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EC number: 235-790-8
CAS number: 12737-27-8
The in-vitro and in-vivo experiments
described in the dataset are in very good agreement with regards to the
negligible level of bioavailability of the elements Cr and Fe contained
in the pigment, indicating a lack of any concern for toxicity to
no signs of local toxicity in an acute inhalation toxicity test at the
limit dose of 5.01 mg/L. The study has been performed according to OECD
TG 436 and which shows no signs of acute toxicity after inhalation
exposure to the pigment chromium iron oxide, indicating a LC50 > 5.01
mg/L. No mortality occurred.
in-vitro dissolution experiments in five different artificial
physiological media, dissolved Cr and Fe concentrations were below 18
µg/L even at the highest loading of 0.1 g/L, corresponding to a
solubility of 0.018 %.
In a 28-day oral
toxicity study with 1,000 mg/kg pigment no increase in Cr and Fe plasma
and urine concentrations were observed when sampled at the end of the
28-day exposure period. From a final dose of 1,000 mg/kg of the pigment
that the animals received on the last day of the study, only cumulated
relative amounts of < 0.0025 % (m/f) were found in the terminal 24-h
urine collection period.
a mass balance study with a single oral dose of 1,000 mg/kg of the
pigment, 89.1% Cr, and 94.1 % Fe of the dose were excreted via faeces
within 3 days, with only <0.0024% of the dose being excreted via urine
at the same time.
In a relative
bioavailability study, the relative bioavailability of orally
administered pigment was calculated 0.07 % (Cr) in relation to a soluble
Comparing the findings of in-vitro dissolution
testing (1) with in-vivo results (2-4), the in-vivo data
consistently demonstrates slightly lower bioavailability. This is in
agreement with the general understanding that in-vitro experiments
in simulated gastric juice provide a conservative estimate of actual (in-vivo)
In conclusion, the oral relative
bioavailability of the pigment "Chromium iron oxide" can be assumed to
be negligible, as demonstrated in three independent in-vivo studies in
rats yielding very comparably results supported by an in-vitro dissolution
experiment in five different artificial physiological media.
A rounded value of <0.01 % for oral
absorption can be taken forward from (i) terminal urine/plasma sampling
in a study involving 28 repeated oral doses of 1,000 mg pigment/kg bw/d (<<0.008
% for both metals) and (ii) a mass balance study involving
a single dose of 1,000 mg pigment/kg bw (0.00009 % for Cr, and <0.0024 %
It is concluded that the pigment was
well tolerated and that no signs of systemic toxicity whatsoever were
observed in rats when administered at a dose of 1000 mg/kg bw/day for up
to 28 days. Either no or only marginal increases in Cr and Fe plasma
concentrations were observed, and only a minor fraction (<0.002 %) of
the total administered dose of Cr and Fe was collected via urine,
documenting the lack of bioavailability of this pigment. The no observed
adverse effect level (NOAEL) in rats is 1000 mg/kg/day.
Based on the information from a pre-natal developmental toxicity study via gavage in rats (according to OECD 414, GLP) it is concluded that maternal toxicity up to the highest dose level of 1000 mg/kg bw/day, and reproduction data of dams were not affected by treatment. Furthermore, there was no embryo-toxicity and no effect on the development of foetuses. No malformations or variations were noted during macroscopic inspection at laparotomy (including an external inspection and gross inspection of the organs), the skeletal examination according to Dawson and the soft tissue examination according to Wilson. No incidences of skeletal retardations were observed.
One GLP and guideline-compliant prenatal developmental toxicity study (OECD 414) in rats is available. Chromium iron oxide in 0.8% aqueous hydroxypropylmethyl-cellulose gel was administered via gavage to groups of pregnant female Crl:CD (SD) rats (n = 20) at dose levels of 100, 300, and 1000 mg/kg bw/day. The administration occurred once daily from gestation day 6 to gestation day 20. A vehicle control group was run concurrently.
During the observation of the dams , no test item-related effects were observed for mortality, clinical signs, body weight, body weight gain, gravid uterus weight, carcass weight, food consumption, water consumption, gross pathology, thyroid weights, thyroid hormone concentrations (triiodothyronine (T3), thyroxine (T4), and thyroid stimulating hormone (TSH)), and histopathology of the thyroid. Furthermore, no test item-related effect was noted on the reproductive parameters (number of corpora lutea, implanation sites, resorptions (total, early and late) and foetuses (dead and alive) as well as the index of pre- and post implantation loss).
In addition, the examination of the foetuses reveal that no foetal deaths occurred and no test item-related effects were observed for body weight, placental weight, and foetal developmental parameters (anogenital distance or testicular developmental of the male foetuses). Also, no test item-related malformations or variations were noted during the macroscopic inspection at laparotomy (including external inspection and a gross inspection of the organs), the skeletal examination according to Dawson and the soft tissue examination according to Wilson. Lastly, no test item-related retardations (delay in ossification) were noted in any of the treatment groups.
Based on the results, the NOAEL for maternal toxicity and developmental toxicity is consider to be greater than 1000 mg/kg bw/day.
Effects on fertility:
It is concluded that the pigment was well tolerated and that no signs of systemic toxicity whatsoever were observed in rats when administered at a dose of 1000 mg/kg bw/day for up to 28 days. Either no or only marginal increases in Cr and Fe plasma concentrations were observed, and only a minor fraction (<0.002%) of the total administered dose of Cr and Fe was collected via urine, documenting the lack of bioavailability of this pigment. The no observed adverse effect level (NOAEL) in rats is 1000 mg/kg/day.No classification for toxicity to reproduction according to EC Regulation No. 1272/2008 is anticipated.
Effects on developmental toxicity:
In one guideline and GLP compliant study, chromium iron oxide did not show any effects on the developing foetuses of rats when administered up to the limit dose of 1000 mg/kg bw/day. In conclusion, based on the data observed for chromium iron oxide in one developmental toxicity study in rats, a classification as reproductive toxicant according to EC Regulation No. 1272/2008 is not justified due to the complete absence of any adverse effects.
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