Registration Dossier

Diss Factsheets

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
Experimental data of read across substances
Justification for type of information:
Weight of evidence approach based on structurally similar chemicals

Data source

Reference
Reference Type:
other: company data
Title:
WoE for repeated dose oral toxicity study for CAS no 84281-74-3
Author:
Sustainability Support Services (Europe) AB
Year:
2018
Bibliographic source:
WoE report, Sustainability Support Services (Europe) AB, 2018

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: as below
Principles of method if other than guideline:
WoE report is based on two repeated dose oral toxicity studies on rats.
1. 17 days repeated dose toxicity study of test chemical in F344 male and female rats were observed to evaluate its toxic potential.
2. Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening test for test chemical.
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
1,3-Benzenediamine, coupled with diazotized m-phenylenediamine, acetates
EC Number:
282-617-7
EC Name:
1,3-Benzenediamine, coupled with diazotized m-phenylenediamine, acetates
Cas Number:
84281-74-3
Molecular formula:
C26H34N8O8
IUPAC Name:
1,3-Benzenediamine, coupled with diazotized m-phenylenediamine, acetates
Details on test material:
- IUPAC Name: 1,3-Benzenediamine, coupled with diazotized m-phenylenediamine, acetates
- Common Name: Basic Brown 1
- Molecular formula : C26H34N8O8
- Molecular weight : 586.597 g/mol
- Smiles notation : CC(=O)O{-}.N{+}c1ccc(N=Nc2cccc(N=Nc3ccc(N{+}.O{-}C(C)=O)cc3N{+}.O{-}C(C)=O)c2)c(N{+}.O{-}C(C)=O)c1
- Substance type : Organic
- Physical state : liquid

Test animals

Species:
rat
Strain:
other: 1. Fischer 344, 2. Crl:CD (SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
1. Details on test animal
TEST ANIMALS
- Source: Frederick Cancer Research Center (Frederick, MD)
- Age at study initiation: 56 days old
- Weight at study initiation: No data
- Fasting period before study: No data
- Housing: rats were housed five per cage throughout the study cage: Polycarbonate, solid bottom (Lab Products Inc., Garfield, NJ)
- Diet (e.g. ad libitum): NIH-07 rat, meal (Zeigler Bros., Inc., Gardners, PA), available ad libitum
- Water (e.g. ad libitum): Tap water (Birmingham Water Works)
in glass water bottles with stainless steel sippers (Edstrom Automatic Watering Systems, Waterford, WI), available ad libitum
- Acclimation period: 20 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.2-23.3 °C
- Humidity (%): 47%-61%
- Air changes (per hr): Minimum 15 change per hours
- Photoperiod (hrs dark / hrs light): 12 hours/day

2. - Source: No data
- Age at study initiation: 9 weeks old
- Weight at study initiation: No data
- Fasting period before study: No data
- Housing: No data
- Diet (e.g. ad libitum): No data
- Water (e.g. ad libitum): No data
- Acclimation period: No data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
- Humidity (%):No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data
IN-LIFE DATES: From: To: No data

Administration / exposure

Route of administration:
other: 1. oral : feed, 2, gavage
Vehicle:
other: 1. NIH-07 rat, meal, 2. 1 w/v% Tween 80 solution
Details on oral exposure:
1. PREPARATION OF DOSING SOLUTIONS: Not applicable

DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- Mixing appropriate amounts with (Type of food): premix of NIH-07 rat as meal, with the appropriate amount of C.I. Pigment Red 23.
- Storage temperature of food: 2 weeks for 45 °C

VEHICLE
- Justification for use and choice of vehicle (if other than water): No data available
- Concentration in vehicle: 0, 6,000, 12,500, 25,000, 50,000 or 100,000 ppm

2. PREPARATION OF DOSING SOLUTIONS: The test chemical was dissolved in 1 w/v% Tween 80 solution to give dose level of 0, 40, 200 or 1000 mg/Kg/day

DIET PREPARATION
- Rate of preparation of diet (frequency): No data
- Mixing appropriate amounts with (Type of food): No data
- Storage temperature of food: No data

VEHICLE
- Justification for use and choice of vehicle (if other than water): 1 w/v% Tween 80 solution
- Concentration in vehicle: 0, 40, 200 or 1000 mg/Kg/day
- Amount of vehicle (if gavage): No data
- Lot/batch no. (if required): No data
- Purity: No data
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
1. Periodic analyses of the dosed-feed formulations were conducted at the study laboratory and at the analytical chemistry laboratory throughout. the studies.

2. not specified
Duration of treatment / exposure:
1. from day 15 to 17th
2. Male: 42 days / - Female: 42 - 48 days (from 14 days before mating to day 4 of lactation)
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Remarks:
1. 0, 6,000, 12,500, 25,000, 50,000 or 100,000 ppm (0, 1200, 2500, 5000, 10000, 50000 mg/kg/day)
Remarks:
2. 0, 40, 200 or 1000 mg/Kg/day
No. of animals per sex per dose:
1. 5animals/dose
2. No data
Control animals:
yes, concurrent vehicle
Details on study design:
No data available
Positive control:
No data available

Examinations

Observations and examinations performed and frequency:
Observations and examinations performed & frequency
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice/day
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once/week and at sacrifice

BODY WEIGHT: Yes
- Time schedule for examinations: once/week and at sacrifice

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): daily/cage (calculated per animal)
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg
body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain
data: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted average
s from the consumption and body weight gain data: No data
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations: No data

OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: No data
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined.

URINALYSIS: No data
- Time schedule for collection of urine: No data
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in table [No.?] were examined.

NEUROBEHAVIOURAL EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data
- Battery of functions tested: No data sensory activity / grip strength / motor activity / other: No data

2. CAGE SIDE OBSERVATIONS: No data
- Time schedule: No data
- Cage side observations checked in table [No.?] were included. No data

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: No data

BODY WEIGHT: Yes
- Time schedule for examinations: No data

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/ kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain
data: No data

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

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations:

OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: No data
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. No data

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. No data

URINALYSIS: Yes
- Time schedule for collection of urine: No data
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in table [No.?] were examined. No data

NEUROBEHAVIOURAL EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data

OTHER: FOB test was performed
Sacrifice and pathology:
1. GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

2. GROSS PATHOLOGY: Yes, organ weight was measured
HISTOPATHOLOGY: Yes
Statistics:
1. Mean ±Standard deviation was observed.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
1. No significant effect were observed at all dose level 0, 1200, 2500, 5000, 10000, 50000 mg/kg/day of treated group compare to control.
Mortality:
no mortality observed
Description (incidence):
1.No significant mortality were observed at all dose level 0, 1200, 2500, 5000, 10000, 50000 mg/kg/day of treated group compare to control.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
1. Differences in mean body weight change and weight gain of exposed group than control were not significant.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
1. No significant effect were observed at all dose level 0, 1200, 2500, 5000, 10000, 50000 mg/kg/day of treated group compare to control.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Description (incidence and severity):
Decreased erythrocyte count observed in all male dose groups and the two highest female dose groups, indicating a mild anemia
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
1. No significant effect were observed at all dose level 0, 1200, 2500, 5000, 10000, 50000 mg/kg/day of treated group compare to control.
Gross pathological findings:
no effects observed
Description (incidence and severity):
1. No significant effect were observed at all dose level 0, 1200, 2500, 5000, 10000, 50000 mg/kg/day of treated group compare to control.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
1. No significant effect were observed at all dose level 0, 1200, 2500, 5000, 10000, 50000 mg/kg/day of treated group compare to control.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Effect levels

Dose descriptor:
NOAEL
Effect level:
1 000 - 5 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
behaviour (functional findings)
body weight and weight gain
clinical biochemistry
clinical signs
food consumption and compound intake
gross pathology
haematology
histopathology: non-neoplastic
mortality
organ weights and organ / body weight ratios
urinalysis
Remarks on result:
other: No effect observed

Target system / organ toxicity

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

Applicant's summary and conclusion

Conclusions:
NONAEL was considered to be 1000-5000 mg/kg bw for diazotized m-phenylenediamine, acetates.
Executive summary:

Data available for the read across chemicals was reviewed to determine the reproductive toxicity of 1,3-Benzenediamine, coupled with diazotized m-phenylenediamine, acetates (CAS no. 84281-74-3). The studies are as mentioned below:

Study 1:

Repeated dose oral toxicity study for the test compound was studied F344 male and female rats by administrating test compound orally at doses 0, 600, 1200, 2500, 5000, 10000 mg/kg/day. There were no clinical and mortality was observed. No biologically significant differences recorded in organ weights among exposed and control rats. Decreased erythrocyte count observed in the two highest female and male dose groups, indicating a mild anemia. Therefore, NOAEL value for test substance is considered to be 5000 mg/kg in F344 female rats.

Study 2:

Sub-chronic repeated dose oral toxicity test for test chemical was studied in male and female Crl:CD (SD) rats. The males were treated for 42 days and the females were treated from 42 - 48 days (from 14 days before mating to day 4 of lactation). The test chemical was mixed 1 w/v% Tween 80 solution to give dose level of 0, 40, 200 or 1000 mg/Kg/day. During the study period, the animals were observed for clinical signs, body weight and food consumption changes, hematology, clinical chemistry and urinalaysis was performed and the animals were subjected to gross pathology and histopathology. No effects were observed during the study period at the highest dose level of 1000 mg/Kg/day. Based on the observations made, No observed adverse effect level for test chemical is considered to be 1000 mg/Kg/day.

Thus, Based on the data available for the read across chemical, No Observed Adverse Effect Level (NOAEL) was considered to be above 1000-5000 mg/kg bw . Thus, comparing this value with the criteria of CLP regulation 1,3-Benzenediamine, coupled with diazotized m-phenylenediamine, acetates (CAS no 84281-74-3) is not likely to classify as repeated dose toxicant.

Categories Display