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GHS Classification Results by the Japanese Government

GENERAL INFORMATION

Item	Information
CAS RN	51-03-6
Chemical Name	5-Propan-1-yl-6-(2,5,8-trioxadodecan-1-yl)-1,3-benzodioxole; Piperonyl Butoxide
Substance ID	R02-A-022-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)	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	Not classified	- -	-	-	A flash point was 179 deg C (closed-cup) (ECHA (Accessed Aug. 2020)).
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	Not classified	- -	-	-	It is estimated that it does not ignite at normal temperatures from an autoignition temperature of 265 deg C (ECHA (Accessed Aug. 2020)).
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 (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)	- -	-	-	The substance is an organic compound containing oxygen (but not fluorine or chlorine) which is chemically bonded only to carbon or hydrogen.
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)	Not classified	- -	-	-	[Rationale for the Classification] It was classified as "Not classified" from (1), (2). [Evidence Data] (1) LD50 for rats: about 5,630 mg/kg (4,570 mg/kg (males), 7,220 mg/kg (females)) (OECD TG 401) (EU CLH report (2019)) (2) LD50 for rats (females): > 2,000 mg/kg (OECD TG 423) (EU CLH report (2019))
1	Acute toxicity (Dermal)	Not classified	- -	-	-	[Rationale for the Classification] It was classified as "Not classified" from (1), (2). [Evidence Data] (1) LD50 for rats: > 2,000 mg/kg (OECD TG 402) (EU CLH report (2019)) (2) LD50 for rabbits: > 2,000 mg/kg (OECD TG 402) (EU CLH report (2019))
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] It was classified as "Not classified" from (1), (2). Besides, because exposure concentrations exceeded the saturated vapor pressure concentration (0.27 mg/L), these were judged as tests on mist. [Evidence Data] (1) LC50 for rats (4 hours): > 5.2 mg/L (OECD TG 403) (EU CLH report (2019)) (2) LC50 for rats (4 hours): > 5.9 mg/L (EU CLH report (2019))
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 = 6) (OECD TG 404, GLP, 72-hour observation), 4 animals showed very slight erythema but recovered within 24 hours (erythema/eschar score: 0/0/0/0/0/0, edema score: 0/0/0/0/0/0) (EU CLH report (2019), REACH registration dossier (Accessed Aug. 2020)). (2) It is reported that in a skin irritation test with rabbits (n = 3) (OECD TG 404, GLP, semi-occlusive, 4-hour application, 3-day observation), no edema was seen in any animal. Very slight erythema was observed after 24 hours, and no skin reactions were found after 72 hours (erythema/eschar score: 0.7/0.3/0.3) (EU CLH report (2019), REACH registration dossier (Accessed Aug. 2020)).
3	Serious eye damage/eye irritation	Category 2B	- Warning	H320	P305+P351+P338 P337+P313 P264	[Rationale for the Classification] It was classified in Category 2B from (1). [Evidence Data] (1) It is reported that in an eye irritation test with rabbits (n = 3) (OECD TG 405, GLP, 5-day observation), all the symptoms seen fully disappeared within 5 days (corneal opacity score: 0/1.7/1.7, iritis score: 0/0.7/0.7, conjunctival redness score: 0.3/1/1, chemosis score: 0/0.3/0.7) (REACH registration dossier (Accessed Aug. 2020)). [Reference Data, etc.] (2) It is reported that in an eye irritation test with rabbits (n = 6) (OECD TG 405, GLP, 7-day observation), all the signs seen fully disappeared within 72 hours (corneal opacity score: 0/0/0/0/0/0, iritis score: 0/0/0/0/0/0, conjunctival redness score: 0/0/0.7/0.3/0/0, chemosis score: 0/0/0/0/0/0) (EU CLH report (2019), REACH registration dossier (Accessed Aug. 2020)).
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 modified Buehler test with guinea pigs (n = 10) (OECD TG 406, GLP, challenge: 100% solution), a positive rate was 0% (0/10) at both 24, 48 hours after challenge (EU CLH report (2019), REACH registration dossier (Accessed Aug. 2020)). (2) It is reported that in a maximization test with guinea pigs (n = 10) (OECD TG 406, GLP, intradermal administration: 10% solution), no animal showed positive reactions at 24, 48 hours after challenge (REACH registration dossier (Accessed Aug. 2020)).
5	Germ cell mutagenicity	Not classified	- -	-	-	[Rationale for the Classification] Based on (1) to (4), it was classified as "Not classified." [Evidence Data] (1) In a micronucleus test using the peripheral blood erythrocytes of mice (dosed by gavage, 2 days), negative results were reported ((REACH registration dossier (Accessed on May 2020), CLH Report (2019)). (2) In bacterial reverse mutation tests, negative results were reported (CLH Report (2019). (3) In a mammalian cell (CHO) gene mutation test, negative results were reported (CLH Report (2019)). (4) In a mammalian cell (CHO) chromosome aberration test, negative results were reported (CLH Report (2019)).
6	Carcinogenicity	Category 2	Warning	H351	P308+P313 P201 P202 P280 P405 P501	[Rationale for the Classification] Based on (1) to (5), it was classified in Category 2. [Evidence Data] (1) As for the classification results by domestic and international organizations, IARC classified this substance in Group 3 (IARC Suppl. 7 (1987)), and EPA classified it in Group C (Possible Human Carcinogen) (EPA Cancer Annual Report 2018 (Accessed Aug. 2020): Classification in 1995). However, the IARC classification was determined based on the old data from earlier reports up to the NCI's (1978) (IARC 30 (1983)) and could not be used for this classification. (2) In a two-year chronic toxicity/carcinogenicity study with rats dosed by feeding, no evidence of carcinogenicity was found at doses of up to 10,000 ppm (500 mg/kg/day) (JMPR (1996), CLH Report (2019)). (3) In a two-year chronic toxicity/carcinogenicity study with rats dosed by feeding, the dose-related incidence and severity of neoplastic lesions of the liver were observed at 6,000 ppm or more and increased hepatocellular adenoma and carcinomas were observed in the mid- and high-dose groups (12,000 and 24,000 ppm). However, systemic toxicity effects such as gastric and cecal hemorrhages, kidney lesions and anemia were observed in all dose groups (JMPR (1996)、CLH Report (2019)). It was concluded that this substance was carcinogenic at doses which caused systemic toxicity (JMPR (1996)). (4) In a 78-week carcinogenicity study with mice dosed by feeding, male and female mice that were given diets at 100 mg/kg/day or more exhibited eosinophilic foci and adenomas with eosinophilic cells in the livers at high frequency (JMPR (1996)). (5) In a 12-month carcinogenicity study with mice dosed by feeding, a dose-related decrease in body weight was observed in the mid- and high-dose groups (6,000 and 12,000 ppm) and increased mortality was also observed in the high-dose group. Increased incidences of hepatocellular adenomas and carcinomas were observed in the treated groups at those doses (JMPR (1996), CLH Report (2019)). Incidences of hepatocellular adenomas and carcinomas, combined, were 1.9%, 24.5%, and 75% in the control dose group, the 6,000 ppm dosed group, and the 12,000 ppm dosed group, respectively. In the 12,000 ppm dosed group, hemangioendothelial sarcoma of the liver was also observed (42% vs the control group 0%) (CLH Report (2019)). With respect to this test result, JMPR concluded that this substance was toxic to the liver and was carcinogenic at doses which caused systemic toxicity (EPA (1995), JMPR (1996)).
7	Reproductive toxicity	Not classified	- -	-	-	[Rationale for the Classification] Based on (1) to (3), it was classified as "Not classified." [Evidence Data] (1) It was reported that in a two-generation reproduction toxicity study with rats dosed by feeding (OECD TG416), a decrease in body weight and reduced body weight gain were only observed in parental animals and the offspring at 500 mg/kg/day (CLH Report (2019)、JMPR (1996)). (2) It was reported that in a developmental toxicity study with rats dosed by gavage (OECD TG414), no developmental toxicity was observed (CLH Report (2019), JMPR (1996)). (3) It was reported that in a developmental toxicity study with rabbits dosed by gavage (OECD TG414), no developmental toxicity was observed (CLH Report (2019), JMPR (1996)).
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) to (4), it was classified as "Not classified" in the oral and dermal routes. Based on (5) and (6), it was classified in Category 3 (respiratory tract irritation). In (1), the doses at which the symptoms were observed were not clear. It was judged based on the reported NOEL that there were no effects at 2,010 mg (in the range corresponding to "Not classified"). [Evidence Data] (1) It was reported that in an acute oral toxicity test with rats dosed by gavage (OECD TG 401, GLP), yellow anogenital staining, ruffled fur, lethargy, dark nasal and ocular staining and ruffed skin were observed in the rats dosed at 2,010 to 11,250 mg/kg, and a gross pathological examination of the rats which died mainly in the higher dose groups showed retention of dark liquid and gas in the lower gastrointestinal tract, staining of the muzzle, hemorrhagic lungs, yellow genital staining, and pale liver and/or kidney. The NOEL of 2,010 mg/kg was reported (EU CLH report (2019), REACH registration dossier (Accessed Aug. 2020)). (2) It was reported that in an acute oral toxicity test with rats dosed by gavage (OECD TG423, GLP), no effects were observed at 2,000 mg/kg (upper limit of Category 2) (EU CLH report (2019), REACH registration dossier (Accessed Aug. 2020)). (3) It was reported that in an acute dermal toxicity test with rats (OECD TG402, GLP), no effects were observed at 2,000 mg/kg (upper limit of Category 2) (EU CLH report (2019), REACH registration dossier (Accessed Aug. 2020)). (4) It was reported that in an acute dermal toxicity test with rabbits (OECD TG 402, GLP), slight erythema and edema were observed at 2,000 mg/kg (upper limit of Category 2), but the recovery was observed from day 2 onwards (EU CLH report (2019), JMPR (1996), REACH registration dossier (Accessed Aug. 2020)). (5) It was reported that in an acute inhalation toxicity test with rats exposed to mist (OECD TG 403, GLP, for 4 hours), slightly reduced motility, slight ataxia, and slight dyspnea were observed at 5.2 mg/L (in the range corresponding to "Not classified") (EU CLH report (2019), REACH registration dossier (Accessed Aug. 2020)). (6) It was reported that in an acute inhalation toxicity test with rats exposed to mist (GLP, for 4 hours), at 5.9 mg/L (in the range corresponding to "Not classified"), nasal discharge, excessive salivation, eye closure, and decreased spontaneous activity were noted, and during the first week after the administration, excessive lacrimation, salivation, nasal discharge, and labored breathing were noted, and at necropsy, red foci were observed in the lungs (2 females) (EU CLH report (2019), REACH registration dossier (Accessed Aug. 2020)).
9	Specific target organ toxicity - Repeated exposure	Category 2 (liver)	Warning	H373	P260 P314 P501	[Rationale for the Classification] Based on (1) and (2), liver effects were observed in the oral route, and it was classified in Category 2 (liver). Based on (3), it was classified as "Not classified" in the dermal route. For the inhalation route, classification was not possible due to lack of data. [Evidence Data] (1) It was reported that in an 8-week oral toxicity test with dogs dosed by feeding (OECD TG 409), reduced body weight gain, liver effects (increases in absolute and relative weight, hepatocellular hypertrophy, an increase in ALP) and a decrease in testicular weight were observed at 2,000 ppm (63 mg/kg/day (males), 61 mg/kg/day (females), within the range for Category 2) (CLH Report (2019)). (2) It was reported that in a one-year oral toxicity test with dogs dosed by feeding (OECD TG 452), liver effects (increases in liver/gallbladder weight, hepatocellular hypertrophy, an increase in ALP) were observed at 2,000 ppm (53 mg/kg/day (males), 71 mg/kg/day (females), within the range for Category 2) (CLH Report (2019)). (3) It was reported that in a 21-day dermal toxicity test with rabbits, skin effects (erythema, edema, desquamation, fissuring, red raised areas) were observed at 100 mg/kg/day (converted guidance value: 23.3 mg/kg/day, within the range for Category 2) but no systemic toxicity was observed at 1,000 mg/kg/day (converted guidance value: 233.3 mg/kg/day, in the range corresponding to "Not classified") (CLH Report (2019)). [Reference Data, etc.] (4) It was reported that in a 90-day oral toxicity test with mice dosed by feeding (OECD TG 408), an increase in relative liver weight (males) and hepatocellular hypertrophy were observed at 102.6 mg/kg/day (males) and 103.5 mg/kg/day (females) (in the range corresponding to "Not classified") (CLH Report (2019)). (5) It was reported that in a 91-day oral toxicity test with rats dosed by feeding, an increase in relative kidney weight was observed at 1,200 mg/kg/day (in the range corresponding to "Not classified") (CLH Report (2019)). (6) It was reported that in a 3-month inhalation toxicity test with rats exposed to mist (OECD TG 413, 6 hours/day, 5 days/week), red nasal discharge and histopathological alterations in the larynx (such as squamous metaplasia with hyperkeratosis (minimal) and inflammation (moderate)) as local effects and liver effects (an increase in relative liver weight, a decrease in serum liver enzymes activity) as systemic effects were observed at 0.512 mg/L (in the range corresponding to "Not classified") (CLH Report (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)	Category 1	Warning	H400	P273 P391 P501	It was classified in Category 1 from 96-hour EC50 = 0.49 mg/L for crustacea (Mysidopsis bahia) (EU CLP CLH, 2019).
11	Hazardous to the aquatic environment Long term (Chronic)	Category 1	Warning	H410	P273 P391 P501	It was classified in Category 1 because it is not rapidly degradable (BIOWIN) and due to 21-day NOEC = 0.03 mg/L for crustacea (Daphnia magna) (EU CLP CLH, 2019).
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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