Registration Dossier

Administrative data

Description of key information

Read across to the a close structural analogue (CAS No 16090-02-1)
oral: subacute (28 day, gavage): NOAEL = 825 mg/kg bw/day, OECD 407 and GLP compliant study

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:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: OECD guideline study 407.
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Qualifier:
according to
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
GLP compliance:
yes
Remarks:
Research and Consulting Company AG
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: BRL, Biological Research Laboratories Ltd., Wolferstrasse 4, CH-4414 Fuellinsdorf
- Age at study initiation: 8-9 weeks
- Weight at study initiation: Males: 164 - 176 g; Females: 143 - 160 g
- Housing: Individually in Makrolon type-3 cages
- Diet: Pelleted standard Kliba no. 343, Batch 81/91 and 83/91 rat maintenance diet ('Kliba', Klingentalmuehle AG, CH-4303 Kaiseraugst) ad libitum.
- Water: Community tap-water, ad libitum
- Acclimation period: Seven days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3 °C
- Humidity (%): 40-70 %
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12


Route of administration:
oral: gavage
Vehicle:
other: Bi-distilled water
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
28 days
Frequency of treatment:
Once daily, 7 days per week for 28 days
Remarks:
Doses / Concentrations:
0, 41, 165 and 825 mg/kg bw/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
0, 50, 200, 1000 mg/kg bw/day
Basis:
other: nominal
No. of animals per sex per dose:
0 and 100 mg/kg bw: 10
50 and 200 mg/kg bw: 5
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: results from a 5-day range-finding study
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once daily

DETAILED CLINICAL OBSERVATIONS: No data


BODY WEIGHT: Yes
- Time schedule for examinations: once during the acclimatization period and weekly thereafter


OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: all animals at termination of treatment and a second time on the recovery individuals of groups 1 and 4 at termination of the recovery period


HAEMATOLOGY: Yes
- Time schedule for collection of blood: at termination of treatment and a second time at termination of the recovery period
- Anaesthetic used for blood collection: Yes, light ether anesthesia.
- Animals fasted: Yes, 18 h
- How many animals: all
- Parameters examined: Erythrocyte count, Hemoglobin, Hematocrit, Mean corpuscular volume, Mean corpuscular hemoglobin, Mean corpuscular hemoglobin concentration, Platelet count, Reticulocyte count, Nucleated erythrocytes, Heinz bodies, Methemoglobin, Total leukocyte count, Differential leukocyte count, Red cell morphology, Thromboplastin time



CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at termination of treatment and a second time at termination of the recovery period
- Animals fasted: Yes, 18 h
- How many animals: all
- Parameters examined: Glucose, Urea, Creatinine, Uric acid, Bilirubin, total Cholesterol, total Triglycerides, Phospholipids, Aspartate aminotransferase, Alanine aminotransferase, Lactate dehydrogenase, Creatine kinase, Alkaline phosphatase, Gamma-glutamyl transferase, Calcium, Phosphorus, Sodium, Potassium, Chloride, Protein total, Albumin, Globulin, Albumin/Globulin ratio.


URINALYSIS: Yes
- Time schedule for collection of urine: at termination of treatment and a second time at termination of the recovery period
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes, 18 h
- Parameters examined: Volume, Specific gravity, Color, pH, Protein, Glucose, Ketone, Bilirubin, Blood, Urobilinogen, Urine Sediment.


NEUROBEHAVIOURAL EXAMINATION: No data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, Samples of the following tissues and organs were collected from all animals at necropsy and fixed in phosphate buffered neutral 4 % formaldehyde solution: Adrenals; Aorta; Bone (sternum, femur); Bone marrow (sternum, femur); Brain; Cecum; Colon; Duodenum; Epididymides; Esophagus; Eyes with optic nerve and Harderian gland; Female mammary gland area; Femur including joint; Heart; Ileum; Jejunum; Kidneys; Larynx; Lacrimal gland, exorbital; Liver; Lung infused with formalin; Lymph nodes, mandibular, mesenteric; Nasal cavities; Ovaries; Pancreas; Pituitary gland; Prostate gland; Rectum; Salivary gland, mandibular, sublingual; Sciatic nerve; Seminal vesicles; Skeletal muscle; Skin; Spinal cord, cervical, midthoracic, lumbar; Spleen; Stomach; Testes; Thymus; Thyroid gland; Tongue; Trachea; Urinary bladder infused with formalin; Uterus; Vagina; Gross lesions

HISTOPATHOLOGY: Yes, Slides of Adrenals, Heart, Kidneys, Liver, Spleen and Stomach collected at terminal sacrifice from the animals of the control and high-dose groups were examined by a pathologist. The same applied to all gross lesions.
Statistics:
Univariate one-way analysis of variance was used to assess the significance of intergroup differences. If the variables could be assumed to follow a normal distribution, the Dunnett test (many to one t-test) based on a pooled variance estimate was applied for the comparison between the treated groups and the control groups for each sex. The Steel-test (many-one rank test) was applied when the data could not be assumed to follow a normal distribution. Group means were calculated for continuous data and medians were calculated for discrete data (scores) in the summary tables.
Details on results:
CLINICAL SIGNS AND MORTALITY
No treatment-related clinical findings were observed during the study period nor during the treatment-free recovery period. No premature death occurred before scheduled time of necropsy.

BODY WEIGHT AND WEIGHT GAIN
The body weights of all treated animals were comparable to each other.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Females of group 4 (1000 mg/kg bw ) ate statistically significantly less food than controls from treatment days 8 to 15 and male rats of the same group consumed statistically significantly more food than controls from treatment day 22 until 28 (end of the treatment period). The relative food consumption rates of male rats of groups 3 and 4 (200- and 1000 mg/kg) were significantly higher from treatment day 22 until 28 when compared to those of controls. These findings were considered to be toxicologically not relevant and within normal biological variations known for these animal-strain and age

OPHTHALMOSCOPIC EXAMINATION
Ophthalmoscopic examination of each animal towards the end of the treatment period and each recovery animal after additional 14-days of treatment-free recovery period did not reveal any clinical findings.

HAEMATOLOGY
The assessment of hematological data indicated no changes of toxicological significance at termination of the treatment nor at the end of the treatment-free recovery period.

CLINICAL CHEMISTRY
The assessment of clinical biochemical data indicated no changes of toxicological significance at termination of the treatment nor at the end of the treatment-free recovery period.

URINALYSIS
The assessment of urinalysis data indicated no changes of toxicological significance at termination of the treatment nor at the end of the treatment-free recovery period.

ORGAN WEIGHTS
At termination of the 4-week treatment period, the kidneys to brain weight ratios of males of groups 2 and 4 (50- and 1000 mg/kg bw) were statistically significantly higher and the heart to brain weight ratios of females of group 4 (1000 mg/kg bw) statistically significantly lower than those of the controls. This was considered to be toxicologically not relevant and therefore incidental as there were no confirmatory findings in the other sex, nor confirmatory macroscopical or microscopical findings. No other significant differences from controls occurred in absolute and relative organ weights.

GROSS PATHOLOGY
No treatment related macroscopic findings were recorded.

HISTOPATHOLOGY: NON-NEOPLASTIC
No treatment related microscopic findings were recorded.
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: highest dose tested
Dose descriptor:
NOAEL
Effect level:
825 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: based on the active substance content of 82.5%
Critical effects observed:
not specified

Based upon the results obtained in this study, the "no-adverse-effect-level" of the test substance is 1000 mg/kg body weight for male and female rats (825 mg/kg bw/d; based on the active substance content of 82.5%) when administered orally by gavage for a period of 28 days followed by a treatment-free 14-day recovery period.

The various statistically significant differences observed (increase/decrease) in food consumption (absolute/relative) and organ weights (relative) were considered to be of no toxicological relevance and did therefore not provide any evidence of toxicity of the test substance at any of the dose levels tested.

Conclusions:
Based upon the results obtained in this study, the "no-adverse-effect-level" of FAT 65'023/L is 1000 mg/kg body weight for male and female rats (825 mg/kg bw/d; based on the active substance content of 82.5%) when administered orally by gavage for a period of 28 days followed by a treatment-free 14-day recovery period.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat

Additional information

Reliable data on repeated dose toxicity are available for a close structural analogue (CAS 16090 -02 -1).

In a GLP compliant subacute 28-day toxicity study following OECD testing guideline 407, the test substance was administered daily by gavage to SPF-bred Wistar rats. The test substance was administered to 4 groups each of 5 male and 5 female SPF-bred Wistar rats by oral gavage at daily doses of 0, 50, 200, 1000 mg/kg bw/day (corresponding to 0, 41, 165 and 825 mg/kg bw/day of active ingredient) for 28 consecutive days (CIBA-Geigy AG, Switzerland 1991b). Two groups of 5 male and 5 female rats were treated accordingly at 0 and 825 mg/kg bw/day for 28 days followed by a 14-day treatment free recovery period. The dose levels used in this study are based on data from acute and subacute studies, especially a subacute 5-day range-finding study (CIBA-Geigy AG, Switzerland 1991a) in which dose levels of 0, 200 and 1000 mg test substance per kg body weight and day were administered to rats. There were no compound related effects in mortality, clinical signs, body weight, food consumption, hematology, clinical chemistry, urinanalysis, organ weights, or gross and histologic pathology observed after 4 weeks of treatment nor at termination of the treatment-free recovery period when the results from the animals of the test article treated groups were compared to those of the control animals. Based upon the results obtained in this study, the "no-adverse-effect-level" of the test substance is 1000 mg/kg body weight (825 mg/kg bw/day active ingredient) for male and female rats when administered orally by gavage for a period of 28 days followed by a treatment-free 14-day recovery period. The various statistically significant differences observed (increase/decrease) in food consumption (absolute/relative) and organ weights (relative) were considered to be of no toxicological relevance and did therefore not provide any evidence of toxicity of the test substance at any of the dose levels tested.

Therefore, it is concluded by read-across that the substance with CAS 133 -66 -4 is not toxic when administered orally to rat over 2 years and have not to be classified for repeated oral toxicity.

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)

The available studies are considered reliable and suitable for classification purposes under 67/548/EEC. As a result the family members are not considered to be classified for repeated toxicity under Directive 67/548/EEC, as amended for the 28th time in Directive 2001/59/EC.

 

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result the family members are not considered to be classified for repeated toxicity under Regulation (EC) No. 1272/2008.