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Diss Factsheets

Administrative data

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:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1997
Report date:
1997

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
Yellow MGi 1301
IUPAC Name:
Yellow MGi 1301
Test material form:
solid

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Duration of treatment / exposure:
28 days
Additional 14 days of recovery in group 1 (0 mg(kg bw/day) and 4 (1000 mg/kg bw/day)
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Dose / conc.:
50 mg/kg bw/day (nominal)
Dose / conc.:
200 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
5
Additional 5 rats per sex and group were used at 0 and 1000 mg/kg (they were allowed a 14-day treatment-free recovery period after the 28-day treatment period).
Details on study design:
In this subacute toxicity study, YELLOW MGi 1301 was administered daily by oral gavage to SPF-bred Wistar rats of both sexes at dose levels of 0, 50, 200 and 1000 mg/kg body weight/day for a period of 28 days.
The groups comprised 5 animals per sex which were sacrificed after 28 days of treatment.
Additional 5 rats per sex and group were used at 0 and 1000 mg/kg. These animals were treated for 28 days and then allowed a 14-day treatment-free recovery period after which they were sacrificed.
Clinical signs, food consumption and body weights were recorded periodically during pretest, the treatment and recovery periods. Ophthalmoscopic examinations wyere performed at pretest, the end of the treatment and recovery periods.
At the end of the dosing period and the treatment-free period, blood samples were withdrawn for hematology and plasma chemistry analyses, and urine samples were collected for urinalyses. All animals were killed, necropsied and examined post mortem. Samples of major organs from all group 1 (control) and group 4 (high dose group) animals, as well as stomach and all gross lesions from all animals were processed as hematoxylin and eosin stained slides and examined by light microscopy.

Examinations

Observations and examinations performed and frequency:
Mortality, clinical signs, food consumption/relative food consumption, body weight, ophthalmoscopic examinations, hematology, clinical biochemistry, urinalysis, organ weights, microscopic findings.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Orange discoloration of urine was recorded in rats of both sexes in group 4 (1000 mg/kg) from treatment day 20 until the fourth day of recovery.
Mortality:
no mortality observed
Description (incidence):
All treated animals survived the scheduled study period.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Body weight was unaffected by the administration of YELLOW MGi 1301.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Food consumption was unaffected by the administration of YELLOW MGi 1301
Ophthalmological findings:
no effects observed
Description (incidence and severity):
There were no test article-related ophthalmoscopic findings noted for any group.
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
In group 4 males: slightly decreased hemoglobin concentration (p<0.05), slightly reduced mean corpuscular volume (p<0.05), slightly reduced mean corpuscular hemoglobin (p<0.05), ), slightly reduced mean corpuscular hemoglobin concentration (p<0.05), slightly increased reticulocyte count (rel. and abs.)(p<0.05, p<0.01), slightly increased white blood cell count (p<0.01). In the differential white blood cell count increased numbers of segmented neutrophil and lymphocyte cells were recorded (p<0.05).
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
In group 4: slightly decreased glucose level (males, p<0.05), slightly increased total bilirubin level (males p<0.01, females p<0.05), slightly increased cholesterol level (females p<0.05), increased triglycerine level (both sexes p<0.01), slightly increased aspartate-aminotransferase level
(males p<0.01), slightly decreased alanine-aminotransferase (females p<0.01), slightly increased sodium level (males p<0.05), slightly decreased albumin level (males p<0.01), slightly decreased total protein level (both sexes p<0.01), slightly decreased globulin level (males p<0.05, females p<0.05).
In group 3 females: increased triglyceride level (p<0.05) and slightly decreased total protein level (p<0.05).
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
Urine discoloration was evident in both sexes of group 4. This discoloration ranged from a lighrorange (3 males, 3 females) to orange (7 males, 2 females) .
Description (incidence and severity):
No test article-related changes of organ weights or ratios were noted.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Morphologic findings attributed to the treatment with the test article were recorded during histopathology in the stomach of females of group 3 and animals of both sexes of group 4 (main test and/or recovery). They took the form of higher incidence and/or severity of hyaline droplets in the glandular mucosa, vacuolation of the squamous epithelium of the limiting ridge in the main test animals and inflammatory cell foci in the glandular submucosa of main test animals.

Effect levels

Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
clinical biochemistry
gross pathology

Target system / organ toxicity

Critical effects observed:
no

Any other information on results incl. tables

The oral administration of YELLOW MGi 1301 to Wistar rats at doses of 50, 200, and 1000 mg/kg/day, for 28 days resulted in no deaths and no effects on food consumption, body weight, ophthalmoscopic findings, organ weights and macroscopical findings.

In animals of group 4 (1000 mg/kg) orange discoloration of urine was recorded in rats of both sexes from treatment day 20 until the fourth day of recovery.

Clinical laboratory investigations

Hematology findings included slightly decreased hemoglobin concentration, slightly reduced mean corpuscular volume, slightly reduced mean corpuscular hemoglobin, slightly reduced mean corpuscular hemoglobin concentration, slightly increased reticulocyte count (rel. and abs.) and slightly increased white blood cell count. In the differential white blood cell count increased numbers of segmented neutrophil and lymphocyte cells were recorded.

Clinical biochemistry revealed slightly decreased glucose level (males), slightly increased total bilirubin level (both sexes), slightly increased cholesterol level (females), increased triglyceride level (both sexes), slightly increased aspartate-aminotransferase level (males), slightly decreased alanine-aminotransferase (females) and slightly increased sodium level (males), slightly decreased albumin level (males), slightly decreased total protein level (both sexes) and slightly decreased globulin level (both sexes).

Relevant urinalysis changes were limited to urine discoloration at week 4.

Recovery period

All of the findings noted for hematology, clinical biochemistry and urinalysis at termination of the treatment period indicated reversibility and/or were found to be similar to those of the controls.

All other differences in the results of the hematology, clinical biochemistry and urinalysis parameters during the treatment or recovery period were considered to be incidental and unrelated to the treatment, and of normal biological variation for rats of this strain and age.

Pathology

The macroscopic findings recorded were within the spontaneous alterations which may be seen in rats of this age and strain. They included dilated renal pelves, discoloration and/or foci in various organs and dilated uterine horns filled with fluid.

Microscopic, test article-related findings were recorded in the stomach. They consisted of a higher incidence and/or severity of hyaline droplets in the glandular mucosa of group 3 females and in animals of both sexes of group 4 (main test and/or recovery animals), vacuolation of the squamous epithelium of the limiting ridge in the main test animals, and inflammatory cell foci in the glandular submucosa of main test animals.

Overall, the daily administration of test item by gavage at 1000 mg/kg bw/day resulted in minor morphological alterations in the stomach. These findings were regarded as indicators of the deposition of test item in the gastric mucosa.

The remainder of microscopic findings recorded were within the range of background pathology encountered in Wistar rats of this age and strain and occurred at similar incidences and severity in both control and treated rats.

Applicant's summary and conclusion

Conclusions:
NOAEL = 50 mg/kg bw/day