 2017). 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 due to being not rapidly degradable and 96-hour LC50 = 0.679 mg a.i./L for fish (Cyprinus carpio) (Document for registration standards for agricultural chemicals set by the Minister of Environment to prevent harm to animals and plants in areas of public waters, 2018). From the above results, it was classified in Category 1. The classification result was changed from the previous classification by using new information (a.i.: active ingredient).
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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