Item | Information |
---|---|
CAS RN | 534-52-1 |
Chemical Name | 4,6-Dinitro-o-cresol |
Substance ID | R02-B-005-MHLW, MOE |
Classification year (FY) | FY2020 |
Ministry who conducted the classification | Ministry of Health, Labour and Welfare (MHLW)/Ministry of the Environment (MOE) |
New/Revised | Revised |
Classification result in other fiscal year | FY2006 FY2014 |
Download of Excel format | Excel file |
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 |
Hazard class | Classification | Pictogram Signal word |
Hazard statement (code) |
Precautionary statement (code) |
Rationale for the classification | |
---|---|---|---|---|---|---|
1 | Explosives | Not classified |
- |
- | - | There is a chemical group associated with explosive properties, a nitro group, present in the molecule, but because it is classified in Division 6.1 in UNRTDG (UN1598), it does not correspond to explosives, hazards of the highest precedence, and it was classified as "Not classified." |
2 | Flammable gases | Not classified (Not applicable) |
- |
- | - | Solid (GHS definition). It was classified as "Not classified." |
3 | Aerosols | Not classified (Not applicable) |
- |
- | - | Not aerosol products. It was classified as "Not classified." |
4 | Oxidizing gases | Not classified (Not applicable) |
- |
- | - | Solid (GHS definition). It was classified as "Not classified." |
5 | Gases under pressure | Not classified (Not applicable) |
- |
- | - | Solid (GHS definition). It was classified as "Not classified." |
6 | Flammable liquids | Not classified (Not applicable) |
- |
- | - | Solid (GHS definition). It was classified as "Not classified." |
7 | Flammable solids | Classification not possible |
- |
- | - | No data available. Besides, there is information that it is combustible (ICSC (2004)). |
8 | Self-reactive substances and mixtures | Type G |
- |
- | - | There is a chemical group associated with explosive properties, a nitro group, present in the molecule, but because it is classified in Division 6.1 in UNRTDG (UN1598), it is considered to be not applicable to self-reactive substances and mixtures, hazards of the highest precedence, and it was classified in Type G. |
9 | Pyrophoric liquids | Not classified (Not applicable) |
- |
- | - | Solid (GHS definition). It was classified as "Not classified." |
10 | Pyrophoric solids | Not classified |
- |
- | - | It was classified as "Not classified" because it is estimated that it does not ignite at normal temperatures from an autoignition temperature of 340 deg C (ICSC (2004)). |
11 | Self-heating substances and mixtures | Classification not possible |
- |
- | - | Classification is not possible because test methods applicable to solid (melting point <= 140 deg C) 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). It was classified as "Not classified." |
13 | Oxidizing liquids | Not classified (Not applicable) |
- |
- | - | Solid (GHS definition). It was classified as "Not classified." |
14 | Oxidizing solids | 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 (N). However, the classification is not possible due to no data. |
15 | Organic peroxides | Not classified (Not applicable) |
- |
- | - | Organic compounds containing no bivalent -O-O- structure in the molecule. It was classified as "Not classified." |
16 | Corrosive to metals | Classification not possible |
- |
- | - | Classification is not possible because test methods applicable to solid substances are not available. |
17 | Desensitized explosives | Not classified |
- |
- | - | There is a chemical group associated with explosive properties, a nitro group, present in the molecule, but this substance was classified as "Not classified" for desensitized explosives because a pure substance does not correspond to any hazard class in explosives. |
Hazard class | Classification | Pictogram Signal word |
Hazard statement (code) |
Precautionary statement (code) |
Rationale for the classification | |
---|---|---|---|---|---|---|
1 | Acute toxicity (Oral) | Category 2 |
Danger |
H300 | P301+P310 P264 P270 P321 P330 P405 P501 |
[Rationale for the Classification] It was classified in Category 2 from (1) - (8). [Evidence Data] (1) LD50 for rats: 7 mg/kg (Environmental Risk Assessment for Chemical Substances vol. 10 (Ministry of the Environment, 2012), GESTIS (Access on April 2020)) (2) LD50 for rats: 10 mg/kg (HSDB (Access on April 2020)) (3) LD50 for rats: 20-85 mg/kg (EHC 220 (2000)) (4) LD50 for rats: 25-85 mg/kg (MAK (DFG) vol.19 (2003)) (5) LD50 for rats: 25 mg/kg (ATSDR (2018)) (6) LD50 for rats: 30 mg/kg (ATSDR (2018)) (7) LD50 for rats: 31 mg/kg (ACGIH (7th, 2019)) (8) LD50 for rats: 40 mg/kg (Environmental Risk Assessment for Chemical Substances vol. 10 (Ministry of the Environment, 2012)) |
1 | Acute toxicity (Dermal) | Category 3 |
Danger |
H311 | P302+P352 P361+P364 P280 P312 P321 P405 P501 |
[Rationale for the Classification] It was classified in Category 3 from (1) - (6). [Evidence Data] (1) LD50 for rats: 200 mg/kg (Environmental Risk Assessment for Chemical Substances vol. 10 (Ministry of the Environment, 2012), ATSDR (2018), HSDB (Access on April 2020)) (2) LD50 for rats: 200-600 mg/kg (MAK (DFG) vol.19 (2003)) (3) LD50 for rats: 600-2,000 mg/kg (EHC 220 (2000)) (4) LD50 for rabbits: 1,000 mg/kg (Environmental Risk Assessment for Chemical Substances vol. 10 (Ministry of the Environment, 2012), ATSDR (2018), EHC 220 (2000), MAK (DFG) vol.19 (2003), GESTIS (Access on April 2020), HSDB (Access on April 2020)) (5) LD50 for rabbits: 1,671 mg/kg (ATSDR (2018)) (6) LD50 for rabbits: 1,732 mg/kg (ATSDR (2018)) |
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) | Category 2 |
Danger |
H330 | P304+P340 P403+P233 P260 P271 P284 P310 P320 P405 P501 |
[Rationale for the Classification] It was classified in Category 2 from (1). Besides, because an exposure concentration was higher than the saturated vapor pressure concentration (0.0013 mg/L), the reference value in units of mg/L was applied as dust. [Evidence Data] (1) LC50 for rats (4 hours): 230 mg/m3 (0.23 mg/L) (EHC 220 (2000), MAK (DFG) vol.19 (2003)) (2) Vapor pressure of this substance: 0.00012 mmHg (25 deg C) (converted value for the saturated vapor pressure concentration: 0.0013 mg/L) (HSDB (Access on April 2020)) |
2 | Skin corrosion/irritation | Category 2 |
Warning |
H315 | P302+P352 P332+P313 P362+P364 P264 P280 P321 |
[Rationale for the Classification] It was classified in Category 2 from (1) - (4). [Evidence Data] (1) This substance is irritating to the human skin, and contact with the skin causes yellow staining of the skin (Environmental Risk Assessment for Chemical Substances vol. 10 (Ministry of the Environment, 2012)). (2) In a skin irritation test by 4-hour semi-occlusive application of this substance (0.5 g) to the rabbit skin, erythema and slight edema occurred, indicative of an irritative effect (EHC 220 (2000), GESTIS (Access on April 2020)). (3) This substance causes irritation through corrosion to the eye and irritation to the skin. And it has the potential to sensitize the skin (GESTIS (Access on April 2020)). (4) This substance causes edema in the rabbit skin and is corrosive to the rabbit eye (EHC 220 (2000)). [Reference Data, etc.] (5) It was classified in Skin Irrit. 2 (H315) in EU CLP classification (EU CLP classification (Access on May 2020)). |
3 | Serious eye damage/eye irritation | Category 1 |
Danger |
H318 | P305+P351+P338 P280 P310 |
[Rationale for the Classification] It was classified in Category 1 from (1), (2). [Evidence Data] (1) This substance is corrosive to the human eye, and entry in the eye causes redness and pain (Environmental Risk Assessment for Chemical Substances vol. 10 (Ministry of the Environment, 2012)). (2) This substance causes edema in the rabbit skin and is corrosive to the rabbit eye (EHC 220 (2000)). [Reference Data, etc.] (3) It was classified in Eye Dam. 1 (H318) in EU CLP classification (EU CLP classification (Access on May 2020)). |
4 | Respiratory sensitization | Classification not possible |
- |
- | - | [Rationale for the Classification] Classification not possible due to lack of data. |
4 | Skin sensitization | Category 1 |
Warning |
H317 | P302+P352 P333+P313 P362+P364 P261 P272 P280 P321 P501 |
[Rationale for the Classification] It was classified in Category 1 from (1), (2). The category was changed due to new data obtained. [Evidence Data] (1) This substance was sensitizing in a skin sensitization test with guinea pigs (maximization test) (EHC 220 (2000)). (2) This substance was a skin sensitizer in guinea pigs (HSDB (Access on April 2020)). [Reference Data, etc.] (3) It was classified in Skin Sens. 1 (H317) in EU CLP classification (EU CLP classification (Access on May 2020)). |
5 | Germ cell mutagenicity | Classification not possible |
- |
- | - | [Rationale for the Classification] From (1) - (3), the main rationale in the previous classification was from tests in which a pesticide containing 50% of this substance was used as a test substance, and those were not adopted this time. New information was added, but only knowledge with clearly positive results was that in Ames, and there was no knowledge on in vivo mutagenicity. Therefore, it was classified as "Classification not possible" due to lack of data. The classification result was changed from the previous classification. [Evidence Data] (1) As for in vivo, it is reported that there was a positive response in chromosomal aberrations in bone marrow cells in rats after intraperitoneal administration (EHC 220 (2000), ATSDR (2018)), and it induced DNA double-strand breaks in hepatocytes in rats after intraperitoneal administration (EHC 220 (2000), ATSDR (2018), Environmental Risk Assessment for Chemical Substances vol. 10 (Ministry of the Environment, 2012)). On the other hand, it is reported that it was negative in chromosomal aberration tests in bone marrow cells in rats after oral administration or mice after intraperitoneal administration, negative in a micronucleus test in mouse bone marrow cells after intraperitoneal administration, and negative in an unscheduled DNA synthesis test in rat hepatocytes after oral administration (EHC 220 (2000), Environmental Risk Assessment for Chemical Substances vol. 10 (Ministry of the Environment, 2012)). (2) As for in vitro, it is reported that it was negative or positive in bacterial reverse mutation tests (Ames) and chromosomal aberration tests (EHC 220 (2000), ATSDR (2018), MAK (DFG) vol.19 (2003), Environmental Risk Assessment for Chemical Substances vol. 10 (Ministry of the Environment, 2012)). (3) It is reported in EHC 220 (2000) that "In conclusion, some positive responses were detected in Salmonella, Drosophila, and mammalian cells in vitro and in vivo. However, in vivo GLP tests were negative. On the basis of all the data available, the mutagenicity of this substance remains equivocal" (EHC 220 (2000)). [Reference Data, etc.] (4) There is the knowledge that when the pesticide called "Krezonit E" containing 50% of this substance was used as a test substance, it was positive for chromosomal aberrations in human leukocytes (the initial culture) without S9 in vitro, and positive in heritable germ cell mutagenicity tests in mice (dominant lethal mutation, meiotic chromosome, chromosomal aberrations in F1 fetuses (embryos)) in vivo (EHC 220 (2000), MAK (DFG) vol.19 (2003), Environmental Risk Assessment for Chemical Substances vol. 10 (Ministry of the Environment, 2012)). In EHC 220 (2000), these in vivo positive results were attributed to some other component contained in Krezonit E. (5) It was classified in Muta. 2 in EU CLP classification (Access on April 2020). |
6 | Carcinogenicity | Classification not possible |
- |
- | - | [Rationale for the Classification] Classification not possible due to lack of data. Besides, there are no classification results by other organizations on this substance. Furthermore, reference data of test results in rats (1) were obtained, but there were no test results in mice. [Reference Data, etc.] (1) There was no increased tumor incidence in a test by 104-week diet administration of this substance (0.00025, 0.0015, 0.01%) to male and female rats (Environmental Risk Assessment for Chemical Substances vol. 10 (Ministry of the Environment, 2012)). |
7 | Reproductive toxicity | Category 2 |
Warning |
H361 | P308+P313 P201 P202 P280 P405 P501 |
[Rationale for the Classification] Based on (1), considering the observed decrease in litter size during the lactation phase at doses at which general toxicity was observed in dams as the basis for classification, it was classified in Category 2 in accordance with the GHS Classification Guidance for the Japanese Government. [Evidence Data] (1) In a two-generation reproduction toxicity study with rats dosed by feeding, a decrease in litter size during the lactation phase was observed at or above a dose (30 ppm) at which maternal toxicity was not observed, and a decrease in body weight of offspring was observed at a dose (100 ppm) at which maternal toxicity (reduced body weight gain during the gestation and lactation phases) was observed (EHC 220 (2000), Environmental Risk Assessment for Chemical Substances Vol. 10 (Ministry of the Environment, 2012)). However, in the EHC220 (2000), effects at a high dose (reduced body weight of offspring and reduced litter size during the lactation phase at a dose at which maternal toxicity was observed) were considered to be limited, and effects at a middle dose (reduced litter size during the lactation phase at a dose at which no maternal toxicity was observed) were not considered to be adverse effects. In conclusion, this substance had slight reproductive effects in the form of reduced body weight or decreased litter size during the lactation phase of offspring, but no effect on other reproductive parameters. On the other hand, in the Environmental Risk Assessment for Chemical Substances Vol. 10 (Ministry of the Environment, 2012), the observed decrease in the litter size during the lactation phase at a dose at which no maternal toxicity was observed was considered to be an adverse effect. [Reference Data, etc.] (2) In a developmental toxicity study with female rats dosed by drinking water on days 6 to 15 of gestation, no maternal toxicity nor embryonic/fetal toxicity was observed (EHC 220 (2000), Environmental Risk Assessment for Chemical Substances Vol. 10 (Ministry of the Environment, 2012)). (3) In a developmental toxicity study with female rabbits dosed by gavage on days 6-18 of gestation, malformations (microphthalmia or anophthalmia, hydrocephaly or microcephaly) were observed in fetuses at a dose at which death (4/16 animals until 5 days after the start of treatment) not related to the treatment and labored respiration were observed in dams. In this study, one animal each died on days 26 and 27 of gestation, and lung and intestinal infections were identified at necropsy (EHC 220 (2000), Environmental Risk Assessment for Chemical Substances Vol. 10 (Ministry of the Environment, 2012)). The quality of the study was considered to be low due to the high incidence of infections and deaths not related to the treatment. Therefore, it was treated as reference information. |
8 | Specific target organ toxicity - Single exposure | Category 1 (central nervous system, cardiovascular system) |
Danger |
H370 | P308+P311 P260 P264 P270 P321 P405 P501 |
[Rationale for the Classification] Based on (1) to (3), it was classified in Category 1 (central nervous system, cardiovascular system). Mainly the information of the information source in List 1 was reviewed, and the classification was changed from the previous classification. [Evidence Data] (1) The symptoms of acute poisoning in humans resulted from the effect on cell metabolism, and included severe thirst, painful colic, diarrhea, and vomiting. Dyspnea, cyanosis, tachycardia, apnea, and cardiac insufficiency with angina were also reported. The first effect on the central nervous system was usually euphoria, later the persons suffered from dizziness, a tendency to collapse, anxiety and restlessness, confusion, unconsciousness, and terminal spasms (MAK (DFG) vol.19 (2003)). (2) In an accidental intoxication case involving a 4-year-old boy, emesis and headache were the first symptoms after skin absorption, and jaundiced skin (especially on the arms), tachypnea, weak heartbeat, and severe general depression were observed. Autopsy revealed focal hemorrhages in the intestinal mucosa, capillary blood (plethora) in the brain, liver, lungs, intestinal walls, myocardium, and kidneys as well as edema of the lung and brain (ACGIH (7th, 2019)). (3) In one case of intoxication, poisoning by this substance resulted from a concentration in the air of 4.7 mg/m3. Reduction of the level to 2.5 mg/m3 eliminated the symptoms. The chief symptoms were fever, increased basal metabolic rate, rapid pulse and respiration, profuse sweating, shortness of breath, and cough (ACGIH (7th, 2019)). [Reference Data, etc.] (4) This substance had the effect of increasing the basal metabolic rate, and was used for body weight loss in the past (ATSDR (2018)). (5) This substance uncoupled oxidative phosphorylation, resulting in energy being given off as heat and manifested as hyperthermia. In an attempt to reduce body temperature, the body increased respiratory rate and heart rate as part of a compensatory mechanism. The most significant and sensitive effects resulting from acute, intermediate, or chronic exposure were related to increased basal metabolic rates (ATSDR (2018)). |
9 | Specific target organ toxicity - Repeated exposure | Category 1 (central nervous system, eye, cardiovascular system, blood system, liver, kidney, skin) |
Danger |
H372 | P260 P264 P270 P314 P501 |
[Rationale for the Classification] Based on (1) and (2), the main effect after oral administration in humans was liver damage, and effects on the central nervous system, eye, cardiovascular system, blood system, kidney, and skin were also considered, and therefore, it was classified in Category 1 (central nervous system, eye, cardiovascular system, blood system, liver, kidney, skin). Mainly the information of the information source of List 1 was reviewed, and the classification was changed from the previous classification. [Evidence Data] (1) Chronic toxic symptoms in humans were headache, weakness, anorexia, and marked weight loss. Later, degenerative changes developed in the heart muscle, liver, and kidneys, and neuritis, leukopenia, Heinz bodies, and methemoglobinemia progressed. Agranulocytosis, and severe toxic dermatitis were sometimes observed as well. Liver damage was the main effect after ingestion of the substance (MAK (DFG) vol. 19 (2003)). (2) There were reports of a case of a pearly swollen cataract in the left eye of a woman who ingested this substance for 3 years, and a case of punctate lenticular opacity in the right eye after diagnosis of cataract, which eventually led to blindness (ATSDR (2018)). [Reference Data, etc.] (3) This substance had the effect of increasing the basal metabolic rate, and was used for body weight loss in the past (ATSDR (2018)). (4) This substance uncoupled oxidative phosphorylation, resulting in energy being given off as heat and manifested as hyperthermia. In an attempt to reduce body temperature, the body increased respiratory rate and heart rate as part of a compensatory mechanism. The most significant and sensitive effects resulting from acute, intermediate, or chronic exposure were related to increased basal metabolic rates (ATSDR (2018)). (5) Dinitrophenols were known to be cataractogenic in humans. The mechanism of cataract formation was considered to be related to the inhibition of oxidative phosphorylation, which was the mechanism of action of this substance (ATSDR (2018)). (6) As a result of a 90-day test with rats dosed by feeding, at or above 2.5 mg/kg/day (within the range for Category 1), a decrease in thyroid hormone, and an increase in lipid metabolism were observed; at or above 5 mg/kg/day (within the range for Category 1), increases in hemoglobin and hematocrit values and MCH/MCV, an increase in BUN, and a reduction in urine creatinine were observed; at or above 10 mg/kg/day (within the range for Category 1), an increase in relative brain weight was observed; and at 20 mg/kg/day (within the range for Category 1), deaths (5/20 animals), an increase in ALT, histopathologic alterations in the salivary glands and fundus, lesions in the adrenal gland and pancreas, atrophy or underdevelopment of the thymus, spleen, and lymph nodes, a decrease in circulating lymphocytes, no corpora lutea in the ovaries, juvenile uteri, and aspermatogenesis were observed (ATSDR (2018)). |
10 | Aspiration hazard | Classification not possible |
- |
- | - | [Rationale for the Classification] Classification not possible due to lack of data. |
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 = 0.145 mg/L for crustacea (Daphnia pulex) (Environmental Risk Assessment for Chemical Substances Vol. 10 (Ministry of the Environment, 2012)). |
11 | Hazardous to the aquatic environment Long term (Chronic) | Category 2 |
- |
H411 | P273 P391 P501 |
It was classified in Category 2 because it was not rapidly degradable (not readily degradable, a 4-week degradation rate by BOD: 4% (Biodegradation and Bioconcentration Results of Existing Chemical Substances under the Chemical Substances Control Law, METI, 2004)) and due to 31-34-day NOEC = 0.183 mg/L for fish (Pimephales promelas) (Environmental Risk Assessment for Chemical Substances Vol. 10 (Ministry of the Environment, 2012)). The classification result was changed from the previous classification by reviewing information. |
12 | Hazardous to the ozone layer | Classification not possible |
- |
- | - | This substance is not listed in the Annexes to the Montreal Protocol. |
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