Diammonium dimolybdate

Carcinogenicity

Description of key information

No evidence of systemic carcinogenicity in a 2-year inhalation study with MoO3, which is a suitable surrogate for other molybdenum substances regarding systemic effects. The marginal evidence for carcinogenicity in the lung in the study with MoO3 is considered a substance specific local effect and is without relevance for the substance under consideration in this dossier (see additional information). Overall, there are no data available that would indicate that the substance discussed in this dossier is carcinogenic.

Justification for classification or non-classification

No evidence of systemic carcinogenicity in a 2-year inhalation study with MoO₃, which is a suitable surrogate for other molybdenum substances regarding systemic effects. The marginal evidence for carcinogenicity in the lung in the study with MoO₃ is considered a substance specific local effect and is without relevance for the substance under consideration in this dossier (see discussion). Overall, there are no data available that would indicate that the substance discussed in this dossier is carcinogenic and “no classification” is concluded.

Additional information

This dossier is one of several dossiers prepared under the auspices of the REACH Molybdenum Consortium (“MoCon”). To avoid unnecessary (animal) testing, a comprehensive grouping and read-across concept has been developed amongst several molybdenum containing substances. This grouping/category approach is described in detail in a separate report, in accordance with the ECHA's "Read-Across Assessment Framework" (RAAF). This document is attached to section 13 in the technical dosser and to the CSR.

 

The key study regarding carcinogenicity of molybdenum substances is a 2 -year inhalation toxicity and carcinogenicity study with MoO₃in rats and mice by the US National Toxicological Programme (NTP, final report 1997). No evidence of systemic carcinogenicity was seen in these inhalation study with MoO3, which is a suitable surrogate for other molybdenum substances regarding systemic effects. The marginal evidence for carcinogenicity in the lung (and other local effects in the respiratory tract) in the study with MoO3 are considered substance specific local effects without relevance for the substance under consideration in this dossier, as detailed below.

 

 

Systemic absorption of molybdate following inhalation of MoO₃, and discussion of substance specific local effects caused by MoO₃in the respiratory tract

 

 

A two year carcinogenicity study (NTP 1997 (1) is available, in which the substance molybdenum trioxide (milled to MMAD of 1.5-1.8 µm) was administered to rats and mice via inhalation. Both in rats and mice (male and female), there was no evidence of systemic carcinogenicity. The substance tested by NTP (i. e. molybdenum trioxide) is considered to represent a reasonable surrogate for other molybdenum substances with regard to systemic effects, including systemic carcinogenicity (“read-across”), based on (i) a relatively high solubility/bioaccessibility of MoO₃(water solubility ca. 1 g/L, significant dissolution in artificial gastric fluid (appendix 4) and (ii) immediate transformation of MoO₃to the MoO₄^2-ions upon dissolution in aqueous media (appendix 5).

Further, an analysis of blood molybdenum levels in the experimental animal studies shows that the administration of MoO₃via inhalation (at 100 mg MoO₃/m³ = ca. 67 mg Mo/m³) leads to a similar systemic levels of molybdate as the oral administration of the soluble sodium molybdate (ca. 20 mg Mo/kgbw/day), as demonstrated below in detail:

(i) toxicokinetic data generated during a 28d oral toxicity study with sodium molybdate in rats (2)

In the context of a 28-day study with sodium molybdate dihydrate in rats (2), conducted as a dose ranging study for a subsequent 90-day oral study (3), a comparison of molybdate blood levels resulting from either gavage or dietary administration was conducted. Blood sampling was conducted on day 28 of the study at 1, 2, 4 and 8 hours post oral dosing (gavage) and for the dietary treatment on day 27 at 3, 5, 7, 9 and 11 hours after initiation of the daylight cycle. Peak blood concentrations after gavage treatment were generally observed 1 h post administration., and for dietary treatment ca. 3-5 h after the daylight cycle initiation, as follows:

 

Table: Molybdate blood levels in a 28 d oral toxicity study with sodium molybdate

Dose levels as   mg   sodium molybdate dihydrate / kg bw/day	Dose levels as   mg Mo/kg bw/day	Blood Levels Cmax   ng Mo/mL   gavage   males	Blood Levels Cmax   ng Mo/mL   gavage   females	Blood Levels Cmax   ng Mo/mL   dietary administration   males	Blood Levels Cmax   ng Mo/mL   dietary administration   females
0	0	23-29	22-25	23-29	22-25
10	4	7020	5290	922	814
50	20	30300	22900	4720	4960

 

(ii) whole blood and serum levels in a 90d dietary study with sodium molybdate in rats

During a 90d dietary study with sodium molybdate dihydrate (3), molybdate concentrations were sampled during dosing in weeks 4 (serum only) and 12 (serum and whole blood), as well as for serum on days 2 and 7 of the post exposure recovery phase. The results are presented below in separate tables for males and females, respectively:

 Table: Serum and whole blood molybdate levels in a 90d dietary study with sodium molybdate - males

		Serum Week 4	Serum Week 12	Whole Blood Week 12	Serum Day 2 Recovery	Serum Day 7 Recovery
Target dose, expressed as mg Na2MoO4. 2 H2O / kg bw/day	Target dose, expressed as mg Mo / kg bw/day	(ng Mo/mL)	(ng Mo /mL)	(ng Mo /mL)	(ng Mo /g)	(ng Mo /g)
0	0	18.7	19.4	11.9	19.0	20.6
12.5	5	1332	1309	912	NA	NA
42.5	17	4687	4674	2930	NA	NA
150	60	16277	18497	9903	4382	2425

 

 Table: Serum and whole blood molybdate levels in a 90d dietary study with sodium molybdate - females

		Serum Week 4	Serum Week 12	Whole Blood Week 12	Serum Day 2 Recovery	Serum Day 7 Recovery
Target dose, expressed as mg Na2MoO4. 2 H2O / kg bw/day	Target dose, expressed as mg Mo / kg bw/day	(ng Mo/mL)	(ng Mo /mL)	(ng Mo /mL)	(ng Mo /g)	(ng Mo /g)
0	0	19.8	17.9	11.1	15.1	33.3
12.5	5	991	1121	720	NA	NA
42.5	17	3370	4311	2628	NA	NA
150	60	13176	15531	7736	6447	2841

 

 (iii) blood levels in a 2yr inhalation study of rats (NTP) with molybdenum trioxide (1)

The blood levels of molybdenum after oral administration of sodium molybdate are compared here to those observed after inhalation exposure to molybdenum trioxide, since any whole-body inhalation exposure study will involve inadvertent oral exposure as well as a considerable translocation to the gut based on particle size dependent deposition in the respiratory tract of the animals, and any material deposited in the alveolar fraction may reasonably be assumed to dissolve and become systemically available also.

 The Mo blood levels following gavage and dietary administration of sodium molybdate as reported above can be compared with the blood levels of molybdenum in the rats in the NTP (1997, (1)) study in which molybdenum trioxide was administered by inhalation for 2 years. (Appendix G in the NTP Report (1)). The blood levels in the rats in the NTP study were:

 

 

 

Table: Molybdate blood levels in a 2-year inhalation study with molybdenum trioxide

Exposure level mg MoO3/m³	Corresponding Exposure level mg Mo/m³	Blood level (males) ng Mo/mL*	Blood level (females) ng Mo/mL*
0	0	221	59
10	6.7	800	355
30	20	1774	655
100	66.7	6036	2411

*: converted from ng/g into ng/mL assuming rel. density of blood=1

 When comparing these values with those shown in the previous tables it is reasonable to assume that blood levels in rats following inhalation of 100 mg/m³molybdenum trioxide (ca. 67 mg Mo/m³) are similar to those resulting from dietary exposure to 17-20 mg Mo/kg bw/d (in the form of sodium molybdate in the diet). These blood values show that molybdenum trioxide administered by inhalation in the NTP study (as 100 mg MoO₃/m³) was readily absorbed yielding a systemic molybdate dose comparable to approx. 20 mg Mo/kg bw/d.

 

It is therefore justified to read-across the absence of any indications of systemic carcinogenicity in the 2-year inhalation carcinogenicity studies with MoO₃to any other molybdenum substance that yields the molybdate ion as the relevant species.

 

In contrast to the absence of any systemic cancer in the MoO₃ inhalation studies with rats and mice, there is marginal evidence for carcinogenicity in the lung in male rats, male mice and female mice but no evidence in female rats: NTP has designated the level of evidence of carcinogenic activity as follows: ”equivocal” in male rats and “some evidence” in male/female mice. Reported findings also include non-neoplastic effects in the lungs such as chronic alveolar inflammation or alveolar metaplasia in both species and sexes.

When considering the occurrence, severity (or absence) of a localised toxicological effect of a solid chemical substance, chemical structure and reactivity, including the dissolution behaviour in physiological fluids, plays an important role. Molybdenum trioxide has a different chemical structure and reactivity compared to other molybdenum substances. These differences in chemical structure and dissolution behaviour between molybdenum trioxide and sodium molybdate (as an example also for other molybdate salts) are noted below and can account for the local effects of molybdenum trioxide that would not occur with sodium molybdate.

Sodium molybdate and molybdenum trioxide are both compounds of molybdenum in oxidation state six (Mo+6), but their structures are different. In sodium molybdate, molybdenum is bound to four oxygen atoms at the corners of a tetrahedron (Figure 1, based on (4)). The molybdate, MoO42-, ions are isolated one from another in an ionic crystal lattice which also includes balancing sodium ions and water molecules in hydrated forms of sodium molybdate. In contrast, in molybdenum trioxide, molybdenum is coordinated by six oxygen atoms at the corners of an octahedron. The octahedra are linked by oxygen atoms in an infinite lattice (Figure 2, based on (5,6)).  There is a range of Mo – O bond lengths in molybdenum trioxide (6). The longer bonds are those with bridging oxygen; they are weaker, more easily broken, than the shorter bonds and are centres of reactivity of molybdenum trioxide. In sodium molybdate, oxygen atoms are bound to only one molybdenum atom; the Mo – O bonds are shorter and less reactive.

 

 

Figure 1. (attached in technical IUCLID dossier in the endpoint summary on "Carcinogenicity") Structure of sodium molybdate dihydrate (based on reference (4). Atom labelling as shown. The structure consists of isolated molybdate and sodium ions and water molecules in an ionic lattice.  Molybdenum – oxygen bond lengths: 1.85, 1.74, 1.77, 1,68 mean 1.76 Å.

 

Figure 2. (attached in technical IUCLID dossier in the endpoint summary on "Carcinogenicity") Structure of molybdenum trioxide (based on reference (5). Atom labels as shown. The structure is an extended lattice of linked [MoO6] octahedra.

 

The different chemical structures of molybdenum trioxide and sodium molybdate also become apparent in different infrared, UV, visible light and Raman spectra (references 6-13, details not repeated here for the sake of brevity).

 

When in contact with aqueous media, sodium molybdate, an anionic salt, simply dissolves in water giving a solution of pH 7 (14). The process of dissolution is simply the breakup of the ionic lattice.

However, in contrast, molybdenum trioxide per se does not simply dissolve in water. Instead it reacts with water giving an acidic solution, in a reaction in which Mo-O-Mo bonds are broken: MoO3+ H2O --> MoO42-+ 2H+. In a water solubility study according to OECD TG 105, a saturated solution of molybdenum trioxide in purified water had a pH 2.5 at 20°C (15).

 

Such acidity is also observed MoO3 particles dispersed in composites, for example in MoO3 mixed-oxide catalysts. Recent research on the antimicrobial property of MoO3 composites with certain polymers and oxides has attributed their antibacterial effect to acidity. It is plausible to envisage an analogous behaviour of inhaled MoO3 particles interacting with the lung surface and, as a composite, developing an acidic reaction. The antibacterial effect and the lung effect is specific to the MoO3 solids (particles or bound in composites) and is not observed for MoO3 dissolved in water.

Some references relating to the antibacterial properties of MoO3 have been included in the technical dossier in section 7.9.4 (specific investigations: other studies; chapter 5.10.1.3 in the CSR).

 

In conclusion, the reported local effects of MoO3 in the lungs of experimental animals are most plausibly related to the particular chemical structure and reactivity of MoO3 particles which, as indicated above, are different from those of sodium molybdate and other molybdenum substances*. In other words, the local effects of MoO3 are most likely due to a direct particle interaction (reaction) with the lung tissue and not related to the molybdate ion which is present after dissolution of MoO3 or other molybdenum substances.  Read-across of the observed local lung effects of MoO3 to other molybdenum substances* is therefore not justified.

 

* Except to the technical form of molybdenum oxide (CAS No. 86089-09-0, EC name: “molybdenum sulfide (MoS2) roasted”), which is an UVCB with the main constituent being MoO3, and to which the local effects of MoO3 in the lungs of the animals are read-across.

 

Overall, there are no data available that would indicate that the substance discussed in this dossier is carcinogenic and “no classification” is concluded.

 

References

(1) NTP Technical Report On The Toxicology And Carcinogenesis Studies Of Molybdenum Trioxide In F344/N Rats And B6c3f1 Mice (Inhalation Studies) National Toxicology Program April 1997 NTP TR 462 NIH Publication.

(2) Hoffman, G. M. (2011a): Sodium molybdate dihydrate: A 28-day oral gavage and dietary administration dose range finder study in rats. Huntingdon Life Sciences, P. O. Box 2360, Mettlers Road, East Millstone, New Jersey 08875-2360, U. S. A. Unpublished study for the International Molybdenum Association (IMOA). Report No. 10-2205. Report date 2011-08-30.

(3) Hoffman, G. M. (2011b): Sodium molybdate dihydrate: A 90-day oral dietary administration study in rats (GLP). Huntingdon Life Sciences, P. O. Box 2360, 100 Mettlers Road, East Millstone, New Jersey 08875-2360, U. S. A. Unpublished study for the International Molybdenum Association (IMOA). Report No. 10-2225. Report date 2011-10-25.

(4) L. O. Atovmyan and O. A. D'yachenko,  Zhurnal Strukturnoi Khimii,10, 1969, 504.

(5) L. Kihlborg, Ark. Kemi., 1963, 24, 357.

(6) L. Seguin, M. Figlarz, R. Cavagnat and J. -C. Lassegues, Spectrochim. Acta, 1995, 51A, 1323.

(7) http: //webbook. nist. gov/cgi/cbook. cgi?ID=B6000473&Mask=8/0#IR-Spec

(8) A. Stoyanova, R. Iordanova, M. Mancheva andY. Dimitriev, Journal Of Optoelectronics And Advanced Materials, 2009, 11, 1127.

(9) P. C. H. Mitchell, Quart. Rev., 1966, 20, 103

(10) J. H. Ashley and P. C. H. Mitchell, J. Chem. Soc. (A), 1968, 2821

(11) J. H. Ashley and P. C. H. Mitchell, J. Chem. Soc. (A) 1969, 2730;

(11) P. C. H. Mitchell and F. Trifiro, J. Chem. Soc. (A), 1970, 3183;

(13) A. W. Armour, PhD Thesis, Reading 1972)

(14) Baer, C. (2008): Water solubility of sodium molybdate dihydrate. eurofins-GAB GmbH, D-Pforzheim, Germany. Unpublished report for the International Molybdenum Association (IMOA). Report No. 20071507/01-PCSB. Report date 2008-08-28.

(15) Baer, C. (2008): Water solubility of molybdenum trioxide. eurofins-GAB GmbH, D-Pforzheim, Germany. Unpublished report for the International Molybdenum Association (IMOA). Report No. 20071505/01-PCSB. Report date 2008-08-29.