NITE - Chemical Management Field

GHS Classification Results by the Japanese Government

GENERAL INFORMATION

Item	Information
CAS RN	1314-41-6
Chemical Name	Trilead tetraoxide
Substance ID	R03-B-013-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	FY2006
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)	- -	-	-	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	Not classified	- -	-	-	It is not combustible (GESTIS (Accessed June 2021)).
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 (Not applicable)	- -	-	-	Solid (GHS definition)
10	Pyrophoric solids	Not classified	- -	-	-	It is not combustible (GESTIS (Accessed June 2021)).
11	Self-heating substances and mixtures	Not classified	- -	-	-	It is not combustible (GESTIS (Accessed June 2021)).
12	Substances and mixtures which, in contact with water, emit flammable gases	Not classified	- -	-	-	It contains metals (Pb), but it is estimated that it does not react vigorously with water from information that it is insoluble in water (GESTIS (Accessed June 2021)).
13	Oxidizing liquids	Not classified (Not applicable)	- -	-	-	Solid (GHS definition)
14	Oxidizing solids	Classification not possible	- -	-	-	It is an inorganic compound containing oxygen, but the classification is not possible due to no data.
15	Organic peroxides	Not classified (Not applicable)	- -	-	-	It is an inorganic compound.
16	Corrosive to metals	Classification not possible	- -	-	-	Test methods applicable to solid substances are not 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] Based on (1), it was classified as "Not classified." [Evidence Data] (1) LD50 for rats: > 2,000 mg/kg (AICIS IMAP (2013))
1	Acute toxicity (Dermal)	Not classified	- -	-	-	[Rationale for the Classification] Based on (1), it was classified as "Not classified." Also, based on the new information, classification results were changed. [Evidence Data] (1) LD50 for rats: > 2,000 mg/kg (AICIS IMAP (2013))
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] 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." Also, based on the new findings, classification results were changed. [Evidence Data] (1) It was reported that, in an acute dermal irritation/corrosion test (OECD TG 404) with rabbits, no skin irritation effects were observed (AICIS IMAP (2013)).
3	Serious eye damage/eye irritation	Not classified	- -	-	-	[Rationale for the Classification] Based on (1), it was classified as "Not classified." Also, based on the new findings, classification results were changed. [Evidence Data] (1) It was reported that, in an acute eye irritation/corrosion test (OECD TG 405) with rabbits, no eye irritation effects were observed (AICIS IMAP (2013)).
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." Also, based on the new findings, classification results were changed. [Evidence Data] (1) It was reported that, in a skin sensitization test (OECD TG 406) with guinea pigs, negative results were obtained (AICIS IMAP (2013)).
5	Germ cell mutagenicity	Category 2	Warning	H341	P308+P313 P201 P202 P280 P405 P501	[Rationale for the Classification] There is no data of this substance itself, and the classification of this hazard class is based on the data of inorganic lead compounds. Based on (1) to (3), it was considered that, when a lead compound was absorbed and the blood lead concentration exceeded a fixed value, genotoxicity appeared, and therefore, it was classified in Category 2. With the additional new information sources, the classification result was changed. [Evidence Data] (1) In numerous epidemiological studies, which had examined genotoxic effects associated with Pb exposure in adults (general populations and workers) and children (most of them were studies of small scale occupational exposure), numerous studies with blood Pb concentration (PbB) ≧ 10 microg/dL reported associations for exposure to Pb and genotoxic endpoints (gene mutation, DNA damage, SCE, MN formation, and DNA methylation) (although some inverse associations had been reported) (ATSDR (2020)). (2) In humans, the followings were reported with PbB > 10 microg/dL: (i) DNA damage; corroborated in numerous studies, (ii) Decreased telomere length, (iii) Chromosomal aberrations; evaluated in numerous studies with mainly positive results, (iv) Sister chromatid exchange; evaluated in numerous studies with mainly positive results, (v) Micronuclei formation; evaluated in numerous studies with mainly positive results, and (vi) DNA methylation (ATSDR (2020)). (3) As for in vivo, positive results were reported in a comet assay using the bone marrow cells, leukocytes, and spermatozoa after administration (inhalation exposure, oral exposure, intraperitoneal/intravenous administration: single or repeated exposure) of lead or lead acetate to rats and mice; negative results were reported in a comet assay using the hepatocytes after oral exposure of lead nitrate at a dose where hepatotoxicity appeared; positive results were reported in a chromosomal aberration test using the bone marrow cells and spermatocytes after single or repeated exposure (intraperitoneal, gavage, dietary) of lead compounds to rats or mice; positive results were reported in a SCE (sister chromatid exchange) test using the bone marrow cells after intravenous administration of lead compounds to rats and mice; and positive results were reported in a micronucleus test using the bone marrow cells after repeated exposure (intraperitoneal, gavage, drinking water) of lead compounds to rats and mice. Also, the increase in chromosomal damage did not demonstrate clear dose-dependence (ATSDR (2020)). [Reference Data, etc.] (4) In an occupational exposure, inorganic lead is absorbed by the respiratory tract, orally, and by the digestive tract, and with particular emphasis, by inhalation from the respiratory organs. When the concentration of lead in the air is low, absorption from the digestive tract cannot be ignored. The lung deposition rate of lead in the air in adults is 30 to 50%, and 40 to 50% of lead particles which have reached the alveolus are absorbed. The deposition rate of lead oxide is 45% when the particle diameter is 0.04 micrometers and 30% when the particle diameter is 0.09 micrometers (OEL Documentations (Japan Society For Occupational Health (JSOH), 2016)).
6	Carcinogenicity	Category 1B	Danger	H350	P308+P313 P201 P202 P280 P405 P501	[Rationale for the Classification] There is no data of this substance itself, and the classification of this hazard class is based on the data of inorganic lead compounds. As for carcinogenicity of lead, based on (2) which indicates that the evidence of carcinogenicity has been considerably accumulated, and based on the IARC classification of (1) and (3), this substance, which is an inorganic lead compound, was classified in Category 1B. The classification result was changed by adding and reviewing new information sources. [Evidence Data] (1) As for the classification results by domestic and international assessment organizations, the IARC classified it in Group 2A as an inorganic lead (IARC 87 (2006)), the ACGIH classified it in A3 as lead and its inorganic compounds (ACGIH (7th, 2001): Classification in 1995), the Japan Society For Occupational Health (JSOH) classified it in Group 2B as lead and a lead compound (OEL Documentations (Japan Society For Occupational Health (JSOH), 2016) : Classification in 1991), the EPA classified it in B2 (IRIS (2004): Classification in 1988), the NTP classified it in R (NTP RoC (14th, 2016): Classification in 2004), and the DFG classified it in Category 2 (DFG MAK Addendum (2019): Classification in 2006). (2) Numerous epidemiological studies have evaluated associations between Pb exposure and cancer. Although studies provide limited evidence of carcinogenicity of Pb in humans, results are inconsistent, with several negative studies, and interpretation of data may be limited due to confounding factors (e.g., smoking status, family history of cancer, co-exposure to other carcinogens). The ATSDR additionally collected and analyzed new epidemiological data (2006 to 2019) assessed by the IARC since 2006 and summarized that, at blood Pb concentration ≦ 10 microg/mL, risks increased for all cancers and lung cancer, and at blood Pb concentration > 10 microg/mL, increased risks were observed for all cancers, respiratory tract cancer, stomach cancer, intestinal cancer, cancer of the larynx, and glioma (ATSDR (2020)). (3) As for carcinogenicity of inorganic lead compounds, the evidence in humans was limited, and the evidence in test animals was sufficient, and therefore, IARC classified it in Group 2A (IARC 87 (2006)). [Reference Data, etc.] (4) As for lead oxide, there was one report indicating that, in a 1-year inhalation toxicity study with male rats (5.3 mg/m3 on average: equivalent to a dose at which kidney tumor was caused in 10% animals by oral administration of lead acetate, according to the original author), there was no increase in the incidence of lung tumor (kidney tumor was observed only in 1 animal) (IARC 87 (2006)).
7	Reproductive toxicity	Category 1A	Danger	H360	P308+P313 P201 P202 P280 P405 P501	[Rationale for the Classification] Based on (1) to (4), it was classified in Category 1A. There is no data of this substance itself, and the classification of this hazard class is based on the data of inorganic lead compounds. Based on (1) to (4), lead and lead compounds were considered to be the substance which showed reproduction/developmental toxicity in humans. [Evidence Data] (1) Health effects of lead on the male reproductive system were damages to sperm (decreased sperm count, concentration, motility, and viability, and increased immature sperm concentration and percentage of morphologically abnormal sperm), alterations in serum levels of reproductive hormones (testosterone, estradiol, LH, and FSH), decreased fertility, and histopathological changes to the testes, and severity of these effects increases with an increase in PbB (blood lead concentration). Studies conducted in populations with PbB ≦ 10 microg/dL provided evidence of damages to sperm, although effects were more consistently observed at PbB > 10 microg/dL. A few studies reported that populations with higher PbB (> 10 microg/ mL) provided evidence of more severe effects, including decreased fertility and histopathological damage to testes (ATSDR (2020), OEL Documentations (Reproductive toxicant classification) (Japan Society For Occupational Health (JSOH)), 2013)). (2) Compared to studies of male reproductive effects, the epidemiologic literature database for effects of Pb on the female reproductive system is smaller, with most epidemiological studies conducted in populations with mean PbB ≦ 10 microg/mL. Studies provided some evidence of alterations in serum reproductive hormone levels (estradiol, LH, and FSH), decreased fertility, increased spontaneous abortion, increased preterm birth, and earlier age at onset of menopause. However, as for the association between PbB and female reproductive effects, results were inconsistent among studies (ATSDR (2020), OEL Documentations (Reproductive toxicant classification) (Japan Society For Occupational Health (JSOH)), 2013)). (3) Numerous epidemiological studies have evaluated developmental effects of lead, with most studies conducted in populations with maternal and/or umbilical cord PbB ≦ 10 microg/dL. Some studies provided evidence of decreased birth size (weight, height, head circumference, trunk length, leg length, arm length, BMI), and delayed onset of puberty in male and female children of the mothers who were exposed to the substance during pregnancy. Although it was difficult to assess dose-dependence for developmental effects within the range of PbB ≦ 10 microg/dL), dose-related decreases in birth weight were observed (ATSDR (2020), OEL Documentations (Reproductive toxicant classification) (Japan Society For Occupational Health (JSOH)), 2013)). (4) Based on the review by the U.S. NTP, the Japan Society For Occupational Health (JSOH) judged that lead had reproductive toxicity in humans, and classified lead and its compounds in Group 1 of reproductive toxicants (OEL Documentations (Reproductive toxicant classification) (Japan Society For Occupational Health (JSOH)), 2013)). [Reference Data, etc.] (5) In the EU CLP classification, this substance was classified as Repr. 1A.
8	Specific target organ toxicity - Single exposure	Category 1 (nervous system, blood system, gastrointestinal tract, kidney)	Danger	H370	P308+P311 P260 P264 P270 P321 P405 P501	[Rationale for the Classification] This substance is classified based on the data of inorganic lead compounds. Based on (1) to (3), the blood system, nervous system, digestive tract, and kidney were judged to be the target organs, and this substance was classified in Category 1 (nervous system, blood system, digestive tract, kidney). Also, based on the new information, classification results were changed. [Evidence Data] (1) In humans, the onset of acute toxicity is rapid, usually occurring within 1-5 days of exposure. The main organ systems involved are the gastrointestinal, hematological, and neurological systems. Signs and symptoms increase in severity with an increasing blood lead concentration (PbB), ranging from mild to severe. Gastrointestinal effects include abdominal colic/pain, nausea, vomiting, and constipation. Hematological effects include decreased hemoglobin synthesis, anemia, and acute hemolytic crisis (characterized by anemia and hemoglobinuria). Neurological symptoms are associated with acute Pb toxicity, including headache, hyperirritability, decreased activity, paresthesia, muscle pain, weakness, ataxic gait, decreased consciousness, cerebral edema leading to seizures and coma, encephalopathy, and death. Other reported symptoms include astringency of the mouth, metallic taste in the mouth, and thirst (ATSDR (2020)). (2) Children are more susceptible than adults to Pb poisoning because the fractional absorption of ingested Pb is higher in children than in adults and the developing central nervous system is more vulnerable to toxicity compared to a fully developed nervous system. In addition, acute toxic in children may have long-lasting effects. For example, children who recover from acute encephalopathy can have long-term decreases in cognitive abilities, attention deficits, and impaired behavior (ATSDR (2020)). (3) Humans may be exposed to lead by inhalation of lead particles from the lung in an industrial site handling lead or by inhalation of lead content orally from the digestive tract. In either case, an increase in the amount of exposure to lead causes disorders of the hematopoietic system (heme synthesis delta-aminolevulinic acid dehydratase inhibition, anemia, etc.), nervous system (peripheral neuropathy, encephalopathy, etc.), digestive system (colic pain, etc.), and kidney (nephropathy, etc.) (OEL Documentations (Japan Society For Occupational Health (JSOH), 2016)).
9	Specific target organ toxicity - Repeated exposure	Category 1 (nervous system, blood system, kidney)	Danger	H372	P260 P264 P270 P314 P501	[Rationale for the Classification] This substance is classified based on the data of inorganic lead compounds. Based on (1) to (4), the blood system, nervous system, and kidney were judged to be the target organs, and this substance was classified in Category 1 (nervous system, blood system, kidney). [Evidence Data] (1) Prospective and large cross-section studies in children provided consistent evidence of decrements in neurological function, including decrements in cognitive function (learning and memory), altered behavior and mood (attention, hyperactivity, impulsivity, irritably, delinquency), and altered neuromotor and neurosensory function (visual-motor integration, dexterity, postural sway, changes in hearing and visual thresholds) as neurological effects of Pb exposure. Numerous studies reported evidence for these effects even at a blood lead concentration (PbB) ≦ 5 microg/dL. Similar neurological effects were also observed in adults, but those effects were caused by exposure to a higher concentration than in children. Furthermore, in the case of adults exposed to higher PbB (> 30 microg/dL), peripheral neuropathy, psychiatric symptoms (depression, panic disorders, anxiety, confusion, schizophrenia, etc.) were reported (ATSDR (2020)). (2) Renal toxic effects of Pb are well-established in numerous epidemiological studies. Studies show consistent evidence of renal damage and reduced renal function at PbB ≧ 10 microg/dL, and some studies report that renal effects were also observed at PbB ≦ 5 microg/dL. Renal dysfunctions include enzymuria, proteinuria, impaired transport of organic anions and glucose, and depressed glomerular filtration rate (GFR), and in cases of exposure to higher PbB (> 30 microg/dL), Pb-induced renal damage characterized by proximal tubular nephropathy, glomerular sclerosis, interstitial fibrosis, and tubular necrosis was caused (ATSDR (2020)). (3) The toxicity of Pb to the blood system has been established in numerous studies in adults and children. Exposure to Pb causes dose-dependent decreases in heme synthesis through inhibition of the delta-aminolevulinic acid dehydratase (delta-ALAD), and decreases in blood hemoglobin and increased red cell membrane fragility result in the development of anemia (ATSDR (2020)). (4) Humans may be exposed to lead by inhalation of lead particles from the lung in an industrial site handling lead or by inhalation of lead content orally from the digestive tract. In either case, an increase in the amount of exposure to lead causes disorders of the hematopoietic system (heme synthesis delta-aminolevulinic acid dehydratase inhibition, anemia, etc.), nervous system (peripheral neuropathy, encephalopathy, etc.), digestive system (colic pain, etc.), and kidney (nephropathy, etc.). In addition to the above, cardiovascular effects including hypertension were also reported (OEL Documentations (Japan Society For Occupational Health (JSOH), 2016)). [Reference Data, etc.] (5) In a large number of epidemiological studies in adults, as cardiovascular effects associated with PbB, numerous results showing increased systolic and diastolic blood pressure were obtained. Although there were not many reports, a few studies reported that increased blood pressure was also observed in children and pregnant women. Other studies reported increased risk of hypertension and heart disease, arteriosclerosis, altered cardiac conduction, and increased mortality due to cardiovascular disease, etc. to be the effects of Pb exposure, and reported with that low-level environmental Pb exposure is an important risk factor for cardiovascular disease mortality (ATSDR (2020)).
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)	Classification not possible	- -	-	-	No data available.
11	Hazardous to the aquatic environment Long term (Chronic)	Classification not possible	- -	-	-	No data available.
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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