Registration Dossier

Diss Factsheets

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

Administrative data

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Justification for type of information:
Data is from qualified publication.

Data source

Reference
Reference Type:
publication
Title:
A Comparative Study of the Chronic Effects of Magenta, Paramagenta, and Phenyl-p-naphthylamine in Syrian Golden Hamsters
Author:
U. Green, J. Holste, and A.R. Spikermann
Year:
1979
Bibliographic source:
J. Cancer Res. Clin. Oncol. 95, 51-55 (1979)

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: As mention below
Principles of method if other than guideline:
To evaluate the toxic nature of Magenta in male and female Hamster by oral gavage for 88 weeks.
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
(4-(4-aminophenyl)(4-iminocyclohexa-2,5-dienylidene)methyl)-2-methylaniline hydrochloride
EC Number:
211-189-6
EC Name:
(4-(4-aminophenyl)(4-iminocyclohexa-2,5-dienylidene)methyl)-2-methylaniline hydrochloride
Cas Number:
632-99-5
Molecular formula:
C20H19N3.ClH
IUPAC Name:
(4-(4-aminophenyl)(4-iminocyclohexa-2,5-dienylidene)methyl)-2-methylaniline hydrochloride
Details on test material:
IUPAC name:((4-(4-aminophenyl)(4-iminocyclohexa-2,5-dienylidene)methyl)-2-methylaniline hydrochloride)
commen name : Basic violet 14
Molecular formula :C20H19N3.ClH
molecular weight: 337.8 g/mol
InChI:1S/C20H19N3.ClH/c1-13-12-16(6-11-19(13)23)20(14-2-7-17(21)8-3-14)15-4-9-18(22)10-5-15;/h2-12,21H,22-23H2,1H3;1H/b20-14-,21-17?
Smiles:C(\c1cc(c(N)cc1)C)(c1ccc(N)cc1)=C1/C=CC(=N)C=C1.Cl
Specific details on test material used for the study:
IUPAC name:Magenta
commen name : Basic violet 14
Molecular formula :C20H19N3.ClH
molecular weight: 337.8 g/mol
InChI:1S/C20H19N3.ClH/c1-13-12-16(6-11-19(13)23)20(14-2-7-17(21)8-3-14)15-4-9-18(22)10-5-15;/h2-12,21H,22-23H2,1H3;1H/b20-14-,21-17?
Smiles:C(\c1cc(c(N)cc1)C)(c1ccc(N)cc1)=C1/C=CC(=N)C=C1.Cl

Test animals

Species:
hamster, Syrian
Strain:
other: Syrian golden
Sex:
male/female
Details on test animals or test system and environmental conditions:
Details on test animal
TEST ANIMALS
- Source: derived from an outbred colony (Coombehurst, Baughurst, England),
- Age at study initiation: 12 weeks
- Weight at study initiation: Not specified
- Fasting period before study: Not specified
- Housing: housed, sex segregated, 5 to a cage in
plastic cages
- Diet (e.g. ad libitum): Pelleted diet (RMH-B, Hope Farms, Woerden, The Netherlands, ad libitum
- Water (e.g. ad libitum): water ad libitum.
- Acclimation period: Not specified

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2(°C
- Humidity (%):50 +_ 5%
- Air changes (per hr): 20 times per hour
- Photoperiod (hrs dark / hrs light): Not specified

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: NaCl solution.
Details on oral exposure:
Details on oral exposure
VEHICLE
- Justification for use and choice of vehicle (if other than water): Since magenta dissolve only a little in water and may not be reabsorbed by the intestinal tract, the effect which was seen in the subcutaneous tissue of rats could well be associated with the physical properties of the compounds
- Concentration in vehicle: 400 and 600 mg/kgbw/day
- Amount of vehicle (if gavage): 0.9%
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
88 weeks
Frequency of treatment:
Twice weekly for life
Doses / concentrationsopen allclose all
Dose / conc.:
0 other: mg/kgbw/day
Dose / conc.:
400 other: mg/kgbw/day
Dose / conc.:
600 other: mg/kgbw/day
No. of animals per sex per dose:
Total number of animals 240 animals
0 mg/kgbw/day,40 male and 40 females
400 mg/kgbw/day,40 male and 40 females
600 mg/kgbw/day,40 male and 40 females
Control animals:
yes, concurrent vehicle
Details on study design:
Not specified
Positive control:
Not specified

Examinations

Observations and examinations performed and frequency:
Observations and examinations performed & frequency
CAGE SIDE OBSERVATIONS: Yes
- Time schedule:Twice daily wice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Twice daily

BODY WEIGHT: Yes

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: Not specified

- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Not specified

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: Not specified


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Not specified


OPHTHALMOSCOPIC EXAMINATION: Not specified


HAEMATOLOGY: Not specified


CLINICAL CHEMISTRY ; Not specified


URINALYSIS: Not specified


NEUROBEHAVIOURAL EXAMINATION: Not specified


OTHER:
Sacrifice and pathology:
Sacrifice and pathology
GROSS PATHOLOGY: Yes, Complete autopsies were
performed on all animals and the organs were fixed in 10% buffered formalin.
HISTOPATHOLOGY: Yes Paraplast sections were stained with haematoxylin and eosin and by the van Gieson method. Step sections were prepared from the urinary tract.
Statistics:
For statistical evaluation, only those animals were considered, which had all organs histologically examined (effective number of animals).
Survival data are from the beginning of treatment.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Significant effect like haemorrhagic enteritis, stomach ulcers and diarrhoea were observed at the dose level of 600 mg/kgbw/day in treated group compare to control.
Mortality:
mortality observed, treatment-related
Description (incidence):
The majority of treatment animals of 600 mg/kgbw/day dose group died within the first 10 weeks of treatment compare to control.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Significant weight loss were observed at the dose level of 600 mg/kgbw/day in treated group compare to control.
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Description (incidence and severity):
No significant effects were observed at the 400 mg/kgbw/day of treated group compare to control.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No significant effect were observed at the 400 mg/kgbw/day of treated group compare to control.
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
Age-dependent alterations included amyloidosis of the kidneys, liver and spleen.The overall tumor incidences for magenta was 5%. Average survival times of tumor bearing animals for magenta was 68 weeks and NaCl controls was 55 weeks. The urinary tract was free of neoplastic growth. Tumors found in the treated groups and not seen in the controls were either isolated observations or known from historic controls. No significant tumour were observed for test substance maganta.
Other effects:
not specified

Effect levels

Dose descriptor:
NOAEL
Effect level:
400 other: mg/kgbw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No significant effects were observed at this dose level.
Remarks on result:
other: No toxic effect were observed

Target system / organ toxicity

Critical effects observed:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Applicant's summary and conclusion

Conclusions:
NOAEL was considered to be 400 mg/kgbw/day for Magenta in male and female Hamster by oral gavage for 88 weeks.
Executive summary:

In a Repeated dose toxicity study for Magenta was conducted in male and female Syrian golden Hamster for 88 weeks by oral gavage.The animals were exposed twice weekly to 0,400 and 600 mg/kgbw/dayoftest substance. In high dose level groups 600 mg/kg b.w. the majority of animals died within the first 10 weeks of treatment.They showed a rapid weight loss, haemorrhagic enteritis, stomach ulcers, and diarrhoea. The data clearly indicate that these dose levels were not tolerated by the Syrian golden hamsters. On the other hand, the lower doses (400 mg/kg was well-tolerated and the body weight developments of these groups were similar to those of the controls, as were the average survival times. Macroscopic alterations and microscopic lesions were similar in experimental and control hamsters, and were not associated with treatment. Age-dependent alterations included amyloidosis of the kidneys, liver and spleen. The overall tumor incidences was 5%;. Average survival times of tumor bearing animals was 68 weeks while NaCl controls, 55 weeks. The urinary tract was free of neoplastic growth.Tumors found in the treated groups and not seen the controls were either isolated observations or known from historic controls.As no significant effect were observed at the doe level of 400mg/kgbw/day. Therefore NOAELwas considered to be 400mg/kgbw/day for Magenta in male and female Hamster by oral gavage for 88 weeks.