Olivine, cobalt silicate blue

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Description of key information

No studies on the toxicity to reproduction with Olivine, cobalt silicate blue are available, thus the toxicity to reproduction will be addressed with existing data on the relevant toxic unit cobalt. The source information is selected based on the read-across approach implemented by the Cobalt REACH consortium for oral systemic effects. Further details on the read-across approach are given in the report attached to IUCLID section 13.

Additional information

The toxicity to reproduction of Olivine, cobalt silicate blue is addressed with existing data on the source substances identified in the read-across of the cobalt category substances as defined by the Cobalt REACH Consortium.

Based on the approach for oral systemic effects assessment, the pigment Olivine, cobalt silicate blue is placed in the bioavailable cobalt substances group (BCoS) for the oral route. Due to the tonnage band of Olivine, cobalt silicate blue, not all information reported for toxicity to reproduction in the Cobalt REACH Consortium dossier for the cobalt category substances are available. However, the hazard conclusion as concluded for the bioavailable cobalt substances group (BCoS) are adopted for Olivine, cobalt silicate blue (please refer to the section “Justification for classification or non-classification”).

 

In a combined repeated dose toxicity studies with the reproduction/developmental toxicity screening test (according to OECD 422 and under GLP) cobalt was administered orally to rats at dose levels of 30, 100, 300 and 1000 mg/kg bw/day during the pre-mating, mating and post-mating periods to parental males as well as during the pre-mating, mating, gestation and lactation periods until day 3 post-partum (or shortly thereafter) to parental female animals.

Piloerection, reduced motility, soft faeces/diarrhoea and reduced food consumption were noted - in relation to the dose - from a dose level of 100 mg cobalt /kg bw/day onwards. In addition, reductions of body weight were noted from 300 mg cobalt /kg bw/day onwards. Premature deaths occurred in five female rats at 100 mg cobalt /kg bw/day and eight female rats at 300 mg cobalt /kg bw/day. Treatment with 1000 mg cobalt /kg bw/day caused the premature death of nine of ten males and all ten females. Macroscopic inspection revealed changes of the gastro-intestinal tract - mainly in the prematurely deceased animals - from a dose level of 100 mg cobalt/kg bw/day onwards and adrenal changes and pulmonal lesions at 1000 mg cobalt/kg bw/day.

Histopathological inspection did not reveal any pathological changes. No histopathological correlate could be found for the macroscopical lesions noted at necropsy. No test item-related influence was noted on the sperm staging or interstitial cell structure (qualitative examination). Treatment with 300 mg cobalt/kg bw/day resulted in an increase of the post-implantation loss and a decrease in the live birth index. No test item-related influence was noted on mating behaviour, fertility and the gestation length. From 30 mg cobalt/kg bw/day onwards, the mean litter weight of pups was slightly reduced in a dose-related way (not significant at p ≤ 0.01), significant only at 300 mg cobalt/kg bw/day. In order to estimate a possible correlation between maternal toxicity and F1-Generation (pups) findings, the litter weight of pups was compared in dams with clinical signs within each group. Dams were classified based on the severity and occurrence of clinical signs. As a result it appeared that the earlier the clinical signs occurred in the dams a more pronounced weight reduction was noted for the pups of the respective dams. An increased F1-Generation (pups) mortality rate and a slightly decreased viability index were noted from 100 mg cobalt/kg bw/day onwards.

The NO(A)EL for effects on the F0-generation was 30 mg cobalt/kg bw/day, based on mortality, clinical signs of toxicity, effects on food consumption and macroscopic pathological changes observed at and above 100 mg cobalt/kg bw/day and reduced body weight at and above 300 mg cobalt/kg bw/day.

The NO(A)EL for effects on the reproductive toxicity was 30 mg cobalt/kg bw/day, based on an increased F1-Generation (pups) mortality rate and a slightly decreased viability index at 100 mg cobalt/kg bw/day and on post-implantation losses, decreases in the live birth index and significantly reduced litter weights of pups observed at 300 mg cobalt/kg bw/day.

Effects on developmental toxicity

Description of key information

No studies on the developmental toxicity with Olivine, cobalt silicate blue are available, thus the developmental toxicity will be addressed with existing data on the relevant toxic unit cobalt. The source information is selected based on the read-across approach implemented by the Cobalt REACH consortium for oral systemic effects. Further details on the read-across approach are given in the report attached to IUCLID section 13.

Additional information

The developmental toxicity of Olivine, cobalt silicate blue is addressed with existing data on the source substances identified in the read-across of the cobalt category substances as defined by the Cobalt REACH Consortium.

Based on the approach for oral systemic effects assessment, the pigment Olivine, cobalt silicate blue is placed in the bioavailable cobalt substances group (BCoS) for the oral route. Due to the tonnage band of Olivine, cobalt silicate blue, not all information reported for developmental toxicity in the Cobalt REACH Consortium dossier for the cobalt category substances are available. However, the hazard conclusion as concluded for the bioavailable cobalt substances group (BCoS) are adopted for Olivine, cobalt silicate blue (please refer to the section “Justification for classification or non-classification”).

 

 

Cobalt dichloride is the source substance for the bioavailable cobalt substances group based on the read-across approach as outlined in IUCLID section 13. Two soluble inorganic cobalt substances, cobalt dichloride and cobalt powder, have been tested for developmental toxicity, resulting in an absence of effects on the developing organism up to the maximum tolerated dose.

 

In a pre-natal developmental toxicity study (according to OECD 414 and under GLP), cobalt dichloride was given to pregnant rats at doses of 0, 25, 50, 100 mg/kg bw/day. A total of 25 females per group were given the test items suspended in 0.5% hydroxypropyl methylcellulose gel orally via gavage once daily from gestation day 6 until gestation day 19.

No test item-related premature death was noted in the control or in any of the test item treated groups.

At 50 or 100 mg/kg bw/day piloerection, a slight to moderate reduced motility and slight to moderate salivation were noted for several dams on one or up to 6 test days.

At 100 mg/kg bw/day a haemorrhagic nose/snout was noted for 3 of 20 dams on gestation days 19 or 20. At 50 or 100 mg/kg bw/day statistically significantly reduced body weights in comparison to the control group were noted after the start of treatment (about 5 to 6% below the control group on gestation day 8 or 9). The reductions in body weight for both dose groups compared to the control group slightly increased during the further course of the study, leading to body weights on gestation day 20, that were 14.2% (intermediate dose group) or 15.1% (high dose group) below the value of the control group. The net weight change (body weight without gravid uterus) after the start of treatment until laparotomy (gestation day 6 to gestation day 20) was statistically significantly reduced for the dams treated with 50 or 100 mg/kg bw/day: control: + 38. 4 g, intermediate dose: -10.6 g, high dose: - 14.1g. Gastro-intestinal lesions in form of haemorrhagic foci in the stomach and intestines with a dark(-brown) content were noted in a dose related way for the dams dosed with 25, 50 or 100 mg/kg bw/day (low dose: 1 of 20 dams, intermediate dose: 3 of 20 dams, high dose: 9 of 20 dams). No test item related influence was noted on the gravid uterus weight. The carcass weights were statistically significantly reduced in comparison to the control group by 8.7, 18.2 and 18.1% for the dams treated with 25, 50 or 100 mg/kg bw/day.

The reproduction data of the dams revealed no test item-related differences for pre-implantation loss, post-implantation loss and resorptions/implantation site ratios between the dams of the control group and the dams treated with 25, 50 or 100 mg/kg bw/day.

No dead foetuses were noted in the litters of the dams of the control group and in the litters of the dams treated with 25, 50 or 100 mg/kg bw/day. No test item-related influence on the ratio of live male foetuses to live female foetuses were noted for all treatment groups. All values of the treatment groups were within the range of laboratory background data.

No test item-related differences of the placental or foetal weights were noted between the control group and the treatment groups.

No test item-related macroscopically visible malformations or variations were noted for the foetuses of the treatment groups during the external examination of the foetuses at laparotomy. The internal examination revealed no malformation or variations in the control or any of the treatment groups. Skeletal examination showed no test-item related malformations, variations or retardations in the control or any of the treatment groups. No test item-related malformations were noted during soft tissue examinations of the foetuses according to WILSON in any of the treatment groups. No test item-related differences for the incidences of the observed soft tissue variations were noted between the control group and the test item treated groups.

Under the test conditions of the pre-natal developmental toxicity study with cobalt dichloride, the no-observed-adverse-effect level (NOAEL) was 25 mg cobalt dichloride/kg bw/day for the dams, based on reduction of body weight and body weight gain, food consumption, changes of haematological parameters as well as gastro-intestinal lesions

The no-observed-adverse effect level (NOAEL) for the foetal organism was above 100 mg cobalt dichloride/kg bw/day. No test item-related changes were noted for the number of resorptions and the foetal body weight. No dead foetuses, no test item-related malformations, variations or retardations were noted at any of the tested dose levels.

 

In a combined repeated dose toxicity studies with the reproduction/developmental toxicity screening test (according to OECD 422 and under GLP) cobalt was administered orally to rats at dose levels of 30, 100, 300 and 1000 mg/kg bw/day during the pre-mating, mating and post-mating periods to parental males as well as during the pre-mating, mating, gestation and lactation periods until day 3 post-partum (or shortly thereafter) to parental female animals.

Piloerection, reduced motility, soft faeces/diarrhoea and reduced food consumption were noted - in relation to the dose - from a dose level of 100 mg cobalt /kg bw/day onwards. In addition, reductions of body weight were noted from 300 mg cobalt /kg bw/day onwards. Premature deaths occurred in five female rats at 100 mg cobalt /kg bw/day and eight female rats at 300 mg cobalt /kg bw/day. Treatment with 1000 mg cobalt /kg bw/day caused the premature death of nine of ten males and all ten females. Macroscopic inspection revealed changes of the gastro-intestinal tract - mainly in the prematurely deceased animals - from a dose level of 100 mg cobalt/kg bw/day onwards and adrenal changes and pulmonal lesions at 1000 mg cobalt/kg bw/day.

Histopathological inspection did not reveal any pathological changes. No histopathological correlate could be found for the macroscopical lesions noted at necropsy. No test item-related influence was noted on the sperm staging or interstitial cell structure (qualitative examination). Treatment with 300 mg cobalt/kg bw/day resulted in an increase of the post-implantation loss and a decrease in the live birth index. No test item-related influence was noted on mating behaviour, fertility and the gestation length. From 30 mg cobalt/kg bw/day onwards, the mean litter weight of pups was slightly reduced in a dose-related way (not significant at p ≤ 0.01), significant only at 300 mg cobalt/kg bw/day. In order to estimate a possible correlation between maternal toxicity and F1-Generation (pups) findings, the litter weight of pups was compared in dams with clinical signs within each group. Dams were classified based on the severity and occurrence of clinical signs. As a result it appeared that the earlier the clinical signs occurred in the dams a more pronounced weight reduction was noted for the pups of the respective dams. An increased F1-Generation (pups) mortality rate and a slightly decreased viability index were noted from 100 mg cobalt/kg bw/day onwards.

The NO(A)EL for effects on the F0-generation was 30 mg cobalt/kg bw/day, based on mortality, clinical signs of toxicity, effects on food consumption and macroscopic pathological changes observed at and above 100 mg cobalt/kg bw/day and reduced body weight at and above 300 mg cobalt/kg bw/day.

The NO(A)EL for effects on the reproductive toxicity was 30 mg cobalt/kg bw/day, based on an increased F1-Generation (pups) mortality rate and a slightly decreased viability index at 100 mg cobalt/kg bw/day and on post-implantation losses, decreases in the live birth index and significantly reduced litter weights of pups observed at 300 mg cobalt/kg bw/day.

 

In addition to the above studies there is a limited number of information on developmental toxicity of soluble cobalt compounds in several species, which suffers from several defects:

 - several studies (in particular those of Wide, 1984; Domingo et al., 1985) report effects on foetuses and neonates, but all studies suffer from several methodical and reporting deficiencies, thus rendering them of very limited use in a regulatory context. In addition, the reference by Gluhcheva et al. (2014) suffers from several methodological and reporting deficiencies, therefore was not relevant for human health risk assessment.

- one study is apparently void of effects (Paternain et al., 1988) with regard to foetal effects, but maternal toxicity was observed at all dose levels, so that this study does not allow the derivation of a maternal no-effect level.

- another study (Szakmary et al., 2001) provides a multitude of information, but which is partly contradictory in nature and also has reporting and methodological shortcomings.

In conclusion, these and other available studies show several deficiencies, thus rendering them of limited use in a regulatory context. Since the results are somewhat contradictory, they are considered unsuitable for a human health risk assessment and DNEL-setting under REACH.

Furthermore, none of the available studies represent state-of-the-art, guideline-compliant, extended one-generation reproduction toxicity studies or other relevant study designs, from which robust no-effect levels for human risk assessment could be derived.

Justification for classification or non-classification

The hazard conclusion for Olivine, cobalt silicate blue for the endpoint toxicity to reproduction is adopted from the bioavailable cobalt substances group (BCoS), based on the read-across approach as outlined in the report attached to section 13.

The current test results for the bioavailable cobalt substances group (BCoS) does not support the identification of any adverse effects towards male reproductive organs for the bioavailable cobalt substances group. However, these is still existing information in the public domain which identified a hazard with regard to male reproduction. Consequently all members of the bioavailable cobalt substances group will be self-classified as toxic for reproduction category 1B (H360F). The available data on the repeated dose toxicity of the bioavailable cobalt substances group is adequate to support a robust risk assessment, by using the point of departure for the most sensitive systemic effect on the haematopoietic system.

The test results with the source substances of the bioavailable cobalt substances group (screening test with cobalt, pre-natal developmental toxicity study with cobalt dichloride in rats and rabbits) does not support the clear identification of adverse effects towards developmental toxicity. However, findings in the pre-natal developmental toxicity study in rabbits manifested as increased early resorptions at presence of some maternal toxicity does not allow to unequivocally conclude on an absence of developmental effects in rabbits. Consequently, cobalt dichloride and subsequently all members of the bioavailable cobalt substances group (BCoS) are self-classified for developmental toxicity Category 2 (H361d).