Cobalt molybdate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

There are no data available.

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

6.4 mg/kg bw/day

Study duration:

subchronic

Species:

mouse

Effect on fertility: via inhalation route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEC

1.14 mg/m³

Study duration:

subchronic

Species:

mouse

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

There are no data available on toxicity to reproduction for cobalt molybdenum oxide. However, there are reliable data for soluble cobalt and molybdenum substances considered suitable for read-across using the analogue approach. For identifying hazardous properties of cobalt molybdenum oxide, the existing forms of cobalt molybdenum oxide at very acidic and physiological pH conditions are relevant for risk assessment of human health effects. Cobalt molybdenum oxide is a metal-organic salt, which is highly water soluble (~ 508 mg/L) and nearly completely dissociates in aqueous solutions. As it is expected that cobalt molybdenum oxide is capable of forming ions at very acidic and physiological pH conditions, cobalt cations and molybdate anions will be present and completely bioavailable, same as for other soluble cobalt and molybdenum compounds.Due to the existing cobalt and molybdate ions, data from other soluble cobalt and molybdenum substances are used in the derivation of toxicological endpoints for cobalt molybdenum oxide. For further details refer to the analogue justification.

 

Cobalt substances

Effects on the male reproductive system have been observed in rats and mice. Male mice were given cobalt chloride hexahydrate in the drinking water at doses of 200, 400 and 800 ppm (corresponding to 6.4, 11.7 and 23.1 mg Co2+/kg bw/day) for 12 weeks, then mated with untreated females (Elbetieha et al., 2007). At all doses, there were decreased implantations, increased number of resorptions, decreased number of viable fetuses, and decreased sperm counts. At the 2 higher doses, there was also decreased relative testes weight, and testes necrosis and degeneration. Therefore, no NOAEL was determined. The LOAEL was 6.4 mg Co2+/kg bw/day.

Reduced fertility, decreased sperm concentration and motility, testicular atrophy, degeneration and necrosis were also reported in several other studies in male mice and rats given higher oral doses of cobalt chloride hexahydrate via drinking water and diet (Anderson et al., 1992; Corrier et al., 1985; Pedigo and Vernon, 1993; Pedigo et al, 1988). In addition, numerous animal data also confirmed reproductive toxicity: both rats and mice exposed to soluble cobalt(II)salts via drinking water or diet exhibited testicular degeneration and atrophy (Nation et al., 1983; Domingo et al., 1984; Anderson et al., 1993).

In a 13-week inhalation study (Bucher, 1991), groups of mice and rats were exposed to cobalt(II)sulfate heptahydrate aerosols at concentrations of 3, 10 and 30 mg/m³ (calculated as the anhydrous salt; equivalent to 1.14, 3.8 and 11.4 mg Co2+/m³) for 6 hours/day and 5 days/week. In male mice, at ≥ 1.14 mg Co2+/m³ cobalt molybdenum oxide, sperm motility was decreased and at a concentration of 11.4 mg Co2+/m³, testicular atrophy, increased abnormal sperm and decreased testis weight were observed. The estrous cycle was significantly longer in female mice exposed to the highest concentration than in the controls. In rats, no significant effects on the male or female reproductive systems were observed.

Taking into account all available data on toxicity to reproduction, soluble cobalt substances caused reduced fertility, decreased sperm concentration and motility, testicular atrophy, degeneration and necrosis in male mice and rats. Therefore, cobalt molybdenum oxide will be classified as a reproductive toxicant for fertility effects.

In order to meet the standard information requirements according to Regulation (EC) 1907/2006 Annex IX, Column I, 8.7.2, a GLP-compliant two-generation reproduction toxicity study according to OECD 416 or an extended one-generation study according to OECD 443 is required. However, in accordance with Regulation (EC) 1907/2006, which specifies that unnecessary tests should be avoided in terms of animal welfare, all available data on toxicity to reproduction were considered and evaluated.

 

Molybdenum substances

The Molybdenum Consortium and the International Molybdenum Association, has recently conducted an extensive literature/data search and evaluation program on animal and human data relating to possible adverse effects of molybdenum substances on fertility and developmental toxicity. All available references evaluated in this process lacked relevance because of severe shortcomings in the applied methodology and/or quality of reporting/documentation, thereby rendering them unsuitable for regulatory purposes (reference evaluation report: Tabular quality and reliability assessment report Molybdenum substances – Human and animal data on effects on fertility and developmental toxicity, EBRC unpublished report June 2010, EBRC Hannover, Germany).

Whereas not specifically designed to investigate effects on reproduction, no test substance related changes in male and female reproductive organs were observed in the 90-day and 2-year inhalation toxicity/carcinogenicity studies with molybdenum trioxide in rats and mice up to the highest concentration tested. Additionally no changes in sperm counts were observed in that 90-day NTP study.

 

References not cited in the IUCLID:

Nation, JR et al., 1983, The effects of chronic cobalt exposure on behaviour and metallothionein levels in the adult rat. Neurobehavioral Toxicology and Teratology, 5: 9 -15

Pedigo, NG et al., 1988. Effects of acute and chronic exposure to cobalt in male reproduction in mice. Reproductive Toxicology, 2: 45 -53

Anderson, MB et al., 1993, Protective action of zinc against cobalt-induced testicular damage in the mouse. Reproductive Toxicology, 7: 49 -54

Short description of key information:
Read-across from cobalt chloride hexahydrate:
LOAEL (mouse, oral via drinking water): 200 ppm (equivalent to 6.4 mg Co2+/kg bw/day)
LOAEC (mouse, inhalation): 3 mg/m3 (equivalent to 1.14 mg Co2+/m3)

Effects on developmental toxicity

Description of key information

Read-across from cobalt sulfate heptahydrate:
LOAEL (rat, oral via gavage): 25 mg/kg bw/day (equivalent to 5.2 mg Co2+/kg bw/day)

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

19.3 mg/kg bw/day

Study duration:

subacute

Species:

rat

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

There are no data available on developmental toxicity for cobalt molybdenum oxide. However, there are reliable data for soluble cobalt and molybdenum substances considered suitable for read-across using the analogue approach. For identifying hazardous properties of cobalt molybdenum oxide, the existing forms of cobalt molybdenum oxide at very acidic and physiological pH conditions are relevant for risk assessment of human health effects. Cobalt molybdenum oxide is a metal-organic salt, which is highly water soluble (~ 508 mg/L) and nearly completely dissociates in aqueous solutions. As it is expected that cobalt molybdenum oxide is capable of forming ions at very acidic and physiological pH conditions, cobalt cations and molybdate anions will be present and completely bioavailable, same as for other soluble cobalt and molybdenum compounds.Due to the existing cobalt and molybdate ions, data from other soluble cobalt and molybdenum substances are used in the derivation of toxicological endpoints for cobalt molybdenum oxide. For further details refer to the analogue justification.

 

Cobalt substances

In the study of Szakmary et al. (2001), groups of rats were dosed by gavage at 25, 50 and 100 mg/kg bw/day of cobalt sulfate heptahydrate (equivalent to 5.2, 10.5 and 21.0 mg Co2+/kg bw/day) from gestation day 1-20. In all treated groups, there was an increased frequency of skeletal retardation, increased frequency of skeletal and urogenital system malformations, decreased perinatal index, decreased pup body weight at postnatal days 1 and 7, and delays in postnatal developmental parameters (ear opening, incisor eruption, descending of testes). Pup body weight and postnatal developmental parameters returned to control levels by postnatal day 21, and the survival index from day 5 to day 21 was the same as controls. Some maternal toxicity was observed at the high dose (increased relative weight of liver, adrenal and spleen, serum alterations). There was also a dose-dependent increase in the number of dams that died during delivery. Therefore, no NOAEL for embryotoxicity/teratogenicity was determined. The LOAEL for embryotoxicity/teratogenicity is 5.2 mg Co2+/kg bw/day.

In contrast, Paternain et al. (1988) found no effects on fetal growth or survival after exposing rats to cobalt(II)chloride during gestation days 6-15. Oral exposure of female rats to cobalt(II)chloride from gestation day 14 to lactation day 21 caused newborn pups to exhibit stunted growth and decreased survival. However, these effects occurred at exposures that also caused maternal toxicity (reduced body weight and altered haemtological parameters), indicating that developmental effects could be secondary to effects on the dams. No teratogenic effects were observed (Domingo et al., 1985).

In mice, when dams were treated with cobalt sulfate heptahydrate at 50 mg/kg bw/day (equivalent to 10.5 mg Co2+/kg bw/day) throughout gestation, an increased frequency of pups had reduced body weights (although the average pup body weight was not different from controls) (Szakmary et al., 2001). Pups also had skeletal retardation and abnormalities of eyelids, kidneys, cranium and spine. No maternal toxicity was reported. In rabbits, when dams were treated at 20 to 200 mg/kg bw/day (equivalent to 4.2 and 42.0 mg Co2+/kg bw/day) throughout gestation, an increased frequency of pups had reduced body weights (although the average pup body weight was not different from controls). Dams had a significantly decreased body weight gain. No signs of teratogenicity were reported in rabbits (Szakmary et al., 2001).

Taking into account all available data on developmental toxicity, it is not clear if developmental effects observed could be secondary to effects on the dams. As a worst-case scenario, cobalt molybdenum oxide will be classified as a reproductive toxicant for developmental effects. In order to meet the standard information requirements according to Regulation (EC) 1907/2006 Annex IX, Column I, 8.7.2, a GLP-compliant prenatal development toxicity study according to OECD 414 is required. However, in accordance with Regulation (EC) 1907/2006, which specifies that unnecessary tests should be avoided in terms of animal welfare, all available data on developmental toxicity were considered and evaluated.

 

Molybdenum substances

The Molybdenum Consortium and the International Molybdenum Association, has recently conducted an extensive literature/data search and evaluation program on animal and human data relating to possible adverse effects of molybdenum substances on fertility and developmental toxicity. All available references evaluated in this process lacked relevance because of severe shortcomings in the applied methodology and/or quality of reporting/documentation, thereby rendering them unsuitable for regulatory purposes (reference evaluation report: Tabular quality and reliability assessment report Molybdenum substances – Human and animal data on effects on fertility and developmental toxicity, EBRC unpublished report June 2010, EBRC Hannover, Germany).

Toxicity to reproduction: other studies

Additional information

There are no data available.

Justification for classification or non-classification

Based on an analogue approach, the available data on toxicity to reproduction meet the criteria for classification as Category 1B (H360) according to Regulation (EC) 1272/2008 and R60 (Category 2) and R63 (Category 3) according to Directive 67/548/EEC.