An update to the toxicological profile for water-soluble and sparingly soluble tungsten substances

Figures & data

Figure 1. Flow chart depicting the processing from tungsten concentrates (raw materials) to tungsten intermediates or final products, each with different water solubility characteristics, ranging from (*) soluble (sodium tungstate, ammonium paratungstate, and ammonium metatungstate) to (†) sparingly soluble (tungsten yellow oxide, tungsten blue oxide, tungsten metal, and tungsten carbide). (‡) Tungsten chemicals include tungsten disulfide (WS₂), which is synthesized from tungsten metal and sulfur.

Table 1. Categories for ranking the reliability of studies or data from the literature or reports, based on the approach described by Klimisch et al. (1997).

Reliability category	Description	Criteria for studies or data
K1	Reliable without restriction	Performed according to valid and/or nationally or internationally accepted testing guidelines, preferably conducted according to the principles of GLP
K2	Reliable with restrictions	Mostly not performed according to GLP, the test parameters do not totally comply with the specific testing guidelines, but are sufficient to accept the data. Such studies are well-documented and scientifically acceptable, and include positive and negative controls, well-described methodology, animal information, test substance purity, data on dose/concentrations, detailed results, etc.
K3	Not reliable	There are interferences between the measuring system and the test substance, or cases in which the test systems were not relevant in relation to the exposure, or were performed using an unacceptable testing method; documentation is not sufficient and not convincing.
K4	Not assignable	Does not provide sufficient experimental detail and was presented as an abstract or was listed in secondary literature

GLP = good laboratory practice

Table 2. Search strings, PubMed^® MeSH query translations, and returned results for tungsten and tungstate publications from January 1, 2004 to May 19, 2014.

Level of search	Search term	MeSh query translation	Findings
Chemical	Tungsten	tungsten[Title/Abstract] AND (“2004/01/01”[PDAT]: “2013/05/15”[PDAT])	2909
Chemical	Tungstate	tungstate[Title] AND (“2005/01/01”[PDAT]: “3000”[PDAT])	463
Chemical and endpoint	Tungsten	((“pharmacokinetics”[Subheading] OR “pharmacokinetics”[All Fields] OR “toxicokinetics”[All Fields] OR “pharmacokinetics”[MeSH Terms] OR “toxicokinetics”[All Fields]) AND (“tungsten”[MeSH Terms] OR “tungsten”[All Fields])) AND (“2005/01/01”[PDAT]: “3000”[PDAT])	29
Chemical and endpoint	Tungsten or Tungstate and Toxicity	(((tungsten OR tungstate)) AND toxicity) AND (“2004/01/01”[Date - Publication]: “3000”[Date - Publication])	163

Table 3. Tungsten substance nomenclature and solubility in water.

Tungsten substance	Abbreviation used in this review	Chemical formula	CAS Registry^SM number	Water-solubility (reference)
Water-soluble substances
Sodium tungstate	ST	Na2WO4	13472-45-2	732 g/L at 21°C (Weast 1973)
Ammonium metatungstate	AMT	(NH4)6(H2W12O40) 3H2O	12028-48-7	1635 g/L at 22°C (Lassner and Schubert 1999)
Sodium metatungstate	SMT	Na6O39W12	314075-43-9	> 1000 g/L at 20°C (RCC NOTOX BV 1992)
Ammonium paratungstate	APT	(NH4)10(H2W12O42) 4H2O	11120-25-5	270.2 g/L (Lassner and Schubert 1999)
Sparingly water-soluble substances
Tungsten metal	W-metal	W	7440-33-7	Insoluble (CDC 2010a)
Tungsten carbide	WC	WC	12070-12-1	< 0.1 mg/L at 20°C (OECD SIDS 2005)
Ditungsten carbide	W2C	W2C	12070-13-2	Insoluble (Weast 1973)
Tungsten trioxide (tungsten yellow oxide)	WO3	WO3	1314-35-8	Insoluble (Budavari 1996)
Tungsten oxides (tungsten blue oxide)	WO3-x	WO2.91; WO2.81; WO2.66; WO2.51	39318-18-8	Insoluble (American Elements 2014)
Tungsten disulfide	WS2	WS2	12138-09-9	Insoluble (Bureau of Reclamation 2011)

CAS = Chemical Abstracts Service

Table 4. Standard toxicity testing summary for water-soluble and sparingly water-soluble tungsten substances.

Endpoint (Test method)	Test substance	Species	Results	References
Toxicokinetics (OECD TG 417)	Sodium tungstate*	Rat/Mouse	–Substance readily absorbed after oral exposure – Rapidly distributed to various organs (intestine, kidney, femur) – Brain relatively protected from oral exposure – Substance crosses placenta – Excreted through urine	McDonald et al. 2007, Weber et al. 2008, Guandalini et al. 2011, Kelly et al. 2013
	Tungsten oxide (WO2.91)†	Rat	–Substance absorbed systemically – Lung, femur, and kidney showed increased levels (lung at least an order of magnitude greater than kidney or femur) – Concentration in tissues reached steady-state by exposure day-14	Rajendran et al. 2012
Skin irritation (OECD TG 404)	Sodium tungstate, ammonium paratungstate, sodium metatungstate*	Rabbit	–Substances deemed to be non-irritating – Caused no-irritation or slight erythema that was reversible within 24 h	RCC NOTOX BV 1991e, Huntingdon Life Sciences Ltd., 1999e, 1999j
	Tungsten metal, tungsten carbide, tungsten trioxide†	Rabbit	– Substances deemed to be non-irritating	Huntingdon Life Sciences Ltd., 1999p, 2000b, ARC Seibersdorf Research GmbH 2002a
Eye irritation (OECD TG 405)	Sodium tungstate, ammonium paratungstate, sodium metatungstate*	Rabbit	–ST and APT showed minimal irritation, which was fully reversible within 21 d in conjunctiva, cornea, or iris – SMT considered an eye irritant	RCC NOTOX BV 1991a, Huntingdon Life Sciences Ltd., 1999d, 1999i
	Tungsten metal, tungsten carbide, tungsten trioxide, tungsten oxide (WO2.91)†	Rabbit	– Substances caused only transient, very-slight to well-defined conjunctival irritation, or elicited no irritation at all	Huntingdon Life Sciences Ltd., 1999o, 2000a, ARC Seibersdorf Research GmbH 2002b, 2003a
Skin sensitization (OECD TG 406)	Sodium tungstate, ammonium paratungstate, sodium metatungstate*	Guinea pig	– Substances elicited no sensitization reaction	RCC NOTOX BV 1991d, Huntingdon Life Sciences Ltd., 1998, 1999k
	Tungsten metal, tungsten carbide†	Guinea pig	– Substances elicited no sensitization reaction	Huntingdon Life Sciences Ltd., 1999q, 1999u
Repeated-dose toxicity (40 CFR 798.2650; OECD TG 412)	Sodium tungstate*	Rat	–Treatment caused progressive nephropathy at 125 and 200 mg/kg/d – LOAEL = 125 mg/kg/d – NOAEL = 75 mg/kg/d	McCain et al. 2010
	Tungsten oxide (WO2.91)†	Rat	–Treatment induced macrophage influx (e.g. pigmented macrophages, alveolar and foamy macrophages) – No toxicologically significant effects – NOAEL > 0.65 mg/L air	Rajendran et al. 2012
Carcinogenicity‡ (OECD TG 451/453)	Sodium tungstate*	Rat/Mouse	–Ongoing, two-year drinking water carcinogenicity study of ST – Estimated exposure doses for rats = 25, 50, 100 mg/kg/d – Estimated exposure doses for mice = 100, 250, 500 mg/kg/d	NTP 2014a
Reproductive toxicity‡ (US EPA OPPTS 870.3650)	Sodium tungstate*	Rat	– Substance did not have any apparent effect on reproductive functions or offspring's physical development	McInturf et al. 2008, 2011
Developmental toxicity‡ (US EPA OPPTS 870.3650)	Sodium tungstate*	Rat	– Substance may produce subtle neurobehavioral effects related to motor activity and emotionality in offspring	McInturf et al. 2008, 2011
Immunotoxicity‡ (FDA 2002/ICH S8 2006)	Sodium tungstate*	Mouse	– Substance did not adversely affect innate immunity, humoral immunity, or cell-mediated immunity in female B6C3F1/N mice exposed via drinking water	NTP 2012

US EPA OPPTS = United States Environmental Protection Agency Office of Prevention, Pesticides and Toxic Substances; FDA, United States Food and Drug Administration; ICH, International Conference on Harmonization; NOAEL = no observable adverse effect level; OECD = Organisation for Economic Co-operation and Development; TG = Testing Guideline.

*Substances are soluble in water.

†Substances are sparingly soluble in water.

‡No data were available for this endpoint for sparingly water-soluble substances.

Table 5. Acute oral, dermal, and inhalation studies on tungsten substances.

Exposure route (Test method)	Tungsten substance tested	Acute toxicity	Reference
Oral (OECD TG 401)	Ammonium metatungstate	F – LD50: > 1000 – < 1373 mg/kg bw	IITRI 2010a
	Sodium tungstate	M/F – LD50: 1453 mg/kg bw	Huntingdon Life Sciences Ltd., 1999h
	Sodium metatungstate	M/F – LD50 1715 mg/kg bw	RCC NOTOX BV 1991c
	Ammonium paratungstate	M/F – LD50: > 2000 mg/kg bw	Huntingdon Life Sciences Ltd., 1999c
	Tungsten metal	M/F – LD50: > 2000 mg/kg bw	Huntingdon Life Sciences Ltd., 1999t
	Tungsten carbide	M/F – LD50: > 2000 mg/kg bw	Huntingdon Life Sciences Ltd., 1999n
	Tungsten trioxide	M/F – LD50: > 2000 mg/kg bw	ARC Seibersdorf Research GmbH 2002d
	Tungsten oxide (WO2.91)	F – LD50 > 2000 mg/kg bw	ARC Seibersdorf Research GmbH 2003b
Dermal (OECD TG 402)	Sodium tungstate	M/F > 2000 mg/kg bw	Huntingdon Life Sciences Ltd., 1999g
	Sodium metatungstate	M/F > 2000 mg/kg bw	RCC NOTOX BV 1991b
	Ammonium paratungstate	M/F > 2000 mg/kg bw	Huntingdon Life Sciences Ltd., 1999b
	Tungsten metal	M/F > 2000 mg/kg bw	Huntingdon Life Sciences Ltd., 1999s
	Tungsten carbide	M/F > 2000 mg/kg bw	Huntingdon Life Sciences Ltd., 1999m
Inhalation (OECD TG 403)	Sodium tungstate	M/F – LC50 (4 h): > 5.01 mg/L	Huntingdon Life Sciences Ltd., 1999f
	Ammonium paratungstate	M/F – LC50 (4 h): > 5.35 mg/L	Huntingdon Life Sciences Ltd., 1999a
	Tungsten metal	M/F – LC50 (4 h): > 5.4 mg/L	Huntingdon Life Sciences Ltd., 1999r
	Tungsten carbide	M/F – LC50 (4 h): > 5.3 mg/L	Huntingdon Life Sciences Ltd., 1999l
	Tungsten trioxide	M/F – LC50 (4 h): > 5.36 mg/L	ARC Seibersdorf Research GmbH 2002c

bw = body weight; LC50 = the concentration required to kill 50% of the test animals; LD50 = the dose required to kill 50% of the test animals; F = female; M = male; OECD = Organisation for Economic Co-operation and Development; TG = Testing Guideline.

Table 6. Genotoxicity studies on tungsten substances.

	Test results (reference)
Tungsten substance	Bacterial reverse mutation test (OECD TG 471)	In vitro mammalian cell gene mutation test (OECD TG 476)	In vitro mammalian chromosome aberration test (OECD TG 473)	Mammalian erythrocyte micronucleus test (OECD TG 474)
Sodium metatungstate	Negative (CCR 1989b)	–	–	Negative (CCR 1989a)
Sodium tungstate	Negative (Covance Laboratories, Inc., 2004e)	Negative (Covance Laboratories, Inc., 2004c)	Negative (Covance Laboratories, Inc., 2003)	Negative (Covance Laboratories, Inc., 2004b)
Tungsten oxide (WO2.91)	Negative (ARC Seibersdorf Research GmbH 2003c)	–	–	–
Tungsten trioxide	Negative (ARC Seibersdorf Research GmbH 2002e)	–	Negative (IITRI 2010c)	–
Tungsten carbide	Negative (Huntingdon Life Sciences Ltd., 2001a)	–	Negative (Huntingdon Life Sciences Ltd., 2001b, Covance Laboratories Ltd., 2008)	–
Tungsten metal	Negative (Covance Laboratories, Inc., 2004f)	Negative (Covance Laboratories, Inc., 2004d)	Negative (Covance Laboratories, Inc., 2004a)	–

OECD = Organisation for Economic Co-operation and Development; TG = Testing Guideline

Table 7. Studies on nano-tungsten substances.

Nano-tungsten substance	Toxicity effects	References
Tungsten metal	–Low cytotoxicity in assays using rat liver cells and human lung epithelial cells – Low activity in oxidative stress tests using rat liver cells	Hussain et al. 2005, Machado et al. 2011
Tungsten carbide	– No acute cytotoxic effects in human pulmonary cell lines or human skin and colon cell lines, or rat neuronal and glial cells – Induced formation of ROS and micronuclei in human keratinocyte cell line – Microarray analysis of human keratinocytes showed low transcriptional responses after 3 d of exposure – In vitro studies on rat hippocampal neurons showed influence on potassium channels and voltage-activated sodium currents, which suggested potential for neurotoxicity	Lanone et al. 2009, Bastian et al. 2009, Busch et al. 2010, Kühnel et al. 2012, Shan et al. 2012, Shan et al. 2013
Tungsten trioxide	– Positive mutagenic response in S. typhimurium strains TA1537 and TA98 – No transformability in BALB/C cells – DNA contact with nano-sized WO3 plates induced damage (demonstrated by mutation of DNA-transferred bacterial cells)	Hasegawa et al. 2012, Thongkumkoon et al. 2014
Tungsten disulfide (tubes)	–No acute cytotoxic effects in cells representing respiratory, immune, and metabolic systems – Did not induce pro-inflammatory cytokines IL-1β, IL-6, IL-8, and TNF-α – Activated antioxidant response	Pardo et al. 2014

ROS = reactive oxygen species.

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