NITE - Chemical Management Field

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

GENERAL INFORMATION

Item	Information
CAS RN	633-65-8
Chemical Name	Berberine hydrochloride
Substance ID	m-nite-633-65-8_v1
Download of Excel format	Excel file

REFERENCE INFORMATION

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

PHYSICAL HAZARDS

Hazard class		Classification	Pictogram Signal word	Hazard statement (code)	Precautionary statement (code)	Rationale for the classification	Classification year (FY)	GHS Classification Guidance for the Japanese Government
1	Explosives	Not classified (Not applicable)	- -	-	-	There are no chemical groups associated with explosive properties present in the molecule.	FY2017	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
2	Flammable gases	Not classified (Not applicable)	- -	-	-	Solid (GHS definition).	FY2017	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
3	Aerosols	Not classified (Not applicable)	- -	-	-	Not aerosol products.	FY2017	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
4	Oxidizing gases	Not classified (Not applicable)	- -	-	-	Solid (GHS definition).	FY2017	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
5	Gases under pressure	Not classified (Not applicable)	- -	-	-	Solid (GHS definition).	FY2017	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
6	Flammable liquids	Not classified (Not applicable)	- -	-	-	Solid (GHS definition).	FY2017	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
7	Flammable solids	Classification not possible	- -	-	-	No data available.	FY2017	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
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.	FY2017	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
9	Pyrophoric liquids	Not classified (Not applicable)	- -	-	-	Solid (GHS definition).	FY2017	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
10	Pyrophoric solids	Classification not possible	- -	-	-	No data available.	FY2017	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
11	Self-heating substances and mixtures	Classification not possible	- -	-	-	No data available.	FY2017	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
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).	FY2017	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
13	Oxidizing liquids	Not classified (Not applicable)	- -	-	-	Solid (GHS definition).	FY2017	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
14	Oxidizing solids	Not classified (Not applicable)	- -	-	-	The substance is an organic compound containing chlorine which is ionically bonded to the element other than carbon or hydrogen (N) but does not contribute to oxidation.	FY2017	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
15	Organic peroxides	Not classified (Not applicable)	- -	-	-	Organic compounds containing no bivalent -O-O- structure in the molecule	FY2017	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
16	Corrosive to metals	Classification not possible	- -	-	-	Test methods applicable to solid substances are not available.	FY2017	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
17	Desensitized explosives	-	- -	-	-	-	-	-

HEALTH HAZARDS

Hazard class		Classification	Pictogram Signal word	Hazard statement (code)	Precautionary statement (code)	Rationale for the classification	Classification year (FY)	GHS Classification Guidance for the Japanese Government
1	Acute toxicity (Oral)	Classification not possible	- -	-	-	Classification not possible due to lack of data.	FY2017	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
1	Acute toxicity (Dermal)	Classification not possible	- -	-	-	Classification not possible due to lack of data.	FY2017	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
1	Acute toxicity (Inhalation: Gases)	Not classified (Not applicable)	- -	-	-	Solid (GHS definition)	FY2017	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
1	Acute toxicity (Inhalation: Vapours)	Not classified (Not applicable)	- -	-	-	Solid (GHS definition)	FY2017	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
1	Acute toxicity (Inhalation: Dusts and mists)	Classification not possible	- -	-	-	Classification not possible due to lack of data.	FY2017	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
2	Skin corrosion/irritation	Classification not possible	- -	-	-	Classification not possible due to lack of data.	FY2017	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
3	Serious eye damage/eye irritation	Classification not possible	- -	-	-	Classification not possible due to lack of data.	FY2017	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
4	Respiratory sensitization	Classification not possible	- -	-	-	Classification not possible due to lack of data.	FY2017	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
4	Skin sensitization	Classification not possible	- -	-	-	Classification not possible due to lack of data.	FY2017	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
5	Germ cell mutagenicity	Classification not possible	- -	-	-	Since information on berberine chloride (CAS RN 633-65-8), tetrahydroberberine (CAS RN 522-97-4), berberine hydrochloride (CAS RN 633-65-8) was confirmed as information for berberine and berberine compounds, these items of information was used for classification. As for in vivo, berberine chloride and tetrahydroberberine were negative in micronucleus tests with mouse bone marrow cells (NTP DB (Access on August 2017), Iran J Basic Med Sci, Vol. 20, No. 5, May 2017), and they were positive in DNA damage tests with mouse bone marrow cells and cardiac cells (Iran J Basic Med Sci, Vol. 20, No. 5, May 2017). As for in vitro, there were positive and negative results in bacterial reverse mutation tests with berberine chloride, berberine hydrochloride and tetrahydroberberine (NTP DB (Access on August 2017), Iran J Basic Med Sci, Vol. 20, No. 5, May 2017). However, neither the in vivo nor in vitro positive results were reproducible. From the above, it was classified as "Classification not possible" according to the GHS classification guidance for the Japanese government.	FY2017	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
6	Carcinogenicity	Classification not possible	- -	-	-	Classification not possible due to lack of data. Besides, there are several reports that berberine exhibits antitumor activity in vitro and in vivo (Kamrani Rad, S.Z, et al. IJBMS, 20, 516-529 (2017)). In addition, the root powder of goldenseal which is a plant containing berberine and other alkaloids was carcinogenic to the liver of rats and mice and is classified as Group 2B by IARC (IARC 108 (2016)).	FY2017	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
7	Reproductive toxicity	Category 2	Warning	H361	P308+P313 P201 P202 P280 P405 P501	When exposed to Chinese medicines containing berberine via the placenta in the fetal period, or when it is ingested via breast milk or directly in the neonatal period, it has been reported that the incidence of jaundice, kernicterus, and brain damage due to jaundice in newborns was high in China and Singapore (Chan E.: Biol. Neonates, 63, 201-208 (1993)). Experimentally, it was confirmed that based on the results of an in vitro test and an in vivo one with rats, berberine liberates bilirubin from the serum binding protein and the blood bilirubin concentration increases (Chan E.: Biol. Neonates, 63, 201-208 (1993), Bateman, J. et al.: Scot. Med. J., 43, 7-15 (1998)). Neonatal jaundice is suspected to be an effect due to this substance which is a component of Chinese medicines. Therefore, it is considered desirable for pregnant women to avoid using herbs or other Chinese medicines containing a large amount of berberine (Jahnke G.S. et al.: Birth Defects Res., 77, 195-206 (2006), Chan E.: Biol. Neonates, 63, 201-208 (1993)). Besides, with respect to side effects of berberine preparations, in the package insert of berberine sulfate hydrate injection which is indicated for diarrhea, it is stated as follows: the safety of administration during pregnancy has not been established, so it is desirable not to administer to pregnant women or women anticipating pregnancy (Ethical Pharmaceuticals 2017 (2016)). As for experimental animals, in developmental toxicity tests for berberine chloride dihydrate (CAS RN 5956-60-5) administered to pregnant rats or pregnant mice by feeding (up to 1,313 mg/kg/day in rats and up to 1,155 mg/kg/day in mice), or by gavage (at 1,000 mg/kg/day in both rats and mice), at 1000-1313 mg/kg/day where maternal toxicity was observed, fetuses showed no effect or only a minor effect (low body weight) in the tests with rats dosed by feeding or gavage (NTP Abstract for TER98008, TER20102 (Access on September 2017), Jahnke G.S. et al.: Birth Defects Res., 77, 195-206 (2006)). On the other hand, in the test with mice by feeding, an increase in water consumption was found at or above 841 mg/kg/day in maternal animals, and an increase in the number of animals with cleft palate was observed in fetuses without statistically significant difference. In administering by gavage to pregnant mice, dead or urgently slaughtered cases of 7/25 were seen in addition to 4/25 deaths due to administration error at 1,000 mg/kg/day in maternal animals, but other than an increase in water consumption, no effect was observed in surviving animals. In fetuses, only a reduced body weight and no cleft palate was found (NTP Abstract for TER20103, TER99002 (Access on September 2017), Jahnke G.S. et al.: Birth Defects Res., 77, 195-206 (2006)). In addition, ovulated female mice were dosed by intramuscular injection with 100 micrograms of this substance for 2-14 days before and after mating with males, and a decrease in the proportion of blastocysts in fertilized eggs and a decrease in the number of live fetuses on gestation day 18.5 were observed, and a possibility is shown that berberine inhibits embryonic development (Tsunoda, Y. and Kato, Y.: J. Mamm. Ova. Res., 28, 40-46 (2011)). From the above, although there are concerns about the findings in humans as side effects of Chinese herbal medicine containing this substance, the causal relationship with this substance is not necessarily clear, and there is weak evidence of reproductive effects on humans. Additionally, many animal tests gave negative results. Therefore, it was judged as appropriate to classify it in Category 2 for this hazard class.	FY2017	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
8	Specific target organ toxicity - Single exposure	Classification not possible	- -	-	-	Classification not possible due to lack of data.	FY2017	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
9	Specific target organ toxicity - Repeated exposure	Classification not possible	- -	-	-	Classification not possible due to lack of data.	FY2017	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
10	Aspiration hazard	Classification not possible	- -	-	-	Classification not possible due to lack of data.	FY2017	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))

ENVIRONMENTAL HAZARDS

Hazard class		Classification	Pictogram Signal word	Hazard statement (code)	Precautionary statement (code)	Rationale for the classification	Classification year (FY)	GHS Classification Guidance for the Japanese Government
11	Hazardous to the aquatic environment Short term (Acute)	Classification not possible	- -	-	-	No data available.	FY2017	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
11	Hazardous to the aquatic environment Long term (Chronic)	Classification not possible	- -	-	-	No data available.	FY2017	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
12	Hazardous to the ozone layer	Classification not possible	- -	-	-	No data available.	FY2017	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))

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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