Registration Dossier

Administrative data

Description of key information

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.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2015-01-16 to 2015-02-13
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Version / remarks:
2008-10-03
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
signed 2014-05-14
Limit test:
yes
Specific details on test material used for the study:
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: at room temperature, kept dry and stored in a tightly closed container
Species:
rat
Strain:
other: Crl:CD(SD)
Details on species / strain selection:
Rats were selected because of their proven suitability in toxicology studies and to comply with regulatory requirements for testing in a rodent animal species.
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories Germany GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany
- Age at first dosing: males: 35 days; females: 36 days
- Weight at first dosing: males: 145.3 g - 164.2 g; females: 134.2 g - 149.8 g
- Housing: kept singly in MAKROLON cages (type III plus) with a basal surface of approx. 39 x 23 cm and a height of approx. 18 cm; bedding material: granulated textured wood (Granulat A2, J. Brandenburg, 49424 Goldenstedt, Germany)
- Diet (ad libitum): commercial ssniff® R/M-H V1530 diet (ssniff Spezialdiäten GmbH, 59494 Soest, Germany)
- Water (ad libitum): tap water
- Acclimation period: 9 days

DETAILS OF FOOD AND WATER QUALITY: no contaminants above the limitiations were noted for drinking water.

ENVIRONMENTAL CONDITIONS
- Temperature: 22 °C ± 3 °C (maximum range)
- Relative humidity: 55 % ± 15 % (maximum range)
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Details on route of administration:
The route of administration was selected according to the expected route of exposure.
Vehicle:
other: 0.8 % aqueous hydroxyl propyl methylcellulose gel
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
The test item was suspended in the vehicle to the appropriate concentration. The administration formulation was continuously agitated by stirring throughout the entire administration procedure.
The administration formulation was freshly prepared every day.
Administration volume: 10 mL/kg bw/day
The amount of the test item was adjusted to each animal's current body weight daily.

VEHICLE
- Source: FAGRON GmbH & Co. KG, 22885 Barsbüttel, Germany
- Batch no.: 12G23-N03
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
For the test item that was mixed with the vehicle, tests by ICP-OES were conducted to determine the concentration, stability and homogeneity of the test item in the formulations (Fraunhofer IME, report no. EBR-151/6-27/y).
For the analysis of the test item-vehicle mixtures, samples of approximately 10 mL were taken at the following times and stored at ≤-20 °C:

1) At study initiation:
- analysis of stability and concentration: immediately after preparation of the administration formulation as well as after 8 and 24 hours storage at room temperature (number of samples: 3).
- homogeneity: at the start of administration, during (middle) administration and before administration to the last animal of the test item treated group (number of samples: 3).

2) at study termination:
- analysis of concentration: during treatment always before administration to the last animal of the test item treated group (number of samples: 1).

The test item-vehicle mixture were initially diluted, filtrated, acidified and measured by ICP-OES. The following solutions were used to calibrate the instrument: blank, 1 μg/L, 2.5 μg/L, 5 μg/L, 7.5 μg/L, 10 μg/L, 25 μg/L, 25 μg/L, 30 μg/L, 40 μg/L, 50 μg/L, 75 μg/L, 100 μg/L, 250 μg/L, 500 μg/L, 750 μg/L and 1000 μg/L (calibrations were adapted to matrix and to concentrations measured in pre measurement series). Calibrations were performed before each measurement. The calibration formula was calculated using the linear regression algorithm of the ICP-OES instrument (correlation coefficient has to be at least 0.995). Concentrations of the respective wavelength data for interference-free measurement with recoveries in the range of the quality control parameters for the validation samples (certified reference material, quality control standards, recalibration standards, fortifications, digested certified reference material) in the measurement series were used. Correlation coefficients (r) for the wavelengths used for evaluation of data were at least 0.999948. For each sample, at least three internal measurements were performed and the mean was calculated. Samples were diluted for adaption to the calibration matrix and to fit into the calibration curve.

Instrumental and analytical set-up for the ICP-OES instrument:
- Agilent 720 (Agilent Technologies, Waldbronn, Germany)
- Nebulizer: sea spray nebulizer from Agilent
- spray chamber: glass cyclonic spray chamber from Agilent
- carrier gas flow: 0.75 L/min
- RF power: 1200W
- Wavelengths:
Fe: 238.204 nm, 241.052 nm, 259.837 and 259.940 nm
Cr: 206.158 nm

The applied LOD/LOQ calculations for the Agilent 720 ICP-OES are (according to DIN 32645) (Chemische Analytik - Nachweis-, Erfassungs- und Bestimmungsgrenze unter Wiederholbedingungen – Begriffe, Verfahren, Auswertung; German version DIN 32645:2008-11. Beuth Verlag.):
LOD: 3 * standard deviation of calibration blank/slope of the calibration
LOQ: 3 * LOD
The resulting LODs/LOQs are as follows:
- LOD: 0.20 µg/L (Fe); 0.34 µg/L (Cr)
- LOQ: 0.60 µg/L (Fe); 1.01 µg/L (Cr)
- correlation coefficient: 0.999986 (Fe); 0.999989 (Cr)
The certified reference materials as well as quality control standards and recalibration standards were analyzed as quality assurance samples along with the test samples.To meet quality assurance requirements recovery needs to be in the range of ± 15 % of the respective certified value.
Selected samples were fortified with a known amount of iron and chromium (by standard addition of commercial standards) to determine the standard recovery of iron and chromium. For fortified test item-vehicle mixture samples, recoveries were 111% for Fe and 98.4 % for Cr.

Results:
Dose verification:
nominal dose: 1,000 mg/kg bw pigment (212 mg/kg bw Cr, 466 mg/kg bw Fe)
Results:
Analysis of stability and concentration (3 samples):
Recovery [%]:
Cr: 88.7 - 93.1
Fe: 89.9 - 96.2

Anaylsis of homogenity (3samples):
Recovery [%]:
Cr: 89.4 - 95.2
Fe: 90.3 - 97.1

Anaylsis of concentration (1sample):
Recovery [%]:
Cr: 94.1
Fe: 96.3

Duration of treatment / exposure:
28 days
Frequency of treatment:
once daily
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
5 males / 5 females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: in agreement with the Sponsor and based on available toxicity data a limit test was performed.
Positive control:
none
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule (clinical signs): before and after dosing at each time of dosing as well as regularly throughout the working day from 7.30 a.m. to 4.30 p.m. and on Saturdays and Sundays from 8.00 a.m. to 12.00 noon with a final check performed at approx. 4.00 p.m.
- Time schedule (mortality): early in the morning and again in the afternoon of each working day as well as on Saturdays and Sundays with a final check at approx 4.00 p.m.
- Cage side observations checked: clinical signs & mortality

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once before the first exposure and once a week thereafter (1, 2, 4, 8 and 24 hours after administration) as well as in test week 4 prior to any laboratory investigations.

BODY WEIGHT: Yes
- Time schedule for examinations: at the time of group allocation, on the day of commencement of treatment and once a week thereafter (always on the same day of the week)

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
The quantity of food left by individual animals was recorded on a weekly basis throughout the experimental period. Food intake per rat (g/rat/week) was calculated using the total amount of food given to and left by each rat in each group on completion of a treatment week.
The relative food consumption (in g/kg bw/day) was determined
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION AND COMPOUND INTAKE: Yes
- Time schedule for examinations: daily

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: prior to the start of administration and at the end of test week 4
- Dose groups that were examined: all dose groups

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at study termination (on the day of dissection)
- Anaesthetic used for blood collection: Yes, isoflurane anaesthesia
- Animals fasted: Yes, overnight
- How many animals: all animals
- Parameters examined: haemoglobin content, erythrocytes, leucocytes, differential blood count (relative and absolute; neutrophilic granulocytes, eosinophilic granulocytes, basophilic granulocytes, lymphocytes, monocytes, and large unstained cells), reticulocytes, platelets, haematocrit value, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, thromboplastin time, and activated partial thromboplastin time

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at study termination (on the day of dissection)
- Animals fasted: Yes, overnight
- How many animals: all animals
- Parameters examined: albumin, globulin, albumin/globulin ratio, bile acids, bilirubin (total), cholesterol (total), creatinine, glucose, protein (total), urea (blood), calcium, chloride, potassium, sodium, alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, and lactate dehydrogenase

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: in test week 4 approx. 1 to 2 hours after dosing and before any blood sampling
- Dose groups that were examined: all dose groups
- Battery of functions tested: sensory reactivity / grip strength / motor activity
1) Observational screening: righting reflex, body temperature, salivation, startle response, respiration, mouth breathing, urination, convulsions, pilo-erection, diarrhoea, pupil size, pupil response, lacrimation, impaired gait, stereotype, toe pinch, tail pinch, wire maneuver, hind leg splay, positional passivity, tremors, positive geotropism, limb rotation, and auditory function
2) Functional tests: grip strength and locomotor activity

IMMUNOLOGY: No

TOXICOKINETC: Yes (please refer to Fraunhofer IME, report no. EBR-151/6-27/y)
Urine and plasma samples were obtained at study termination. Urine and plasma samples were analysed for chromium and iron levels by ICP-OES and ICP-MS.
- urine sample: individual urine samples were collected from all animals before scheduled sacrifice following the last administration on test day 28. The animals were placed in metabolic cages during a 24-hour collection period, directly after the last oral administration. The urine weight/animal was determined upon removal of the sample. Pooled blank urine were obtained from spare animals.
- plasma sample: on the scheduled day of sacrifice, a terminal blood sample was collected from all animals under isoflurane anaesthesia in order to obtain LiHeparin plasma/animal. Afterwards, the animals were sacrificed and dissected.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

On test day 29 (approx. one day after the last administration), the animals were sacrifice and macroscopically inspected. All superficial tissues were examined visually and by palpation and the cranial roof was removed to allow observation of the brain, pituitary gland and cranial nerves. After ventral midline incision and skin reflection all subcutaneous tissues were examined. The condition of the thoracic viscera was noted with due attention to the thymus, lymph nodes and heart.
The abdominal viscera were examined before and after removal, the urinary bladder was examined externally and by palpation. The gastro-intestinal tract was examined as a whole and the stomach and caecum were incised and examined. The lungs were removed and all pleural surfaces examined. The liver and the kidneys were examined. Any abnormalities in the appearance and size of the gonads, adrenal glands, uterus, intra-abdominal lymph nodes and accessory reproductive organs were recorded.

The weights of the following organs of all animals were determined before fixation: adrenal gland (2), brain, epididymis (2), heart, kidney (2), liver, ovary (2), spleen, testicle (2), thymus, as well as prostate and seminal vesicles with coagulating glands as a whole.
Paired organs were weighed individually and identified as left or right.

The following organs or parts of organs of all animals were fixed in 7% buffered formalin (exceptions: eyes fixed in Davidson's solution and testes in Bouin's solution): adrenal gland (2), bone (os femoris with joint), bone marrow (os femoris), brain (3 levels: cerebrum, cerebellum, medulla/pons), epididymis (2), eye with optic nerve (2), gross lesions observed, heart (3 levels: right and left ventricle, septum), large intestine (colon, rectum), small intestine (duodenum, jejunum, ileum, incl. Peyer´s patches; Swiss roll method), kidney and ureter (2), liver, lungs (with mainstem bronchi and bronchioles (preserved by inflation with fixative and then immersion)), lymph node (1, cervical), lymph node (1, mesenteric), mammary gland (male and female), muscle (skeletal, leg), nerve (sciatic), ovary (2), pituitary, prostate and seminal vesicles with coagulating glands, spinal cord (3 sections), spleen, stomach, testicle (2), thymus, thyroid (2) (incl. parathyroids), tissue masses or tumours (incl. regional lymph nodes), trachea (incl. larynx), urinary bladder, uterus (incl. cervix and oviducts), and vagina

The above-listed organs of all animals were examined histologically after preparation of paraffin sections and haematoxylin-eosin staining.
In addition, frozen sections of the heart, liver and one kidney were made, stained with Oil Red O and examined microscopically.
Parathyroids cannot always be identified macroscopically. They were examined microscopically if in the plane of section and in all cases where they were noted as grossly enlarged.
Statistics:
The test item-treated group was compared with the vehicle control group:
The following statistical methods were used:

1) STUDENT's t-test: all numerical functional tests / body weight / food consumption / haematology and coagulation / clinical biochemistry / relative and absolute organ weights (p ≤ 0.05 and p ≤ 0.01)
The following limits were used:
p = 0.05/0.01 about t = 2.3060/3.3554 (for 8 degrees of freedom)

2) Exact test of R. A. FISHER: histology (p ≤ 0.05 and p ≤ 0.01)
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Details on results:
CLINICAL SIGNS
- no changes in behaviour or external appearance were noted for the male and female rats treated with 1000 mg chromium iron oxide/kg bw/day or for the animals treated with the vehicle control.
- all male and female rats treated with 1000 mg Chromium iron oxide/kg bw/day revealed black discoloured faeces as of test day 8 (not an adverse effect; finding is considered to be due to the test item (black powder)).
- faeces of the control and test item-treated animals were formed normally.

MORTALITY
- none of the animals died prematurely during the study.

BODY WEIGHT AND WEIGHT CHANGES
- no test item-related influence was observed for the body weight, the body weight gain and body weight at autopsy in the male and female rats treated with 1000 mg chromium iron oxide/kg bw/day (all data are regarded to be within the normal range).

FOOD CONSUMPTION AND COMPOUND INTAKE
- no test item-related changes in relative food consumption were noted for the male and female rats treated with 1000 mg chromium iron oxide/kg bw/day compared to the control group.

WATER CONSUMPTION AND COMPOUND INTAKE
- visual appraisal of the drinking water consumption did not reveal any test item-related influence.

OPHTHALMOLOGICAL FINDINGS
- ophthalmological examination revealed no changes of the eyes and the optic region in the male and female rats treated with 1000 mg chromium iron oxide/kg bw/day or for the animals treated with the vehicle control.

HAEMATOLOGICAL FINDINGS
- no test item-related influence in haematological and coagulation parameters was noted for the male and female rats treated with 1000 mg chromium iron oxide/kg bw/day compared to the control group.
- statistically significant differences (p ≤ 0.05) in a haematological parameters of test item-treated animals compared to the control animals was recorded (no test item-related findings):
females (test day 29): decreased haemoglobin content and increased absolute basophilic granulocytes

CLINICAL BIOCHEMISTRY FINDINGS
- no test item-related influence in biochemical parameters was noted for the male and female rats treated with 1000 mg Chromium iron oxide/kg b.w./day once daily for 28 days compared to the control group.
- statistically significant differences (p ≤ 0.05) in a biochemical parameters of test item-treated animals compared to the control animals was recorded (no test item-related findings):
males (test day 29): increased cholesterol and increased potassium
females (test day 29): decreased sodium

BEHAVIOUR (FUNCTIONAL FINDINGS)
- neurological screening did not reveal any test item-related influence in the male and female rats treated with 1000 mg test item/kg bw/day
- examination results of the animals treated with the vehicle control were also in the normal range.
- statistically significant difference (p ≤ 0.05) in a neurological parameter of a test item-treated animal compared to the control animals was recorded (no test item-related finding):
males (test week 4): increased forelimb grip strength

ORGAN WEIGHT FINDINGS INCLUDING ORGAN / BODY WEIGHT RATIOS
- no test item-related changes in relative and absolute organ weights were noted for the male and female rats treated with 1000 mg chromium iron oxide/kg bw/day compared to the control group.
- statistically significant differences in organ weights of test item-treated animals compared to the control animals was recorded (no test item-related finding): males (test day 29; p ≤ 0.01 and p ≤ 0.05): increased absolute brain weight, increased absolute kidney weight (left), increased absolute kidney weight (right), and increased absolute liver weight
females (test day 29; p ≤ 0.05): increased relative ovary weight (right) and increased absolute ovary weight (right)

GROSS PATHOLOGICAL FINDINGS
- none of the male and female rats treated with 1000 mg test item/kg bw/day revealed any test item-related macroscopic changes at necropsy on test day 29.
- 2/5 male and 3/5 female animals treated with 1000 mg chromium iron oxide/kg bw/day revealed a green discoloured content of the intestines (caecum, colon and rectum)(not an adverse effect; finding is considered to be due to the test item).

HISTOPATHOLOGICAL FINDINGS: NON-NEOPLASTIC
- histomorphological examination did not reveal any morphological changes which are considered to be related to the administration of the test item (no difference between the groups).
- granular black material in the mucus in the intestine-lumen of the male and female rats of test item treated group appeared to be test substance. It was not observed in the control animals. This material did not cause any damages to the intestine-epithelium. This finding correlated with the macroscopic findings.
- inflammatory lesions in different organs are considered to be coincidental findings or spontaneous organ changes and are thus not test item-related (no differences were noted between the groups).
- fatty infiltration in the hepatocytes and in the tubular epithelial cells of the kidneys in male and female rats of the control and test item-treated groups were within the physiological limits.
- involution of the thymus in the rats of both groups corresponded in type, incidence and severity to the age of the animals.
- coincidental findings from different organs in a small number of control and test item-treated animals are considered to be spontaneous organ changes and are thus not test item-related.

TOXICOKINETICS
Chromium and iron are of negligible bioavailability from the test substance Chromium iron oxide: by recalculating the urine levels and setting them into relation to the administered dose of the individual elements Cr and Fe, it is reasonable to assume that the majority of the dose (>99.9%) represents non-absorbable, “inert” pigment, likely to be excreted via faeces. Please also refer to the field "Attached background material" below.
Furthermore, there were either no appreciable or only negligible increases in blood plasma levels for both metals.
Key result
Remarks on result:
not determinable due to absence of adverse toxic effects
Critical effects observed:
no
Conclusions:
NOAEL (oral; rats) > 1000 mg chromium iron oxide/kg bw/day

No test item-related changes were observed for clinical signs, mortality, neurologically screening, body weight/body weight gain, food consumption, water consumption, haematology, clinical chemistry, organ weights, ophthalmology, gross pathology, and histopathology.
The uptake of chromium and iron during a 24 hour urine and plasma sampling period was demonstrated to be negligible considering that <<0.003% of the dose was excreted via urine for all two metals, mirrored by either minimal or no increases in blood plasma concentrations. This supports the assumption that two elements are not biologically available upon ingestion of the pigment Chromium iron oxide.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

A 28-day repeated dose toxicity study (LPT, 2017) was conducted in rats as a limit test to assess the effect of the pigment on rats following repeated oral administration. The study was performed according to OECD test guideline 407 and in compliance with GLP.

Male and female rats were administered with the pigment by oral gavage for 28 days at a dose of 1000 mg/kg bw/day in 0.8% aqueous hydroxyl propyl methylcellulose gel. A concurrent control group was administered untreated vehicle.

No clinical signs of toxicity were observed, and no animals died during the administration period. No changes in bodyweight gains, food consumption, haematology, clinical chemistry, organ weights or macropathology were observed which could be attributed to treatment with the test compound. The histomorphological examination of rat organs did not reveal any morphological lesions attributable to the administration of the test item. There were no morphological differences between the control rats and the test item-treated animals. No adverse effects were observed on the male and female reproductive organs.

Furthermore, individual 24-hour urine samples were collected from all animals after the last dosing prior to the scheduled sacrifice, and in addition plasma samples were collected from each animal at the day of sacrifice. The plasma and urine samples were analysed for total chromium and iron content. The comparison of the total administered final pigment dose of 1000mg/kg bw with the total mean Cr and Fe content recovered in 24-urine samples, as calculated from the mean 24h-urine collection volumes of 12.1 ml for males and of 8.5 ml for females, would correspond to a total bioavailable chromium fraction of 0.0022% for males and <0.0001% for females, and a total bioavailable iron fraction of 0.00005% for males and 0.00002 for females (under the simplified assumption that excretion of both elements occurs to a relevant extent via urine which is the case for chromium, whereas for iron excretion via faeces also plays a role)1. The Cr and Fe concentrations of plasma samples, collected from control and dose group animals at the day of sacrifice, were below 0.0006 µg and 0.0013 µg Cr and below 0.24 µg and 0.20 µg Fe/L plasma.

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.

 

1: Excretion of iron predominantly occurs via faeces, although trace amounts of iron are also excreted via urine, desquamated gastrointestinal cells, and bile(INACG, 1993; IOM, 2001; EFSA, 2004; EVM, 2003, Gordeuk et al., 1986; Huebers et al., 1986;Lopez and Cámara Martos, 2004; Teucher et al., 2004). Most chromium(III) is cleared rapidly from the blood and excreted in the urine with small amounts also being lost in perspiration, bile and faeces (Anderson et al., 1997b; Gargas et al. 1994; Jeejeebhoy, 1999; ATSDR, 2000; IOM, 2001; Hepburn and Vincent, 2002).

Justification for classification or non-classification

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.The no observed adverse effect level (NOAEL) in rats is 1000 mg/kg/day.

No classification for repeated dose toxocity according toEC Regulation No. 1272/2008 is anticipated.