NITE - Chemical Management Field

Latest GHS Classification Results by the Japanese Government (edited by NITE)

GENERAL INFORMATION

Item	Information
CAS RN	58-55-9
Chemical Name	Theophylline
Substance ID	m-nite-58-55-9_v1
Download of Excel format	Excel file

REFERENCE INFORMATION

Item	Information
Guidance used for the classification (External link)	To Guidance List
UN GHS document (External link)	To UN GHS document
FAQ（GHS classification results by the Japanese Government）	To FAQ
List of Information Sources (Excel file)	List of Information Sources
List of Definitions/Abbreviations	Definitions/Abbreviations
Sample Label by MHLW (External link)	MHLW Website (in Japanese Only)
Sample SDS by MHLW (External link)	MHLW Website (in Japanese Only)
OECD/eChemPortal (External link)	To OECD/eChemPortal (External link)

PHYSICAL HAZARDS

Hazard class		Classification	Pictogram Signal word	Hazard statement (code)	Precautionary statement (code)	Rationale for the classification	Classification year (FY)	GHS Classification Guidance for the Japanese Government
1	Explosives	Not classified (Not applicable)	- -	-	-	There are no chemical groups associated with explosive properties present in the molecule.	FY2012	GHS Classification Guidance by the Japanese Government （July, 2010）
2	Flammable gases	Not classified (Not applicable)	- -	-	-	Solid (GHS definition)	FY2012	GHS Classification Guidance by the Japanese Government （July, 2010）
3	Aerosols	Not classified (Not applicable)	- -	-	-	Not aerosol products.	FY2012	GHS Classification Guidance by the Japanese Government （July, 2010）
4	Oxidizing gases	Not classified (Not applicable)	- -	-	-	Solid (GHS definition)	FY2012	GHS Classification Guidance by the Japanese Government （July, 2010）
5	Gases under pressure	Not classified (Not applicable)	- -	-	-	Solid (GHS definition)	FY2012	GHS Classification Guidance by the Japanese Government （July, 2010）
6	Flammable liquids	Not classified (Not applicable)	- -	-	-	Solid (GHS definition)	FY2012	GHS Classification Guidance by the Japanese Government （July, 2010）
7	Flammable solids	Classification not possible	- -	-	-	No data available. Besides, for this substance, there is information that it is hardly flammable (SIDS (2003)), while there is information that it is a combustible solid (GESTIS (Access on May 2012)).	FY2012	GHS Classification Guidance by the Japanese Government （July, 2010）
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.	FY2012	GHS Classification Guidance by the Japanese Government （July, 2010）
9	Pyrophoric liquids	Not classified (Not applicable)	- -	-	-	Solid (GHS definition)	FY2012	GHS Classification Guidance by the Japanese Government （July, 2010）
10	Pyrophoric solids	Not classified	- -	-	-	It is estimated that it does not ignite at normal temperatures from an autoignition temperature of > 600 deg C (SIDS (2003)).	FY2012	GHS Classification Guidance by the Japanese Government （July, 2010）
11	Self-heating substances and mixtures	Classification not possible	- -	-	-	No data available.	FY2012	GHS Classification Guidance by the Japanese Government （July, 2010）
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).	FY2012	GHS Classification Guidance by the Japanese Government （July, 2010）
13	Oxidizing liquids	Not classified (Not applicable)	- -	-	-	Solid (GHS definition)	FY2012	GHS Classification Guidance by the Japanese Government （July, 2010）
14	Oxidizing solids	Not classified (Not applicable)	- -	-	-	The substance is an organic compound containing chlorine and oxygen (but not fluorine) which are chemically bonded only to carbon or hydrogen.	FY2012	GHS Classification Guidance by the Japanese Government （July, 2010）
15	Organic peroxides	Not classified (Not applicable)	- -	-	-	Organic compounds containing no bivalent -O-O- structure.	FY2012	GHS Classification Guidance by the Japanese Government （July, 2010）
16	Corrosive to metals	Classification not possible	- -	-	-	Test methods applicable to solid substances are not available.	FY2012	GHS Classification Guidance by the Japanese Government （July, 2010）
17	Desensitized explosives	-	- -	-	-	-	-	-

HEALTH HAZARDS

Hazard class		Classification	Pictogram Signal word	Hazard statement (code)	Precautionary statement (code)	Rationale for the classification	Classification year (FY)	GHS Classification Guidance for the Japanese Government
1	Acute toxicity (Oral)	Category 3	Danger	H301	P301+P310 P264 P270 P321 P330 P405 P501	It was classified in Category 3 based on LD50 values of 272 mg/kg and 225 mg/kg for rats (both SIDS (2003)).	FY2012	GHS Classification Guidance by the Japanese Government （July, 2010）
1	Acute toxicity (Dermal)	Not classified	- -	-	-	It was classified as "Not classified" because there were no dead animals after administration of 2,000 mg/kg to rats, and an LD50 value was > 2,000 mg/kg (SIDS (2003)).	FY2012	GHS Classification Guidance by the Japanese Government （July, 2010）
1	Acute toxicity (Inhalation: Gases)	Not classified (Not applicable)	- -	-	-	Solid (GHS definition)	FY2012	GHS Classification Guidance by the Japanese Government （July, 2010）
1	Acute toxicity (Inhalation: Vapours)	Classification not possible	- -	-	-	No data available.	FY2012	GHS Classification Guidance by the Japanese Government （July, 2010）
1	Acute toxicity (Inhalation: Dusts and mists)	Not classified	- -	-	-	It was classified as "Not classified" because there were no dead animals in a test by 4-hour exposure to 6.7 mg/L (dust) in rats (OECD TG403), and an LC50 value was > 6.7 mg/L (SIDS (2003)).	FY2012	GHS Classification Guidance by the Japanese Government （July, 2010）
2	Skin corrosion/irritation	Not classified	- -	-	-	In a test by a 4-hour semi-occlusive application of 0.5 g of a 50% solution of this substance to the skin of three rabbits (OECD TG404), only slight erythema was observed in two animals 4 hours after the application, and no irritation symptoms were seen at observation after 24, 48, and 72 hours. And the average irritation index (PDII) was 0, and it was judged as not irritating (SIDS (2003)). Therefore, it was classified as "Not classified."	FY2012	GHS Classification Guidance by the Japanese Government （July, 2010）
3	Serious eye damage/eye irritation	Not classified	- -	-	-	In a test in which 0.51 mg of undiluted this substance was applied to the conjunctival sac of three rabbits (OECD TG405), very slight corneal opacity was observed in 1-2 animals up to day 8, and slight to well-defined conjunctival redness and swelling were found in all three animals up to 72 hours. Two out of three animals recovered, and one showed conjunctival redness, slight corneal opacity, and keratitis on day 8, and the iris was unaffected in each animal at each time. The average irritation index was 0.6 for corneal opacity, 0.0 for iritis, 1.8 for conjunctival redness, and 0.6 for conjunctival swelling (SIDS (2003)). Because it was less than 1 for corneal opacity and iritis and less than 2 for conjunctival redness and swelling, it was classified as "Not classified."	FY2012	GHS Classification Guidance by the Japanese Government （July, 2010）
4	Respiratory sensitization	Classification not possible	- -	-	-	No data available.	FY2012	GHS Classification Guidance by the Japanese Government （July, 2010）
4	Skin sensitization	Classification not possible	- -	-	-	No data available.	FY2012	GHS Classification Guidance by the Japanese Government （July, 2010）
5	Germ cell mutagenicity	Not classified	- -	-	-	It was classified as "Not classified" based on a negative result in a chromosomal aberration test with spermatogonial cells after 75-week diet administration to rats (in vivo germ cell mutagenicity test) (SIDS (2003)) and negative results in a chromosomal aberration test with bone marrow cells after intraperitoneal administration to mice and a micronucleus test with peripheral blood after oral administration to mice (in vivo somatic cell mutagenicity test) (NTP DB (Access on May 2012), SIDS (2003)). Besides, as for sister chromatid exchange tests with mouse bone marrow cells (in vivo somatic cell genotoxicity test), there is a report on a negative result after intraperitoneal administration and a positive result after oral administration (SIDS (2003)), and as for in vitro tests, it was reported to be negative in both an Ames test and a chromosomal aberration test with CHO cells (NTP DB (Access on May 2012)).	FY2012	GHS Classification Guidance by the Japanese Government （July, 2010）
6	Carcinogenicity	Classification not possible	- -	-	-	It was classified as "Classification not possible" based on Group 3 in the IARC's carcinogenicity assessment (IARC 51 (1991)). Besides, it is reported that there was no evidence of carcinogenicity in both sexes of both species in 2-year gavage administration carcinogenicity tests with rats and mice (NTP TR 473 (1998)).	FY2012	GHS Classification Guidance by the Japanese Government （July, 2010）
7	Reproductive toxicity	Category 2,	Warning	H361 H362	P308+P313 P201 P202 P260 P263 P264 P270 P280 P405 P501	In a test with mice administered by feeding during 18-week continuous mating (RACB protocol), a decrease in the number of live pups per litter and a decrease in the number of deliveries were observed at the high dose (500 mg/kg/day) (NTP RACB 84074 (1985)). A decrease in the number of live pups per litter was found at or above the middle dose (218 mg/kg/day) in a test with pregnant rats administered by feeding during the organogenesis period (NTP TER 84110 (1985)), and in a test with pregnant mice given drinking water administration during the organogenesis period, the percent of resorptions, dead fetuses, and malformed live fetuses increased, and there was a trend toward an increase in the incidence of litters with one or more malformed fetuses and the incidence of external malformations (NTP TER 84111 (1985)). Based on these results, because parent animals showed general toxicity such as alopecia, reduced weight gain, and decreased food consumption at the same doses, it was classified in Category 2. Furthermore, there is a case report that tachycardia and transient jitteriness were observed as adverse effects in three out of 12 newborns from mothers who were administered this substance to treat asthma (SIDS (2003)), and it is also described in the package insert of the medicine for this substance that breastfeeding should be avoided during its use because it may cause irritability in nursing infants by transferring to breast milk (Ethical Pharmaceuticals (2010), corresponding to List 1). Therefore, it was classified in the Additional category: Effects on or via lactation.	FY2012	GHS Classification Guidance by the Japanese Government （July, 2010）
8	Specific target organ toxicity - Single exposure	Category 1 (nervous system, cardiovascular system)	Danger	H370	P308+P311 P260 P264 P270 P321 P405 P501	This substance has been used as a medicine of bronchodilator, and as poisoning symptoms from an overdose, there is a description of neuropsychiatric symptoms such as headache, insomnia, anxiousness, excitement, convulsion, delirium, clouding of consciousness, and coma and, cardiovascular symptoms such as tachycardia, ventricular tachycardia, auricular fibrillation, and drop of blood pressure (Ethical Pharmaceuticals (2010)). There is a report on a case of 50-year-old women who attempted suicide with this substance, she was comatose on admission at the hospital and developed several generalized convulsive episodes, and the examination revealed ventricular tachycardia and fibrillation in addition to tachypnea, dyspnea, and peripheral cyanosis (SIDS (2003)). And there is another case report that two patients without a history of neurological damage developed seizures due to overdose of this substance (SIDS (2003)). From the above, it was classified in Category 1 (nervous system, cardiovascular system). Besides, as for animal tests, signs of convulsions, accelerated respiration, eyelid closure, and salivation were observed after oral administration of 1,000 mg/kg (corresponding to Category 2) to rats (SIDS (2003)).	FY2012	GHS Classification Guidance by the Japanese Government （July, 2010）
9	Specific target organ toxicity - Repeated exposure	Category 1 (nervous system, cardiovascular system)	Danger	H372	P260 P264 P270 P314 P501	This substance has been used as a medicine of bronchodilator, and as poisoning symptoms from an overdose, there is a description of neuropsychiatric symptoms such as headache, insomnia, anxiousness, excitement, convulsion, delirium, clouding of consciousness, and coma and cardiovascular symptoms such as tachycardia, ventricular tachycardia, auricular fibrillation, and drop of blood pressure (Ethical Pharmaceuticals (2010)). According to a comprehensive summary of reports on the toxicity of this substance between 1980 and 1990, the majority of the adverse effects occur in two categories of neurologic symptoms and cardiovascular symptoms: seizures were observed in 198 patients; arrhythmia was the most frequent cardiovascular complication; 525 patients showed abnormal conduction ranging from sinus tachycardia to ventricular tachycardia or fibrillation; and there is a report on 63 deaths (SIDS (2003)). And there is a report on nine cases of poisoning in adults, signs of severe toxicity such as hypotension and cardiac arrhythmias were common in patients aged over 50, convulsions in three patients, tachycardia in all patients, and hypotension in four occurred, and three died of finally cardiorespiratory arrest with convulsions and hypotension (SIDS (2003)). It was classified in Category 1 (nervous system, cardiovascular system) based on the above reports. Besides, there is a report on the results of 14-week repeated-dose tests by oral administration to rats and mice, but no findings indicating severe toxicity effects are reported in either test (NTP TR 473 (1998)).	FY2012	GHS Classification Guidance by the Japanese Government （July, 2010）
10	Aspiration hazard	Classification not possible	- -	-	-	No data available.	FY2012	GHS Classification Guidance by the Japanese Government （July, 2010）

ENVIRONMENTAL HAZARDS

Hazard class		Classification	Pictogram Signal word	Hazard statement (code)	Precautionary statement (code)	Rationale for the classification	Classification year (FY)	GHS Classification Guidance for the Japanese Government
11	Hazardous to the aquatic environment Short term (Acute)	Category 3	- -	H402	P273 P501	It was classified in Category 3 from 96-hour LC50 = 100 mg/L for fish (Leuciscus idus) (SIDS, 2004).	FY2012	GHS Classification Guidance by the Japanese Government （July, 2010）
11	Hazardous to the aquatic environment Long term (Chronic)	Not classified	- -	-	-	If chronic toxicity data are used, then it is classified as "Not classified" due to rapid degradability (readily biodegradable: 90-100% (SIDS, 2004)), and 72-hour NOEC = 12.5 mg/L for algae (Desmodesmus subspicatus) (SIDS, 2004). If acute toxicity data are used for a trophic level for which chronic toxicity data are not obtained, then it is classified as "Not classified" due to rapid degradability (readily biodegradable: 90-100% (SIDS, 2004)), and a low bioaccumulation estimate (LogKow = -0.02 (PHYSPROP Database, 2009)), although it corresponds to Category 3 in acute toxicity for fish (SIDS, 2004). From the above results, it was classified as "Not classified."	FY2012	GHS Classification Guidance by the Japanese Government （July, 2010）
12	Hazardous to the ozone layer	Classification not possible	- -	-	-	This substance is not listed in the Annexes to the Montreal Protocol.	FY2012	GHS Classification Guidance by the Japanese Government （July, 2010）

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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