Cobalt(2+) hydrogen citrate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

Quality of whole database:

The available information comprises adequate, reliable (Klimisch score 2) and consistent studies from reference substances with similar structure and intrinsic properties. Read-across is justified based on the basic assumption that the cobalt ion is the determining factor for biological activity. Please refer to the endpoint discussion for further details.

Effect on fertility: via inhalation route

Endpoint conclusion:

adverse effect observed

Quality of whole database:

The available information comprises adequate, reliable (Klimisch score 2) and consistent studies from reference substances with similar structure and intrinsic properties. Read-across is justified based on the basic assumption that the cobalt ion is the determining factor for biological activity. Please refer to the endpoint discussion for further details.

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

There are no data available on effects on fertility for cobalt hydrogen citrate. However, there are reliable data for soluble cobalt compounds considered suitable for read-across using the analogue approach.

Cobalt hydrogen citrate is a metal-organic compound, which is water soluble and nearly completely dissociates in aqueous solutions. For identifying hazardous properties of cobalt hydrogen citrate concerning human health effects, the existing forms of the target chemical at physiological and very acidic pH conditions (e. g. in the stomach) are relevant for risk assessment. For cobalt hydrogen citrate, it can be assumed that cobalt cations are released under biological conditions that are considered to be toxicologically relevant. Furthermore it is anticipated that the cobalt cation released by the parent compound is the determining factor for toxicological effects, same as for other soluble cobalt compounds. Therefore, data originating from soluble cobalt compounds can be used in the derivation of toxicological endpoints for cobalt hydrogen citrate. For further details, please refer to the analogue justification attached in section 13 of the technical dossier.

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 25.7, 47 and 93 mg/kg bw/day (corresponding to 26.8, 50.0, 96.9 mg/kg bw/day cobalt hydrogen citrate) 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 25.7 mg/kg bw/day (26.8 mg/kg bw/day cobalt hydrogen citrate; recalculated value).

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 4.8, 16.1 and 48.2 mg/m³ cobalt hydrogen citrate)

for 6 hours/day and 5 days/week. In male mice, at ≥ 3 mg/m³ , sperm motility was decreased and at a concentration of 10 mg/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 effects on fertility, soluble cobalt substances caused reduced fertility, decreased sperm concentration and motility, testicular atrophy, degeneration and necrosis in male mice and rats. Therefore, cobalt hydrogen citrate 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.

 

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 with soluble cobalt(II)salts:
LOAEL (oral): 20.6 - 26.8 mg/kg bw/day cobalt hydrogen citrate (recalculated values)
LOAEC (inhalation): 4.8 mg/m³ cobalt hydrogen citrate (recalculated value)

Justification for selection of Effect on fertility via oral route:
No study was selected as hazard assessment was conducted by a weight of evidence of appropriate read-across substances. Available data on soluble cobalt (II) salts were pooled for assessment based on the basic assumption that the cobalt ion is the determining factor for biological activity.

Justification for selection of Effect on fertility via inhalation route:
No study was selected as hazard assessment was conducted by a weight of evidence of appropriate read-across substances. Available data on soluble cobalt (II) salts were pooled for assessment based on the basic assumption that the cobalt ion is the determining factor for biological activity.

Effects on developmental toxicity

Description of key information

The available data on developmental toxicity using soluble cobalt (II) salts are inconclusive and not sufficient for classification.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Quality of whole database:

The available information comprises adequate, reliable (Klimisch score 2) and consistent studies from reference substances with similar structure and intrinsic properties. Read-across is justified based on the basic assumption that the cobalt ion is the determining factor for biological activity. Please refer to the endpoint discussion for further details.

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 effects on developmental toxicity for cobalt hydrogen citrate. However, there are reliable data for soluble cobalt compounds considered suitable for read-across using the analogue approach.

Cobalt hydrogen citrate is a metal-organic compound, which is water soluble and nearly completely dissociates in aqueous solutions. For identifying hazardous properties of cobalt hydrogen citrate concerning human health effects, the existing forms of the target chemical at physiological and very acidic pH conditions (e. g. in the stomach) are relevant for risk assessment. For cobalt hydrogen citrate, it can be assumed that cobalt cations are released under biological conditions that are considered to be toxicologically relevant. Furthermore it is anticipated that the cobalt cation released by the parent compound is the determining factor for toxicological effects, same as for other soluble cobalt compounds. Therefore, data originating from soluble cobalt compounds can be used in the derivation of toxicological endpoints for cobalt hydrogen citrate. For further details, please refer to the analogue justification attached in section 13 of the technical dossier.

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 calculated as the anhydrous salt (equivalent to 40, 80 and 160 mg/kg bw/day cobalt hydrogen citrate) 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 25 mg/kg bw/day (corresponding to 40 mg/kg bw/day cobalt hydrogen citrate; recalculated value).

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 calculated as the anhydrous salt (equivalent to 80 mg /kg bw/day cobalt hydrogen citrate) 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 cobalt sulfate heptahydrate calculated as the anhydrous salt (equivalent to 32 and 320 mg/kg bw/day cobalt hydrogen citrate) 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. Therefore, the available data on developmental toxicity are inconclusive and not sufficient for classification.

References not cited in the IUCLID:

Szakmary et al. (2001) Effects of cobalt sulfate on prenatal development of mice, rats, and rabbits, and on early postnatal development of rats. Journal of Toxicology and Environmental Health, Part A 62: 367-386 (Data on rats were given in IUCLID, but not on mice and rabbits.)

Justification for selection of Effect on developmental toxicity: via oral route:
No study was selected as hazard assessment was conducted by a weight of evidence of appropriate read-across substances. Available data on soluble cobalt (II) salts were pooled for assessment based on the basic assumption that the cobalt ion is the determining factor for biological activity.

Toxicity to reproduction: other studies

Additional information

For details please refer to section 7.8.1 of the technical dossier.

Justification for classification or non-classification

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