Registration Dossier

Administrative data

Description of key information

The substance is assessed to be of low repeated dose oral toxicity as assessed from analogue substances.

The analogue pigment caused no adverse effects at the limit dose in the subacute oral toxicity study in rats. Discoloration of feces indicated passage of the pigment through the intestinal tract. NOEL of 600 mg/kg bw is based on the worst case assumption of a cation not present in the source pigment.

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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
Experimental Toxicology and Ecology, BASF SE
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, 97633 Sulzfeld
- Age at study initiation: 42 +/- 1 days
- Weight at study initiation: mean 173.5 g (males), 138.9 g (females)
- Housing: (5 animals per cage) in H-Temp (PSU) cages supplied by TECNIPLAST, Hohenpeißenberg, Germany (floor area about 2065 cm2);
- Diet (e.g. ad libitum): ground Kliba maintenance diet mouse/rat “GLP”, meal, supplied by Provimi Kliba SA, Kaiseraugst, Switzerland; ad libitum
- Water (e.g. ad libitum): drinking water (from water bottles); ad libitum
- Acclimation period: 6 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12 / 12
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
The test substance was applied as a suspension. To prepare the suspension, the appropriate amount of test substance was weighed out depending on the desired concentration. Then the vehicle (drinking water with 1% Carboxymethylcellulose) was filled up to the desired volume, subsequently mixed using a magnetic stirrer. The suspension was hold homogeneous by magnetic stirrer during application. The test-substance preparations were prepared daily, because no stability analysis was carried out. The test substance does not change chemical identity in aqueous suspensions. The sponsor approved the stability of the test substance in physiologic vehicles.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The analyses were carried out as a separate study at the test facility GKA Competence Center Analytics BASF SE, Ludwigshafen, Germany under the response of the Study Director of this test facility. The study was carried out in complaince with the Principles of Good Laboratory Practice.
Determination by inductively coupled plasma-optical emission specrometry (ICP-OES) after acid digestion
Duration of treatment / exposure:
28 d
Frequency of treatment:
daily
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: by request of the sponsor
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: made twice daily on working days and once daily on Saturdays, Sundays and public holidays
- Cage side observations checked in table were included.


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: prior to the administration period and thereafter at weekly intervals


BODY WEIGHT: Yes
- Time schedule for examinations: before the start of the administration period in order to randomize the animals. During the administration period the body weight was determined on day 0 (start of the administration period) and thereafter at weekly intervals


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- 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: Yes


WATER CONSUMPTION AND COMPOUND INTAKE: Yes
- Time schedule for examinations: daily by visual inspection of the water bottles for any overt changes in volume


OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: Yes
- Time schedule for collection of blood: in the morning at the end of application period
- Anaesthetic used for blood collection: Yes (isofluran)
- Animals fasted: Yes
- How many animals: 5 animals per test group and sex
- Parameters examined: leukocyte count, erythrocyte count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, differential blood count, reticulocytes, clotting analyses, prothrombin time


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: in the morning at the end of application period
- Animals fasted: Yes
- How many animals: 5 animals per test group and sex
- Parameters examined: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, γ-glutamyltransferase, sodium, potassium, chloride, inorganic phosphate, calcium, urea, creatinine, glucose, total bilirubin, total protein, albumin, globulins, triglycerides, cholsetsreol, magnesium


URINALYSIS: Yes
- Time schedule for collection of urine: in the morning at the end of application period
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters examined: pH, protein, glucose, ketones, urobilinogen, bilirubin, blood, specific gravity, sediment, color, turbidity, volume


NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: after about 4 weeks of treatment
- Battery of functions tested: sensory activity / grip strength / motor activity / FOB

METABOLIC PROFILE
- Time schedule for collection of serum: in the morning at day 29
- Method: GC-MS and LC-M
- Analysis of data: MetaMap Tox-database
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Body weight loss (assumed as worse-case assumption) with a NOEL of 600 mg/kg bw.
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Dose descriptor:
NOAEL
Effect level:
600 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
histopathology: non-neoplastic
other: Assumption for worst-case leaching
Critical effects observed:
yes
Lowest effective dose / conc.:
1 000 mg/kg bw/day (nominal)
System:
urinary
Organ:
kidney
Treatment related:
yes
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
600 mg/kg bw/day
Study duration:
subacute
Species:
rat

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

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008 ( amended for fourteenth time in Regulation (EC) No. 2020/217)

No adverse effects are predicted to occur at doses of 600 mg/kg bw or lower upon subacute oral exposure. Accordingly the GHS criteria for STOT RE are not met.