GHS Classification Results by the Japanese Government
GENERAL INFORMATION
REFERENCE INFORMATION
PHYSICAL HAZARDS
HEALTH HAZARDS
ENVIRONMENTAL HAZARDS
NOTE:
GENERAL INFORMATION
| Item | Information |
|---|---|
| CAS RN | - |
| Chemical Name | Dioxins |
| Substance ID | R03-B-019-MHLW |
| Classification year (FY) | FY2021 |
| Ministry who conducted the classification | Ministry of Health, Labour and Welfare (MHLW) |
| New/Revised | Revised |
| Classification result in other fiscal year | FY2017 FY2009 FY2006 FY2015 FY2015 FY2015 FY2007 FY2007 FY2007 FY2007 FY2007 FY2007 FY2007 FY2007 FY2006 FY2007 FY2014 FY2007 FY2006 FY2006 FY2006 FY2006 FY2006 FY2006 FY2006 FY2006 FY2006 FY2006 FY2006 FY2006 FY2006 FY2006 FY2006 FY2006 FY2006 FY2006 FY2006 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) | |
| Model SDS by MHLW (External link) | |
| 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 (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) (2,3,7,8-TCDD) |
| 3 | Aerosols | Not classified (Not applicable) |
- |
- | - | Not aerosol products. |
| 4 | Oxidizing gases | Not classified (Not applicable) |
- |
- | - | Solid (GHS definition) (2,3,7,8-TCDD) |
| 5 | Gases under pressure | Not classified (Not applicable) |
- |
- | - | Solid (GHS definition) (2,3,7,8-TCDD) |
| 6 | Flammable liquids | Not classified (Not applicable) |
- |
- | - | Solid (GHS definition) (2,3,7,8-TCDD) |
| 7 | Flammable solids | Classification not possible |
- |
- | - | No data available. |
| 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) (2,3,7,8-TCDD) |
| 10 | Pyrophoric solids | Not classified |
- |
- | - | Since 2,3,7,8-TCDD is classified in Division 6.1, PG I in UNRTDG (UN 2811), and it is considered to be not applicable to pyrophoric solids, hazards of the highest precedence, it was classified as "Not classified." |
| 11 | Self-heating substances and mixtures | Classification not possible |
- |
- | - | No data 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) |
- |
- | - | Solid (GHS definition) (2,3,7,8-TCDD) |
| 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. |
| 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 |
- |
- | - | 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. |
| Hazard class | Classification | Pictogram Signal word |
Hazard statement (code) |
Precautionary statement (code) |
Rationale for the classification | |
|---|---|---|---|---|---|---|
| 1 | Acute toxicity (Oral) | Category 1 |
 Danger |
H300 | P301+P310 P264 P270 P321 P330 P405 P501 |
[Rationale for the Classification] As for this hazard class, it was classified based on the toxicity information of 2,3,7,8-TCDD. Based on (1) to (8), it was classified in Category 1. Besides, other dioxins may be classified in different categories. [Evidence Data] (1) LD50 for rats (males): 0.022 mg/kg (EHC 88 (1989)) (2) LD50 for rats (females): 0.045 mg/kg (EHC 88 (1989)) (3) LD50 for rats (males): 0.026 mg/kg (NTP TR521 (2006)) (4) LD50 for rats (females): 0.022 mg/kg (NTP TR521 (2006)) (5) LD50 for rats (males): 0.165 mg/kg (NTP TR209 (1982)) (6) LD50 for rats (females): 0.125 mg/kg (NTP TR209 (1982)) (7) LD50 for rats (males): 0.164 to 0.34 mg/kg (EHC 88 (1989)) (8) LD50 for rats (males): 0.297 mg/kg (EHC 88 (1989)) |
| 1 | Acute toxicity (Dermal) | Category 1 |
Danger |
H310 | P302+P352 P361+P364 P262 P264 P270 P280 P310 P321 P405 P501 |
[Rationale for the Classification] As for this hazard class, it was classified based on the toxicity information of 2,3,7,8-TCDD. Based on (1), it was classified in Category 1. Besides, other dioxins may be classified in different categories. [Evidence Data] (1) LD50 for rabbits: 0.275 mg/kg (EHC 88 (1989), HSDB (Accessed Oct. 2021)) |
| 1 | Acute toxicity (Inhalation: Gases) | Not classified |
- |
- | - | [Rationale for the Classification] Solid (GHS definition). It was classified as "Not classified." As for this hazard class, it was classified based on the information of 2,3,7,8-TCDD. Besides, the properties may differ for other dioxins. |
| 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 | Classification not possible |
- |
- | - | [Rationale for the Classification] Classification not possible due to lack of data. |
| 3 | Serious eye damage/eye irritation | Classification not possible |
- |
- | - | [Rationale for the Classification] Classification not possible due to lack of data. |
| 4 | Respiratory sensitization | Classification not possible |
- |
- | - | [Rationale for the Classification] Classification not possible due to lack of data. |
| 4 | Skin sensitization | Classification not possible |
- |
- | - | [Rationale for the Classification] Classification not possible due to lack of data. |
| 5 | Germ cell mutagenicity | Not classified |
- |
- | - | [Rationale for the Classification] Based on (1) to (3), it was classified as "Not classified." Also, based on the new findings, the classification result was changed. [Evidence Data] (1) As for genotoxicity of dioxins, negative results were obtained in most studies with animals orally exposed to 2,3,7,8-TCDD. Therefore, it was comprehensively judged to be non-genotoxic (Fact Sheet (Food Safety Commission of Japan, 2020)). (2) There is much evidence that dioxins (PCDDs (polychlorinated dibenzo-p-dioxins), PCDFs (polychlorinated dibenzofurans) and DL-PCBs (dioxin-like polychlorinated biphenyls) induce no direct genotoxicity in standard test methods (EFSA (2018)). (3) The evidence for the direct genotoxicity of TCDD is negative or equivocal based on in vitro and in vivo test results for many genotoxicity endpoints (such as aneuploidy, chromosomal aberrations, DNA damage, dominant lethal mutation, gene mutation, micronuclei induction, gene conversion, and sister chromatid exchange) (EFSA (2018)). [Reference Data, etc.] (4) There were no recent reports showing positive genotoxicity for PCDDs and PCDFs. As for in vitro, in an interlaboratory comparison of TCDD among five laboratories, a micronucleus test using the human peripheral blood showed negative results. As for in vivo, a micronucleus test for TCDD using transgenic mice (twice a week, 6-week exposure) showed negative results (EFSA (2018)). (5) Studies have shown induction of oxidative stress-related DNA damage by high-dose acute exposure to TCDD. It has been hypothesized that TCDD-mediated persistent activation of AhR (aryl hydrocarbon receptor) may be responsible for inducing oxidative stress and associated indirect genotoxicity (EFSA (2018)). |
| 6 | Carcinogenicity | Category 1A |
 Danger |
H350 | P308+P313 P201 P202 P280 P405 P501 |
[Rationale for the Classification] Based on (1) to (3), as for this hazard class, it was classified in Category 1A as dioxins since the IARC classified in Group 1 for carcinogenicity for 2,3,7,8-TCDD and each one substance selected from the respective homologues of PCDF (polychlorodibenzofuran) and coplanar PCB. It was classified based on the new information source. [Evidence Data] (1) As for the classification results by domestic and international organizations, the IARC classified 2,3,7,8-TCDD, 2,3,4,7,8-pentachlorodibenzofuran (2,3,4,7,8-PeCDF), and 3,3’,4,4’,5-pentachlorobiphenyl (3,3’,4,4’,5-PCB) in Group 1 (IARC 100F (2012)). In addition, the Japan Society For Occupational Health (JSOH) classified 2,3,7,8-TCDD in Group 1 (OEL Documentations (Carcinogenicity classification (Japan Society For Occupational Health (JSOH), 2000)), the NTP classified it as K (NTP RoC 14th (2016)), and the DFG classified it in Category 4 (List of MAK and BAT values 2020 (Accessed Oct. 2021)). (2) As a result of epidemiological studies in humans for 2,3,7,8,-TCDD, the IARC judged that, in an evaluation of cancers of all sites, there was sufficient evidence to conclude that it was carcinogenic to humans, and it also suggested a carcinogenic potential at specified sites because a positive association was observed between exposure to 2,3,7,8,-TCDD and soft tissue sarcoma, non-Hodgkin lymphoma, and cancer of the lung. In contrast, it was confirmed that, for 2,3,4,7,8-PeCDF and 3,3’,4,4’,5-PCB, there was no epidemiological evidence in humans (IARC 100F (2012)). (3) As for the carcinogenicity in experimental animals, sufficient evidence was provided for all of 2,3,7,8-TCDD, 2,3,4,7,8-PeCDF, and 3,3’,4,4’,5-PCB. The mechanisms of carcinogenesis of 2,3,7,8-TCDD were an aryl hydrocarbon receptor-mediated mechanism (promotion of tumor development through modification of cell replication and apoptosis) and a mechanism via oxidative stress, and these mechanisms were conserved across species and operated even in humans. The carcinogenic mode of action with similar mechanisms was also seen with 2,3,4,7,8-PeCDF and 3,3’,4,4’,5-PCB, which were judged to have a common carcinogenic mechanism of action. Accordingly, two substances without epidemiological study results were also classified in Group 1, which is the same as 2,3,7,8-TCDD, based on the evidence obtained in experimental animals and the strong evidence of mechanism of action (IARC 100F (2012)). [Reference Data, etc.] (4) The EFSA panel examined several studies in the IARC report which showed a positive correlation between the incidence of tumors for all cancer sites combined and TCDD exposure and found that there was neither clear link of carcinogenesis to any specific site nor evidence of direct genotoxicity. Due to the lack of a clear dose-response relationship and multiple co-exposures, the panel did not consider these studies suitable for the risk assessment. In addition, some studies noted that the follow-up of highly exposed groups was too short to reveal an increased incidence of certain tumors questioning the interpretation of the epidemiological study results and refuted the IARC classification (EFSA (2018)). |
| 7 | Reproductive toxicity | Category 1A, Additional category for effects on or via lactation |
Danger |
H360 | P308+P313 P201 P202 P280 P405 P501 |
[Rationale for the Classification] Based on (1) to (3), since reproductive effects in humans (impaired semen quality of boys born from exposed mothers, lower sex ratio in offspring of exposed fathers (lower number of boys relative to girls)) were observed, it was classified in Category 1A. Also, based on (1) and (4), effects on lactation were added. [Evidence Data] (1) In a follow-up study after the Seveso incident in Italy, cases such as reproductive dysfunction were reported. In men who were 1 to 9 years old at the time of the incident, impaired semen quality was observed some 20 years later. In addition, in men who were breastfed by mothers who had been pregnant during the incident and had serum TCDD of 19 pg/g fat, impaired semen quality was observed in later years (at an average age of 22.5 years). These results indicated that there may be a postnatal period of high sensitivity that might expand into puberty (Fact Sheet (Food Safety Commission of Japan, 2020), EFSA (2018)). (2) In a follow-up study of 8- to 9-year-old boys who lived in the contaminated area with dioxins, etc. in Russia, the serum TCDD was 2.9 pg/g fat and PCDD toxicity equivalence quantity (TEQ) was 8.7 pg TEQ/g fat around puberty. It was reported that the serum TCDD and PCDD TEQ levels around puberty were associated with impaired sperm quality (Fact Sheet (Food Safety Commission of Japan, 2020), EFSA (2018)). (3) In the follow-ups in Italy and Russia, lower sex ratio in offspring (lower number of boys relative to girls) of fathers who were highly exposed to TCDD when they were boys was reported (Fact Sheet (Food Safety Commission of Japan, 2020), EFSA (2018)). (4) Dioxins are transferred to fetuses but the concentration in the fetal body will not be higher than that in the mother's body. In addition, dioxins are secreted into breast milk and transferred to newborns via milk. It was reported that, in a 48-hour observation of infants within three months after birth, the infants absorbed 60% or more of dioxine through intake of breast milk (Fact Sheet (Food Safety Commission of Japan, 2020), EFSA (2018), ATSDR addendum (2012)). (5) In a developmental toxicity study with female rats given a single dose of TCDD by gavage administration on day 15 of gestation, reduced litter size and lower body weight in newborns at or above 200 ng/kg, and delayed sexual maturation (preputial separation) and decreased testis weight in male newborns (postnatal days 70 and 120) at 1,000 ng/kg were observed but no adverse effects on fertility were observed (EFSA (2018)). (6) It was reported that, in a developmental toxicity study with female rats fed diets containing TCDD for 12 weeks during premating, mating, and gestation (dams after parturition given basic diet), delayed preputial separation in male pups at or above 2.4 ng/kg/day, an increase in litter loss (fetal stage) at or above 8 ng/kg/day, and a slight decrease in testis weight and increased number of abnormal sperms at the highest dose of 40 ng/kg/day (postnatal day 70) were observed (EFSA (2018)). (7) It was reported that, in an early-gestation administration study with female mice given TCDD by gavage on days 1 to 8 of gestation, an increase in embryonic loss (mainly in the pre-implantation period) was observed in the group of the highest dose of 100 ng/kg/day (EFSA (2018)). (8) It was reported that, in a test with maternal animals dosed with 2,3,7,8-TCDD at or above 500 ng/kg/day, renal dysplasia in rats and cleft palate and hydronephrosis in mice were observed; in a test with mother rats given 2,3,7,8-TCDD by single oral administration at or above 200 ng/kg on day 15 of gestation, dysplasia of reproductive organs in female pups was observed; in female rhesus monkeys given 2,3,7,8-TCDD by oral administration for 4 years, a significant increase in the incidence and severity of endometriosis was observed 10 years after the start of administration; and in a test with rhesus monkeys in which dams were dosed with 2,3,7,8-TCDD (from 7 months before gestation to weaning stage, 0.15 ng/kg/day), lower performance in a learning behavior test was observed in pups (Fact Sheet (Food Safety Commission of Japan, 2020), ATSDR addendum (2012)). |
| 8 | Specific target organ toxicity - Single exposure | Category 1 (skin, immune system, liver, reproductive organs) |
Danger |
H370 | P308+P311 P260 P264 P270 P321 P405 P501 |
[Rationale for the Classification] Based on (1), effects on the skin and liver were observed in humans, and effects on the skin, immune system, liver, and reproductive organs were observed in animal studies within the dose range for Category 1 in (2) to (7). Therefore, it was classified in Category 1 (skin, immune system, liver, reproductive organs). Also, based on the new information, the classification result was changed. [Evidence Data] (1) Short-term exposure of humans to high levels of dioxins may result in skin lesions, such as chloracne and patchy darkening of the skin, and altered liver function (WHO (2016)). (2) It was reported that, in a single-dose oral exposure test with rats using TCDD as the test substance, the LD50s were in the range between several 10 micro g/kg to several 100 micro g/kg (within the range for Category 1) and characteristic effects associated with TCDD exposure were observed in the skin (chloracne), thymus (atrophy), liver (hepatotoxicity, increased serum concentrations of liver enzymes, hypertriglyceridemia, increased liver weight, hepatic Vitamin A depletion), etc. (NTP TR521 (2006)). (3) It was reported that, in a single-dose oral administration test with rats (females) using TCDD as the test substance, decreased ovarian weight, ovulation rate, and number of ova released were observed at 10 micro g/kg (within the range for Category 1) (ATSDR addendum (2012)). (4) It was reported that, in a single-dose oral administration test with cynomolgus monkeys using TCDD as the test substance, at 4 micro g/kg (within the range for Category 1), anovulation, which was accompanied by reduced levels of serum progesterone (no alterations in serum estradiol levels), and the lack of menstrual cycles were observed 1 to 2 years after administration (ATSDR addendum (2012)). (5) It was reported that, when administered in doses sufficient to cause overt toxicity, TCDD caused testicular atrophy and degeneration characterized by reduced spermatogenic activity in mice, rats and guinea pigs, and furthermore, 7 days after TCDD-treatment, dose-dependent decreases in male sex organ weight (seminal vesicles, ventral prostate, testes, and caput epididymis) were caused and the EC50 was 15 mg/kg (EHC 88 (1989)). (6) In all animal species given lethal doses of TCDD, macroscopically severe thymus atrophy was found at autopsy and histological examinations revealed lymphoid cell depletion in thymus cortex, spleen, and lymph nodes (EHC 88 (1989), ATSDR addendum (2012)). (7) It was reported that, in a test with mice by acute exposure to TCDD, humoral immunosuppression effects (suppressed production of antigen-specific IgM and IgG1, suppressed antibody production to sheep erythrocyte) were observed (ATSDR addendum (2012)). |
| 9 | Specific target organ toxicity - Repeated exposure | Category 1 (skin, nervous system, immune system, endocrine system, liver, reproductive organs) |
Danger |
H372 | P260 P264 P270 P314 P501 |
[Rationale for the Classification] Based on (1) to (5), effects on the skin, nervous system, immune system, endocrine system, liver, and reproductive organs were observed in humans, and therefore, it was classified in Category 1 (skin, nervous system, immune system, endocrine system, liver, reproductive organs). Also, based on the new information, the classification result was changed. [Evidence Data] (1) Short-term exposure of humans to high levels of dioxins may result in skin lesions, such as chloracne and patchy darkening of the skin, and altered liver function. Long-term exposure may result in effects linked to impairment of the immune system, the developing nervous system, the endocrine system, and reproductive functions (WHO (2016)). (2) As for effects on the liver, it was reported that increased levels of beta-lipoproteins, cholesterol, and triglycerides were associated with increased body burden of TCDD in workers from the Czech Republic who were exposed for 30 years or more to chemicals containing TCDD. It was also reported that, in one occupationally exposed cohort, increased chronic liver disease history was associated with higher exposures of chemical workers (former chloracne cases) and significant increases in serum gamma-GGT, GOT (AST) and GPT (ALT) activities were observed in the exposed group compared to the controls (ATSDR addendum (2012)). (3) As for effects on the endocrine, it was reported that, in environmentally expose groups, diabetes (9 cases) was associated with higher levels of dioxins and dioxin-like chemicals, and in a study with individuals living in the vicinity of a hazardous wastes site, plasma insulin concentrations post glucose challenge were correlated with higher blood TCDD levels, and the results suggested the possibility of insulin resistance in those affected (ATSDR addendum (2012)). (4) As for effects on the immune system, it was reported that increased odds of having lower counts of activated T cells were associated with TCDD exposure in a group of phenoxy herbicide workers exposed several years prior to the examination in two chemical plants (ATSDR addendum (2012)). (5) As for effects on the nervous system, it was reported that, in a 10-year follow-up of about 350 workers who were accidentally exposed to TCDD during the production of herbicides in the former Czechoslovakia, polyneuropathy and encephalopathy were observed in some workers. Only a small group of workers (13 workers) was available for the examination, but abnormal electromyography, electrocardiography, and visual evoked potentials were observed in a high percentage (23 to 54%) of the workers. It was reported that most of the 12 former workers who had long-lasting chloracne experienced fatigue, headache, and sleeping and memory problems. In another follow-up of 15 former workers conducted 30 years after the exposure to TCDD, etc., clinical signs of polyneuropathy (diminished sensation to touch and pain, diminished vibration sense, diminished or lost ankle and/or knee jerks) were observed in nine individuals, and among them, lower nerve conduction velocity was observed in three, and neurasthenic syndrome (headache, fatigue, emotional lability, memory disturbance), abnormal electrocardiography, and visual evoked potentials were observed in eight (ATSDR addendum (2012)). [Reference Data, etc.] (6) In setting the TDI (tolerable daily intake) based on the findings from the tests with experimental animals, the WHO identified the follwoing as important effects: (i) neurobehavioral toxicity observed in rhesus monkeys (decreased learning, LOAEL: up to 0.16 ng/kg/day, body burden: 42 ng/kg), (ii) endometriosis observed in rhesus monkeys (LOAEL and body burden: same as (i)), (iii) decreased sperm count in offspring observed in rats (LOAEL: 64 ng/kg/day, body burden: 28 ng/kg/day), (iv) increased genital malformations in offspring observed in rats (LOAEL: 200 ng/kg/day, body burden: 37 ng/kg/day), and (v) immune suppression in offspring observed in rats (LOAEL: 100 ng/kg/day, body burden: 25 ng/kg/day) (WHO (1998), EFSA (2018)). (7) In a repeated dose 4-week to 2-year oral administration study with rats, at several ng/kg/week to several micro g/kg/week (within the range for Category 1), liver lesions were observed in all reports. In addition, it was reported that thymic atrophy was observed and, in an immunotoxicity study (4-week gavage administration test with rats, 100 ng/kg or above), a dysregulation of the humoral immune response (marked suppression of the percentage of LPS-induced IgM+ cells, etc.) was observed. Also, a few reports described that tissue changes in the lung, pancreas, thymus, thyroid, adrenal gland, heart, clitoral gland, etc. were observed (EFSA (2018), NTP TR 521 (2006)). |
| 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) | - |
- |
- | - | - |
| 11 | Hazardous to the aquatic environment Long term (Chronic) | - |
- |
- | - | - |
| 12 | Hazardous to the ozone layer | - |
- |
- | - | - |
NOTE:
|