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GHS Classification Result

GENERAL INFORMATION

Item	Information
CAS RN	14409-72-4
Chemical Name	26-(4-Nonylphenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-ol (Nonoxynol-9 (p-form))
Substance ID	H30-A-001-METI, MOE
Classification year (FY)	FY2018
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 (FY2013 revised edition (Ver. 1.1))
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 applicable	- -	-	-	There are no chemical groups associated with explosive properties present in the molecule.
2	Flammable gases (including chemically unstable gases)	Not applicable	- -	-	-	Liquid (GHS definition) (the number of moles of added ethylene oxide <15).
3	Aerosols	Not applicable	- -	-	-	Not aerosol products.
4	Oxidizing gases	Not applicable	- -	-	-	Liquid (GHS definition)
5	Gases under pressure	Not applicable	- -	-	-	Liquid (GHS definition)
6	Flammable liquids	Classification not possible	- -	-	-	No data available. Besides, this substance is a p-form of Nonoxynol-9, and a flash point (Nonoxynol-9 (a mixture of o-, m-, and p-forms)) is 197 deg C [closed-cup] (ICSC (2006)).
7	Flammable solids	Not applicable	- -	-	-	Liquid (GHS definition)
8	Self-reactive substances and mixtures	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 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 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 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 applicable	- -	-	-	Liquid (GHS definition)
15	Organic peroxides	Not applicable	- -	-	-	Organic compounds containing no bivalent -O-O- structure in the molecule
16	Corrosive to metals	Classification not possible	- -	-	-	No data available.

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] Based on (1), it was classified as "Not classified" (Category 5 in UN GHS classification). [Evidence Data] (1) LD50 for rats (Nonoxynol-9 (p-isomer)): 3,000 mg/kg (CIR (Cosmetic Ingredient Review) Expert Panel (2016)) [Reference Data, etc.] (2) LD50 for rats (Nonoxynol-9 (a mixture of o-, m-, and p-isomers)): 1,410-5,600 mg/kg (Canada PS assessment report (2001), Toxicology and Applied Pharmacology, 14, 315-334 (1969)) (3) LD50 for rats (Nonoxynol-10): 1,300 mg/kg (male, female) (CIR (Cosmetic Ingredient Review) Expert Panel (2016)) (4) LD50 for rats (Nonoxynol-2, -4, -5, -6, -15): 1,980-7,500 mg/kg (CIR (Cosmetic Ingredient Review) Expert Panel (2016))
1	Acute toxicity (Dermal)	Not classified	- -	-	-	[Rationale for the Classification] Based on (1), it was classified as "Not classified" (Category 5 in UN GHS classification). Besides, isomer ratio information is unknown in (2). [Evidence Data] (1) LD50 for rabbits (Nonoxynol-9 (p-isomer)): 4,400 mg/kg (CIR (Cosmetic Ingredient Review) Expert Panel (2016)) [Reference Data, etc.] (2) LD50 for rabbits (NP9EO (Nonoxynol-9)): 2,830 mg/kg (Canada PS assessment report (2001)) (3) LD50 for rabbits (50% solution of Nonoxynol-40): >10,000 mg/kg (CIR Expert Review (2016))
1	Acute toxicity (Inhalation: Gases)	Not applicable	- -	-	-	[Rationale for the Classification] Liquid (GHS definition)
1	Acute toxicity (Inhalation: Vapours)	Classification not possible	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.
1	Acute toxicity (Inhalation: Dusts and mists)	Classification not possible	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.
2	Skin corrosion/irritation	Not classified	- -	-	-	[Rationale for the Classification] Based on (1), it was classified as "Not classified." [Evidence Data] (1) As for humans, in an irritation/sensitization test in which undiluted Nonoxynol-9 (p-isomer) was applied occlusively to the dorsal skin of men and women, 50 each, for 5 hours and applied again to the skin after 3 weeks, no irritating reaction was observed (CIR Expert Panel (2016)). [Reference Data, etc.] (2) This substance is used as a cosmetic additive, and 27 items of Nonoxynols including Nonoxynol-9 (p-isomer) are judged not to be irritative under normal usage and dosage (CIR Expert Review (2016)). (3) As a result of occlusive application of a 20% solution of Nonoxynol-10 (p-isomer) for 48 hours to 528 dermatitis patients suspected of allergic contact dermatitis, no irritating reaction to Nonoxynol-10 (p-isomer) was observed except that erythema was observed in one patient on Day 7 (CIR Expert Panel (2016)).
3	Serious eye damage/eye irritation	Category 1	Danger	H318	P305+P351+P338 P280 P310	[Rationale for the Classification] Based on (1) and (2), it was classified in Category 1. [Evidence Data] (1) There is a report that in a test in which a 20% solution of Nonoxynol-9 (p-isomer) was applied to a rabbit eye, moderate-severe irritation was observed (CIR Expert Panel (2016)). (2) There is a report that in a test in which a two drops of a 1-25% solution of Nonoxynol-9 (p-isomer) or Nonoxynol-10 (p-isomer) was applied in the rabbit eye study, very slight conjunctivitis at 1%, slight conjunctivitis and moderate corneal damage at 5%, and moderate-to-severe corneal damage at 25% were observed (CIR Expert Panel (2016)).
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), it was classified as "Not classified." Besides, the classification of "Not classified" is consistent with the fact that this substance has been continuously used as a cosmetic additive. In addition, also in the data on the test substance close to EO=9 such as in (2), sensitization is not shown. [Evidence Data] (1) As for humans, undiluted Nonoxynol-9 (p-isomer) was applied occlusively to the dorsal skin of men and women, 50 each, for 5 hours and this undiluted solution as a challenge was applied to the skin for 48 h after a 3-week rest period, but no sensitization reaction was observed (CIR Expert Panel (2016), J. Am. Col. Toxicol., 2, 35-60 (1983)). [Reference Data, etc.] (2) It is reported that no allergic reaction to Nonoxynol-10 was observed when 582 patients suspected of allergic contact dermatitis were patch tested with Nonoxynol-10 (p-isomer, 20% solution) (CIR Expert Panel (2016)). (3) There is a report that as a result of occlusive application of 0.2 mL of 4- nonylphenol ethoxylate to the dorsal skin of a total of 110 men and women three times per week for 3 weeks, 9 times in total, followed by occlusive application 2 times as a challenge after 5 weeks, only primary skin irritation was seen in 3 cases, no allergic contact dermatitis was observed, and this substance is considered to be not sensitizing in humans (REACH registration dossier (Accessed Sept. 2018)).
5	Germ cell mutagenicity	Classification not possible	- -	-	-	[Rationale for the Classification] Based on (1)-(3), it was classified as "Classification not possible" in accordance with the GHS Classification Guidance for the Japanese Government. [Evidence Data] (1) As for in vivo, there are reports that Nonoxynol-9 (isomer ratio is unknown) did not induce abnormalities in germ cells in mice and did not induce cell proliferation in peritoneal cells in rats (Canada PS Assessment report (2001)). (2) As for in vitro, it is reported that a mammalian cell gene mutation test with Nonoxynol-9 (Isomer ratio is unknown) was positive (Canada PS Assessment report (2001)). (3) As for in vitro, it is reported that bacterial reverse mutation tests with Nonoxynol-9 (Isomer ratio is unknown) were negative (Canada PS Assessment report (2001), REACH registration dossier (Accessed Sept. 2018)).
6	Carcinogenicity	Classification not possible	- -	-	-	[Rationale for the Classification] Among the available results on the carcinogenicity in humans and experimental animals, there are no reports of concern for carcinogenicity for Nonoxynol-9 as (1) and (2), although the ratio of isomers is unknown. However, as for the human report, the duration of administration is not sufficiently long considering the intended use. Since there are also no classification results by domestic and international organizations, it was classified as "Classification not possible" for this hazard class. [Evidence Data] (1) In a randomized study on 1,536 women for the clinical application of Nonoxynol-9 (Isomer ratio is unknown) as a spermicide, vaginal application of this substance in various formulations and dosages for 7 months resulted in no abnormalities in 640 women for whom cervical cytology was possible (CIR Expert Panel (2016)). (2) In 2-year studies in which Nonoxynol-9 (isomer ratio is unknown) was administered by feeding to rats at 140 mg/kg/day or to dogs at 30 mg/kg/day, no carcinogenicity was observed (J. Am. Col. Toxicol., 2, 35-60 (1983), Canada PS Assessment report (2001), CIR Expert Panel (2016)). (3) There are no classification results by domestic and international organizations.
7	Reproductive toxicity	Classification not possible	- -	-	-	[Rationale for the Classification] There is only one report indicating teratogenicity in humans shown in (1), and its association with Nonoxynol-9 application is unknown. In addition, since information on animal experiments is also insufficient, it was classified as "Classification not possible" due to lack of data. [Evidence Data] (1) There is a report that in a randomized, double-blind study to compare the clinical use of nonoxynol-9 (p-isomer) with other agents (mixture of two surfactants) as a spermicide, as a result of 12-month follow-up on 633 women, who used Nonoxynol-9, 43 surviving children out of 633 women were born, and 2 children (4.3%) of these had congenital anomalies (cardiac anomalies in one child, gastroschisis in the other child), which were regarded as potentially related to the use of Nonoxynol-9 (CIR Expert review (2016)). [Reference Data, etc.] (2) There are plural reports that intravaginal administration (25-50 mg/kg/day) or intrauterine administration (0.5 mg) of NP9EO (Nonoxynol-9) to female rats resulted in a decrease in the number of surviving fetuses and a decrease in the number of implantations (Government of Canada, PSL2 (2001)). (3) There are reports that as a result of oral administration of NP9EO (Nonoxynol-9) during the organogenesis period of pregnant rats, as developmental effects, a decrease in the number of fetuses per litter, an increase in preimplantation embryonic loss, and an increase in skeletal abnormalities were observed at or above 250 mg/kg/day where decreased body weight gain was observed in maternal animals, and that no reproductive or teratogenic effects were observed after dermal administration of NP9EO at up to 500 mg/kg/day during the organogenesis period of pregnant rats (Government of Canada, PSL2 (2001)). On the other hand, skeletal abnormalities observed in the fetuses appear as extra ribs (REACH registration dossier (Accessed Sept. 2018)).
8	Specific target organ toxicity - Single exposure	Classification not possible	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.
9	Specific target organ toxicity - Repeated exposure	Classification not possible	- -	-	-	[Rationale for the Classification] Based on (1), by oral route, this substance corresponds to "Not classified." However, human information, toxicity information by other routes is overall insufficient. Therefore, it was classified as "Classification not possible." [Evidence Data] (1) In three tests in which Nonoxynol-9 (p-isomer) was administered by feeding to rats for 90 days and in a 90-day feeding test with dogs, no effect was observed at doses within the range of Category 2. In addition, in tests in which Nonoxynol-9 (p-isomer) was administered by feeding to rats and dogs for 2 years, in rats, no effect was observed at up to 135 mg/kg/day exceeding the range of Category 2, and in dogs, an increase in the relative liver weight was observed within the range of Category 2, but it is not accompanied by histopathological changes and is not considered to be a toxic effect (J. Am. Col. Toxicol., 2, 35-60 (1983)). [Reference Data, etc.] (2) In a study in which nonoxynol-10 (p-isomer) was administered by feeding to mice for 2 years, increases in the relative weight of the brain and kidney were observed within the dose range of Category 2 but this was not accompanied by histopathological changes, and it is not considered to be a toxic effect (CIR Expert Panel (2016)). (3) There are reports that no abnormal findings were observed at doses within the guidance value range for Category 2 in any test in which Nonoxynol-4, -6, -15, -20, -30, -40 (p-isomer) was administered by feeding to rats and/or dogs for 90 days (CIR Expert Panel (2016), J. Am. Col. Toxicol., 2, 35-60 (1983)). (4) There are reports that dogs administered at 400 mg/kg/day or above of Nonoxynol-20 (p-isomer) developed cardiac lesions, and focal myocardial necrosis was observed at 1,000 mg/kg/day, but no cardiac lesions were observed in rats even at 5,000 mg/kg/day (CIR Expert Panel (2016)).
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 (Acute)	Classification not possible	- -	-	-	No data available.
11	Hazardous to the aquatic environment (Long-term)	Classification not possible	- -	-	-	No data available.
12	Hazardous to the ozone layer	Classification not possible	- -	-	-	No data available.

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.

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