GHS Classification Result
GENERAL INFORMATION
REFERENCE INFORMATION
PHYSICAL HAZARDS
HEALTH HAZARDS
ENVIRONMENTAL HAZARDS
NOTE:
GENERAL INFORMATION
| Item | Information |
|---|---|
| CAS RN | 100-97-0 |
| Chemical Name | 1,3,5,7-Tetraazatricyclo[3.3.1.1(3,7)]decane |
| Substance ID | H27-B-08-METI/M-013B_P |
| Classification year (FY) | FY2015 |
| 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 (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) | 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 applicable |
- |
- | - | There are no chemical groups associated with explosive properties present in the molecule. |
| 2 | Flammable gases (including chemically unstable gases) | Not applicable |
- |
- | - | Solid (GHS definition). |
| 3 | Aerosols | Not applicable |
- |
- | - | Not aerosol products. |
| 4 | Oxidizing gases | Not applicable |
- |
- | - | Solid (GHS definition). |
| 5 | Gases under pressure | Not applicable |
- |
- | - | Solid (GHS definition). |
| 6 | Flammable liquids | Not applicable |
- |
- | - | Solid (GHS definition). |
| 7 | Flammable solids | Category 2 |
 Warning |
H228 | P370+P378 P210 P240 P241 P280 |
It was classified in Category 2 because it is classified in Division 4.1 (flammable substance), PG III (UN1328) in UNRTDG. |
| 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 | Not applicable |
- |
- | - | Solid (GHS definition). |
| 10 | Pyrophoric solids | Not classified |
- |
- | - | It is estimated that it does not ignite at normal temperatures from an autoignition temperature of 390 deg C (ICSC (2002)). |
| 11 | Self-heating substances and mixtures | Not classified |
- |
- | - | Because it is classified in Division 4.1 (flammable substance), PG III (UN1328) in UNRTDG and not classified as self-heating substances and mixtures (Division 4.2, PG II, III) with the highest precedence, it was classified as "Not classified." |
| 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 |
- |
- | - | Solid (GHS definition). |
| 14 | Oxidizing solids | Not applicable |
- |
- | - | Organic compounds containing no oxygen, fluorine or chlorine |
| 15 | Organic peroxides | 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. |
| Hazard class | Classification | Pictogram Signal word |
Hazard statement (code) |
Precautionary statement (code) |
Rationale for the classification | |
|---|---|---|---|---|---|---|
| 1 | Acute toxicity (Oral) | Not classified |
- |
- | - | Based on reports of LD50 values for rats of > 2,000 mg/kg (Initial Risk Assessment Report (NITE, CERI, NEDO, 2008)), > 5,000 mg/kg, 9,200 mg/kg (DFGOT Vol. 5 (1993)), and > 20,000 mg/kg (EU-RAR (2008), DFGOT Vol. 5 (1993)), it was classified as "Not classified." |
| 1 | Acute toxicity (Dermal) | Not classified |
- |
- | - | Based on a report of an LD50 value (OECD TG402) of > 2,000 mg/kg for rats (EU-RAR (2008)), it was classified as "Not classified." |
| 1 | Acute toxicity (Inhalation: Gases) | Not applicable |
- |
- | - | Solid (GHS definition) |
| 1 | Acute toxicity (Inhalation: Vapours) | Not applicable |
- |
- | - | Solid (GHS definition) |
| 1 | Acute toxicity (Inhalation: Dusts and mists) | Classification not possible |
- |
- | - | Classification not possible due to lack of data. |
| 2 | Skin corrosion/irritation | Not classified |
- |
- | - | There is a report that in a skin irritation test (OECD TG404) with rabbits, as a result of an occlusive application of 0.5 mL of this substance for 4 hours, no irritation was observed (EU-RAR (2008), Initial Risk Assessment Report (NITE, CERI, NEDO, 2008)). On the other hand, irritant dermatitis, redness, edema, etc. were reported in occupational exposure, but reversibility etc. are unknown (EU-RAR (2008)). It is described in EU-RAR (2008) that since this substance is hydrolyzed to form formaldehyde and ammonia on contact with human skin or sweat, irritation observed in occupational exposure may be caused by the decomposition products, formaldehyde and ammonia, there is insufficient evidence to conclude that this substance is irritating (EU-RAR (2008)). From the above, it was classified as "Not classified" (Category 3 in UN GHS classification) based on the test compliant with the test guideline. |
| 3 | Serious eye damage/eye irritation | Not classified |
- |
- | - | There is a report that in an eye irritation test (OECD TG405) with rabbits, as a result of an application of 0.1 mL of this substance, no irritation was observed (EU-RAR (2008), Initial Risk Assessment Report (NITE, CERI, NEDO, 2008)). From the above, it was classified as "Not classified." |
| 4 | Respiratory sensitization | Classification not possible |
- |
- | - | As for occupational exposure, there are multiple reports of allergic symptoms such as wheezing, severe asthma in workers exposed to this substance (EU-RAR (2008), Initial Risk Assessment Report (NITE, CERI, NEDO, 2008), DFGOT Vol. 5 (1993)). Since all the cases were due to combined exposure, and exposure to other irritants and sensitizing chemicals occurred at the same time, respiratory hypersensitivity cannot be clearly associated with this substance, therefore, it is not concluded in EU-RAR (2008) that this substance is a respiratory sensitizer (EU-RAR (2008)). From the above, it was classified as "Classification not possible." Since the information in the previous classification may be the effect of combined exposure, and it cannot be concluded to be effects from this substance, the category was changed. |
| 4 | Skin sensitization | Category 1 |
 Warning |
H317 | P302+P352 P333+P313 P362+P364 P261 P272 P280 P321 P501 |
There is a report that in a sensitization test (OECD TG406) with guinea pigs, positive reactions were observed in 15/20 animals (75%) (EU-RAR (2008), Initial Risk Assessment Report (NITE, CERI, NEDO, 2008)). In addition, it is reported that in an LLNA test (OECD TG429) with mice, an EC3 value was 30.6%, and it was a skin sensitizer (EU-RAR (2008)). Moreover, there are multiple reports of skin reactions due to this substance in occupational exposure (EU-RAR (2008), Initial Risk Assessment Report (NITE, CERI, NEDO, 2008), Environmental Risk Assessment for Chemical Substances Vol.3, Tentative Hazard Assessment Sheet (Ministry of the Environment, 2004)). From the above, it was classified in Category 1. Besides, this substance was classified as "Skin sens. 1 H317" in EU CLP classification (ECHA CL Inventory (Access on September 2015)). |
| 5 | Germ cell mutagenicity | Classification not possible |
- |
- | - | The substance was classified as "Classification not possible" because it was not possible to classify a substance as "Not classified" according to the revised GHS classification guidance for the Japanese government. As for in vivo, negative or weak mutagenicity was observed in mouse dominant lethal tests, but there is a description that there are problems with the test method such as not providing the positive control (EU-RAR (2008), DFGOT Vol. 5 (1993)). There are negative results in chromosomal aberration tests with mouse bone marrow cells (Initial Risk Assessment Report (NITE, CERI, NEDO, 2008), EU-RAR (2008), DFGOT Vol. 5 (1993)). As for in vitro, bacterial reverse mutation tests and a mouse lymphoma test with mammalian cultured cells were negative, and a chromosomal aberration test and a sister chromatid exchange test with mammalian cultured cells were positive (Initial Risk Assessment Report (NITE, CERI, NEDO, 2008), EU-RAR (2008), DFGOT Vol. 5 (1993), NTP DB (Access on November 2015)). |
| 6 | Carcinogenicity | Classification not possible |
- |
- | - | There is a description that in a health survey on workers who worked in steel foundry and in the tire and rubber industries, and were exposed to multiple substances including this substance, an increase in mortality due to cancers consisting of mainly lung and urinary bladder cancers was observed, but the relationship between exposure to this substance and the increase in cancer mortality could not be confirmed (EU-RAR (2008)). There is a description that even administration of 2-4 g/day for prevention of recurrent urinary infections did not cause serious adverse effects, and side effects were reported in less than 3.5%, but that there is no information on carcinogenicity in the extensive clinical use of this drug (EU-RAR (2008)). In addition, there is also a description that this substance is used as one of several reaction accelerators in the rubber industry, therefore, this substance was suggested as a potential cause of the higher incidence of gastrointestinal and skin cancers, and skin cancers were associated with dermatitis-inducing potential and skin sensitization of this substance, but that there is no test report to be definitive evidence (PATTY (6th, 2012)). As for experimental animals, tests with a small number of animals or only with one dose etc., there is no test report equivalent to the guideline with full protocol. However, in all the tests in a total four of carcinogenicity tests in which rats were dosed by gavage for 333 days, dosed by feeding for lifetime or dosed by drinking water for 50 weeks or 104 weeks, and 30- or 60-week tests with mice dosed by drinking water, no increase in the incidence of tumors related to administration of this substance was observed (EU-RAR (2008), Initial Risk Assessment Report (NITE, CERI, NEDO, 2008)). It is reported that the doses in these tests were reported to be equivalent to 80 mg/kg/day at the minimum and 1,500-2,500 mg/kg/day at the maximum in rats and 12,500 mg/kg/day in the 30-week administration in mice (EU-RAR (2008), Initial Risk Assessment Report (NITE, CERI, NEDO, 2008)). The Ministry of Health, Labour and Welfare also reported results from 2-year tests with rats and mice dosed by drinking water, and at the high dose of 30,000 ppm in rats, a decrease in survival rate was observed in males, but no increase in tumor incidence was shown. On the other hand, it is reported that in mice, there was little difference in the survival rate in administration at doses of up to 40,000 ppm, and no increase in the tumor incidence was shown in males, whereas in females, an increasing trend related to the doses in the incidence of adenomas in the mammary glands (0/50, 0/50, 1/50, and 3/50 in the groups of control, low dose, medium dose, and high dose, respectively) and the combined incidence of adenomas and adenocarcinomas (1/50, 1/50, 3/50, and 6/50, respectively) was observed in a Peto test and a Cochran-Armitage test (Results from Carcinogenicity Studies (Ministry of Health, Labour and Welfare, 1997)). Besides, there is no data available for evaluating carcinogenicity in the dermal and inhalation routes (EU-RAR (2008)). It is concluded in the EU risk assessment report that evidence suggesting that there is no carcinogenicity in humans is limited under specific conditions from research reports on carcinogenic mortality in occupational exposure, but from the test results with 2 species of experimental animals, there is no evidence of carcinogenicity in the oral route, and the evidence for considering this substance as a human carcinogen is insufficient in light of the criteria of the EEC directive for hazardous substances, therefore, it is not necessary to classify and label it as a carcinogen (EU-RAR (2008)). Besides, there are no classification results by other organizations. From the above, it is considered to correspond to "Not classified" if the EU risk assessment result is followed. However, since an increasing tendency of female mammary gland tumors although in a low incidence in a 2-year test with mice dosed by drinking water was observed, there was no available information on carcinogenicity for routes other than the oral route, and it was difficult to judge that there is sufficient evidence to conclude that there is no evidence for carcinogenicity from the results of the epidemiological survey on occupational exposure, it could not be classified as "Not classified." Therefore, it was classified as "Classification not possible" for this hazard class. |
| 7 | Reproductive toxicity | Category 2 |
 Warning |
H361 | P308+P313 P201 P202 P280 P405 P501 |
As for humans, there is a report of research in which the salt of this substance was used as a pharmaceutical ingredient, and this was used for risk assessment of this substance in the EU. There are descriptions that in a test in which healthy pregnant women were given a single oral dose of 1g of the hippurate of this substance in order to study the pharmacokinetics of this substance, this substance showed placental permeability, and the umbilical cord blood concentration was lower than the maternal blood concentration in the early stages after administration, but it reached the same level as the maternal blood concentration after 4 hours (EU-RAR (2008)), and that gestation period lengths and birth weights were not different from those in the control group, and the number of cases of abortions, intrauterine deaths and fetal abnormalities did not differ from the number of cases per the general population when the hippurate of this substance at 2 g/day or the mandelate of this substance at 4 g/day was administered to pregnant women with asymptomatic urinary tract infection for therapeutic purposes (EU-RAR (2008)), and it is also described that congenital abnormalities or disorders did not occur, or the number of their occurrences was less than the predicted value for ordinary people even on medication of this substance in early pregnancy (EU-RAR (2008)). From the above, EU calculated NOAEL (human, reproductive effect) as 27 mg/kg/day (= 4,000 (mg) * (140/292) (converted molecular weight)/70 (kg)) considering that this substance does not cause reproductive and developmental toxicity at up to 4 g/day in humans. In addition, there is also a description that although this substance was excreted in breast milk with peak levels reaching 1 hour after administration, no adverse effects in infants were reported (PATTY (6th, 2012)). As for experimental animals, no adverse effect on fertility was shown in the following breeding tests with rats: a test in which the dose corresponding to 100 mg/kg/day was administered by feeding to F0 for three months before mating, or to F1 from weaning until 18 weeks of age, and a test in which doses corresponding to 2,000-2,500 mg/kg/day were administered by drinking water, although both these tests were incomplete (EU-RAR (2008), Initial Risk Assessment Report (NITE, CERI, NEDO, 2008)), and in the second test on the latter, in which the same dose was administered by drinking water to a few female and male parental animals and mating was repeated, pups had been obtained up to the F3 generation (EU-RAR (2008), Initial Risk Assessment Report (NITE, CERI, NEDO, 2008)). Thus, it was considered that it did not show adverse effects on fertility of female and male parental animals. As for a developmental toxicity test, it is reported that in a test with beagle dogs by the oral route (feeding), an increase in mortality within 1 month of birth and a retardation of growth were observed in pups born from the high dose group (31 mg/kg/day) (EU-RAR (2008), Initial Risk Assessment Report (NITE, CERI, NEDO, 2008)). From the above, although placental permeability in pregnant women is indicated for this substance, even in oral administration to pregnant patients, no adverse effects on the next generation were seen at up to the equivalent of 27 mg/kg/day, therefore, EU recommends 27 mg/kg/day as NOAEL for reproductive and developmental toxicity (EU-RAR (2008)). As for experimental animals, in the developmental toxicity test in which an equivalent of 31 mg/kg/day was administered orally to dogs, an increase in mortality and retardation of growth were observed in F1 pups, and this is considered to be a finding suggesting a developmental toxicity effect of this substance in experimental animals. In conclusion, there is no evidence showing reproductive and developmental toxicity by administration of this substance from findings in humans, but fetal transfer is obvious, and developmental toxic effects are observed in dogs, therefore, it was judged as appropriate to classify it in Category 2 for this hazard class. |
| 8 | Specific target organ toxicity - Single exposure | Classification not possible |
- |
- | - | There is no information on exposure limited to this substance. Therefore, classification was not possible due to lack of data. |
| 9 | Specific target organ toxicity - Repeated exposure | Category 1 (urinary bladder, kidney, systemic toxicity) |
Danger |
H372 | P260 P264 P270 P314 P501 |
As for humans, this substance is used for the prevention and treatment of urinary diseases. Adverse effects were reported in less than 3.5% of patients dosed with this substance or its salt. The most frequent adverse effects were gastrointestinal disorders such as nausea, vomiting, diarrhea, stomach convulsions and anorexia. Rarely, hypersensitivity reactions such as rash, pruritus, urticaria and stomatitis were observed. Other than this, although the number of cases was small, headache, dyspnoea, generalized edema, tinnitus, muscle cramps, dysuria, and microscopic or gross haematuria were reported as side effects (EU-RAR (2008)). It is reported that no adverse effects were observed in patients dosed with 2-4 g/day (corresponding to about 28-57 mg/kg/day) of this substance for several weeks to several months, but that when administration of this substance was repeated at a high dose of 8 g/day (corresponding to about 114 mg/kg/day) over 3 to 4 weeks, clinical symptoms such as urinary bladder irritation, frequent micturition with pain, albuminuria and haematuria occurred (EU-RAR (2008)). In addition, it is reported that inflammation of the renal tubules and renal pelvis by the large amount of oral intake, and dermatitis and urticaria by repeated use may occur (HSDB (Access on November 2015)). As for experimental animals, multiple long-term toxicity studies were conducted. In a 104-week toxicity test with rats dosed by drinking water, mineralization in the heart, mineralization in the kidney, increases of AST and ALT, etc. were observed at the high dose of 30,000 ppm, but the dose was out of the range of Category 2 (Results from Carcinogenicity Studies (Ministry of Health, Labour and Welfare, 1997)). No adverse effects were observed within the range of Category 2 in other long-term tests. From the above, when it was used for treatment in humans, as side effects, hypersensitivity reactions and effects on the urinary bladder and kidney may be observed in some cases in addition to irritation of the gastrointestinal tract. Besides, hypersensitivity response was regarded as systemic toxicity. Therefore, it was classified in Category 1 (urinary bladder, kidney, systemic toxicity). Besides, in the previous classification, the respiratory organs were adopted as the target organs based on "acute symptoms such as respiratory disorder and chest tightness," but since these were acute effects, and it was considered to be hypersensitivity response, it was not adopted as the target organs this time. |
| 10 | Aspiration hazard | Classification not possible |
- |
- | - | 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 (Acute) | Not classified |
- |
- | - | From 72-hour ErC50 > 100 mg/L for algae (Pseudokirchneriella subcapitata), 48-hour EC50 > 100 mg/L for crustacea (Daphnia magna), and 96-hour LC50 > 100 mg/L for fish (Oryzias latipes) (all Results of Aquatic Toxicity Tests of Chemicals conducted by Ministry of the Environment in Japan (Ministry of the Environment, 2002)), it was classified as "Not classified." |
| 11 | Hazardous to the aquatic environment (Long-term) | Not classified |
- |
- | - | If chronic toxicity data are used, then it is classified as "Not classified" due to being not rapidly degradable (a degradation rate by 14-day BOD = 22%, a degradation rate by TOC = 45%, a degradation rate by HPLC = 48% (Official Bulletin of Ministry of International Trade and Industry, 1979)), 72-hour NOEC = 100 mg/L for algae (Pseudokirchneriella subcapitata), and 21-day NOEC (reproduction) > 99 mg/L for crustacea (Daphnia magna) (both Results of Aquatic Toxicity Tests of Chemicals conducted by Ministry of the Environment in Japan (Ministry of the Environment, 2002)). 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 96-hour LC50 > 100 mg/L for fish (Oryzias latipes) (Results of Aquatic Toxicity Tests of Chemicals conducted by Ministry of the Environment in Japan (Ministry of the Environment, 2002)) although being not rapidly degradable. From the above, it was classified as "Not classified." |
| 12 | Hazardous to the ozone layer | Classification not possible |
- |
- | - | No data available. |
NOTE:
| * A blank or "-" in a cell of classification denotes that the classification of the hazard class was not conducted. * Hazard_statement_and/or_Precautionary_statement will show when hovering the mouse over a code of Hazard_statement_and/or_Precautionary_statement. Hazard_statement_and/or_Precautionary_statement are also provided in the Excel file. * Classification was conducted by relevant Japanese Ministries in accordance with GHS Classification Guidance for the Japanese Government, and is intended to provide a reference for preparing GHS labelling and SDS for users. * This is a provisional English translation of classification results and is subject to revision without notice. * The responsibility for any resulting GHS labelling and SDS referenced from this site is with users. * Codes assigned to each of the hazard statements and codes for each of the precautionary statement are based on the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) in United Nations. |