Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

The low order of toxicity to reproduction of Hematite chromium green black is manifested in (i) an absence of a concern for the endpoint reproductive toxicity for the soluble forms of the metals present in Hematite chromium green black, (ii) the very clear finding that Hematite chromium green black is of poor bioavailability in a wide range of physiological media (iii) Hematite chromium green black shows no effects in a number of in vitro and in vivo toxicological tests and (iv) the physico-chemical properties demonstrate Hematite chromium green black is of general inertness. Furthermore, concerning this minimal fraction of dose that is available for systemic absorption, the inorganic nature of the metals present in Hematite chromium green black precludes any form of metabolism in mammals.

 

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

The low order of toxicity to reproduction of Hematite chromium green black is manifested in (i) an absence of a concern for the endpoint developmental toxicity for the soluble and insoluble forms of the metals present in Hematite chromium green black, (ii) the very clear finding that Hematite chromium green black is of poor bioavailability in a wide range of physiological media(iii) Hematite chromium green black shows no effects in a number of in vitro and in vivo toxicological tests and (iv)the physico-chemical properties demonstrate Hematite chromium green black is of general inertness. Furthermore, concerning this minimal fraction of dose that is available for systemic absorption, the inorganic nature of the metals present in Hematite chromium green black precludes any form of metabolism in mammals.

(i) Supporting information for toxicity to reproduction with metals contained in Hematite chromium green black

 

Chromium

Several “studies do not show evidence of reproductive or developmental toxicity. There were no changes in testis or epididymis weights in rats following treatment with chromium picolinate or chromium chloride (9 mg Cr(III)/kg b.w. per day) in the diet for 24 weeks (Anderson et al., 1997). There was no evidence of reproductive or developmental toxicity in male or female rats following dietary exposure to chromium oxide (50000 mg/kg diet equivalent to 1806 mg Cr(III)/kg b.w. per day) for 60 days prior to gestation and during gestation (Ivankovic and Preussmann, 1975). In the 3-month studies on rats and mice following administration of chromium picolinate in the diet up to 50000 mg/kg diet (equivalent to 506 mg Cr(III)/kg b.w. per day in rats and 1090 mg Cr(III)/kg b.w. per day in mice), there were no significant changes in reproductive organ weights in male or female animals, in sperm parameters, or in estrous cyclicity (NTP, 2010). Developmental effects were not observed following dietary treatment of female mice with 200 mg chromium chloride/kg b.w. (39 mg Cr(III)/kg b.w. per day) (Bailey et al., 2006). Dietary exposure of male mice to 200 mg chromium picolinate/kg b.w. per day (25 mg Cr(III)/kg b.w. per day) before mating had no effect on fertility, prenatal mortality, fetal weight or skeletal morphology (McAdory et al., 2011)” (EFSA CONTAM Panel, 2014).

 

Aluminium

“The multigeneration reproductive studies conducted with aluminium sulfate and aluminium ammonium sulfate administered to rats in the drinking-water did not provide evidence of reproductive toxicity. The major developmental effects observed in both studies were delayed maturation of the female offspring, decreased body weight gain and changes in some organ weights. These effects are likely to have been related to the reported decrease in maternal fluid and feed consumption. Thus, it is not possible to attribute the findings to a direct effect of the aluminium. No effects on motor activity or learning ability were observed in these studies” (JECFA, 2012).

 

No reproductive effects were observed in female Sprague-Dawley rats exposed to 158 mg Al/kg/day as aluminum hydroxide or aluminum citrate by gavage and base diet from gestation day 6 to 15 (Gomez et al. 1991), or in THA rats treated with 73.1 mg Al/kg/day as aluminum chloride by gavage (aluminum in base diet not reported) from gestation day 7 to 16 (Misawa and Shigeta 1992).

  

Iron

“The JECFA evaluation on iron (1983) reported that an eight-generation reproduction study was carried out in Wistar rats. Dog food containing 570 mg of iron/lb as iron oxide was fed continuously. Rats ate an estimated 25 mg of iron/day, assuming 20 g/day of dog food consumption. No signs of toxicity were evident; reproduction performance was superior to expected values (Carnation Co., 1967)” (EFSA, 2015).

The effects of different metal oxide nanoparticles, including Fe2O3, on Xenopus laevis embryos were recently examined by employing the FETAX (Frog Embryo Teratogenesis Assay Xenopus) approach, a powerful and flexible bioassay for developmental toxicants (Nations et al., 2011). The results obtained from these analyses showed that Fe2O3 nanoparticles caused no mortality or significant malformation after 48 hours of exposure; effects noted were limited to snout vent length and total body length at the highest concentration tested (1000 mg/l).

 

(ii) in vitro bioaccessibility resultswithHematite chromium green black in several physiological media

For the pigmentHematite chromium green blackthis has been investigated experimentally in vitro by simulating dissolution under physiological conditions considered to mimic the most relevant exposure routes (oral, dermal and inhalation; Herting & Wallinder, 2010). With a 100 mg loading at pH 1.5 (gastric fluid conditions) and an assumed gastric phase of digestion of about 2 hours, 7.8 μg/L of Al and <0.5 μg/L (<LOD) of Cr were dissolved. Based on 100 mg of pigment, this results in 0.01 wt-% dissolved Al. A relative bioaccessibility for chromium could not be determined, since the measured concentrations were below the limit of detection.

Effects on developmental toxicity

Description of key information

The low order of toxicity to reproduction of Hematite chromium green black is manifested in (i) an absence of a concern for the endpoint developmental toxicity for the soluble and insoluble forms of the metals present in Hematite chromium green black, (ii) the very clear finding that Hematite chromium green black is of poor bioavailability in a wide range of physiological media(iii) Hematite chromium green black shows no effects in a number of in vitro and in vivo toxicological tests and (iv)the physico-chemical properties demonstrate Hematite chromium green black is of general inertness. Furthermore, concerning this minimal fraction of dose that is available for systemic absorption, the inorganic nature of the metals present in Hematite chromium green black precludes any form of metabolism in mammals.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
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

The low order of toxicity to reproduction of Hematite chromium green blackis manifested in (i) an absence of a concern for the endpoint developmental toxicity for the soluble and insoluble forms of the metals present in Hematite chromium green black, (ii) the very clear finding that Hematite chromium green blackis of poor bioavailability in a wide range of physiological media (iii) Hematite chromium green black shows no effects in a number of in vitro and in vivo toxicological tests and (iv) the physico-chemical properties demonstrate Hematite chromium green blackis of general inertness (point iii and iv please refer to the respective waiber). Furthermore, concerning this minimal fraction of dose that is available for systemic absorption, the inorganic nature of the metals present in Hematite chromium green black precludes any form of metabolism in mammals.

 

Under the umbrella of the MISA programme, a read-across for oral systemic and inhalation local effects is currently being developed for the inorganic pigments category. The read-across approach will consider all constituents of substances being a member of the inorganic pigments category. In the data matrix, representative members of the inorganic pigments category will be selected, based on the criteria (i) constituents of known toxicological activity present, (ii) highest relative bioavailability. Experimental studies will be conducted or proposed for these representative substances and read-across to other members of the inorganic pigments category.

 

We note that ECHA issued a final decision on five members of the inorganic pigments category, which have similar properties and including several constituents present in Hematite, chromium green black. ECHA demands the conduct of a pre-natal developmental toxicity study (OECD 414) of the following substances:

 

-                    Chromium iron oxide (EC# 235-790-8), containing chromium and iron and with a crystalline structure of hematite(ECHA decision number TPE/CCH-D-2114482416-44-01/F)

-                    Manganese alumina pink corundum (EC# 269-061-0) containing aluminium (ECHA decision number TPE/ CCH-D-2114482457-38-01/F)

 

The results of these studies will be used in the read-across framework for inorganic pigments as source information and read-across to the target substances, such as Hematite chromium green black.

The results of these tests will serve as additional evidence for the present adaptation and will be included in a future update to this Registration dossier.

 

Overall, the conduct of a pre-natal developmental toxicity study cannot be expected to contribute any relevant information to the assessment of (otherwise negative) information on toxicity to reproduction. As a result, the need for such testing is waived in accordance with regulation (EC) 1907/2008, Annex XI, Section 1.2. Based on the weight-of-evidence information forHematite chromium green blackit is concluded thatHematite chromium green blackdoes not present a toxicity to reproduction hazard, as follows:

 

(i) Supporting information for toxicity to reproduction with metals contained in Hematite chromium green black

 

Chromium

According to the EFSA CONTAM Panel “[t]here was no evidence of reproductive or developmental toxicity in male or female rats following dietary exposure to chromium oxide (50000 mg/kg diet equivalent to 1806 mg Cr(III)/kg b.w. per day) for 60 days prior to gestation and during gestation (Ivankovic and Preussmann, 1975).” No effects on maternal body weight and food consumption were noted and haematology parameters were comparable to those of control animals. All females became pregnant in due course, had a normal gestation period of 23 days and the new-born showed no malformations or other adverse effects. The litter size was in a normal range.

Further on, according to EFSA CONTAM Panel“[d]evelopmental effects were not observed following dietary treatment of female mice with 200 mg chromium chloride/kg b.w. (39 mg Cr(III)/kg b.w. per day) (Bailey et al., 2006). Dietary exposure of male mice to 200 mg chromium picolinate/kg b.w. per day (25 mg Cr(III)/kg b.w. per day) before mating had no effect on fertility, prenatal mortality, fetal weight or skeletal morphology (McAdory et al., 2011)” (EFSA CONTAM Panel, 2014).

 

Aluminium

Aluminium hydroxide was orally administered twice a day (splitted administration) to pregnant rats from GD 6-15 at doses of 192, 384 and 768 mg Aluminium hydroxide/kg bw/day. No mortality or clinical signs were observed in treated animals and body weight and food consumption were comparable to those of controls. Haematology and clinical chemistry did not show any effects and organ weights and gross pathology were inconspicuous. No Al treatment-related differences in number of live fetuses per litter, gender ratio, fetal body weight were detected. No malformations could be observed (Gomez et al. 1990).

No reproductive effects were observed in female Sprague-Dawley rats exposed to 158 mg Al/kg/day as aluminum hydroxide or aluminum citrate by gavage and base diet from gestation day 6 to 15 (Gomez et al. 1991), or in THA rats treated with 73.1 mg Al/kg/day as aluminum chloride by gavage (aluminum in base diet not reported) from gestation day 7 to 16 (Misawa and Shigeta 1992).

“The multigeneration reproductive studies conducted with aluminium sulfate and aluminium ammonium sulfate administered to rats in the drinking-water did not provide evidence of reproductive toxicity. The major developmental effects observed in both studies were delayed maturation of the female offspring, decreased body weight gain and changes in some organ weights. These effects are likely to have been related to the reported decrease in maternal fluid and feed consumption. Thus, it is not possible to attribute the findings to a direct effect of the aluminium. No effects on motor activity or learning ability were observed in these studies” (JECFA, 2012).

 

Iron

The Environmental Protection Agency reported that no treatment-related teratogenic or embryotoxic effects were observed in rats given 2.7 mg iron/kg-day as ferric chloride on gestational days 6-15 (Nolen et al., 1972). Groups of 20 pregnant rats were treated with 7.8 mg ferric chloride/kg bw/day (equal to 2.7 mg iron/kg bw/day) from days 6 to 15 of gestation. The material was administered in distilled and deionized drinking water. Ferric chloride did not induce any change in body weight or food and water consumption in dams. No changes in haematology could be observed. No changes in resorption were noted and number of live fetuses was comparable to control animals. The effects on number of litter sizes were observed and no soft-tissue or skeletal malformations were observed in fetuses.

Further on, rats and mice given 0,120,380 and 1200 mg ferrous sulfate/kg bw/day (equal to 24-76 mg iron/kg-day) for 6 days during gestation (days unspecified) did not show any effect on survival of dams or survival, development and abnormalities of foetuses and offspring. Some embryonic mortality occurred in rats in the high dose group (1200 mg ferrous sulfate/kg bw/day). This dose level was considered as over the maximum tolerance dose in rats (Tadokoro et al., 1979), (U.S. EPA, 2006).

The effects of different metal oxide nanoparticles, including Fe2O3, on Xenopus laevis embryos were recently examined by employing the FETAX (Frog Embryo Teratogenesis Assay Xenopus) approach, a powerful and flexible bioassay for developmental toxicants (Nations et al., 2011). The results obtained from these analyses showed that Fe2O3 nanoparticles caused no mortality or significant malformation after 48 hours of exposure; effects noted were limited to snout vent length and total body length at the highest concentration tested (1000 mg/l).

 

(ii) in vitro bioaccessibility resultswithHematite chromium green black in several physiological media

For the pigmentHematite chromium green blackthis has been investigated experimentally in vitro by simulating dissolution under physiological conditions considered to mimic the most relevant exposure routes (oral, dermal and inhalation; Pardo Martinez, 2010). With a 100 mg loading at pH 1.5 (gastric fluid conditions) and an assumed gastric phase of digestion of about 2 hours, 7.8 μg/L of Al and <0.5 μg/L (<LOD) of Cr were dissolved. Based on 100 mg of pigment, this results in 0.01 wt-% dissolved Al. A relative bioaccessibility for chromium could not be determined, since the measured concentrations were below the limit of detection.

Justification for classification or non-classification