Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From April 4, 2017 to May 2, 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2017
Report date:
2017

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

Test material

Constituent 1
Chemical structure
Reference substance name:
Reaction products of cuprate(4-), [C-(aminosulfonyl)-C-[[[2-[[4-chloro-6-[(2,5-disulfophenyl)amino]-1,3,5-triazin-2-yl]amino]ethyl]amino]sulfonyl]-29H,31H-phthalocyanine-C,C-disulfonato(6-)-N29,N30,N31,N32]-, tetrasodium and lithium chloride
EC Number:
942-810-5
Molecular formula:
C43H24ClCuN15O16S6.xLi.yNa, (x + y) = 4; 0 < (x,y) < 4 with 1341.9 < MW < 1374 g/mol (UVCB substance), and traces of NaCl and NaSO4
IUPAC Name:
Reaction products of cuprate(4-), [C-(aminosulfonyl)-C-[[[2-[[4-chloro-6-[(2,5-disulfophenyl)amino]-1,3,5-triazin-2-yl]amino]ethyl]amino]sulfonyl]-29H,31H-phthalocyanine-C,C-disulfonato(6-)-N29,N30,N31,N32]-, tetrasodium and lithium chloride
Test material form:
solid: particulate/powder

Test animals

Species:
rat
Strain:
Wistar
Remarks:
Crl:WI
Details on species / strain selection:
Wistar rat as a rodent is one of the standard strains for repeat-dose toxicity studies.
Sex:
male/female
Details on test animals or test system and environmental conditions:
- Source: Charles River Laboratories, Research Models and Services
- Number of animals: 20 male and 20 female rats (5 rats/sex/group) plus a sufficient number of spare animals.
- Age at study initiation: about 7-8 week old
- Females (if applicable) nulliparous and non-pregnant: yes
- Weight at study initiation: Males: 306-324 g, females: 206-227 g
- Housing: Rodents were housed 2 or 3 animals of the same sex and group/cage.
- Acclimation period: At least 5 days
- Temperature (°C): 19.3-24.9 °C
- Relative Humidity (%): 24-65%
- Ventilation: 15-20 air exchanges/hour
- Photoperiod: 12 hours daily, from 6.00 a.m. to 6.00 p.m.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Duration of treatment / exposure:
28 days
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Control
Dose / conc.:
100 mg/kg bw/day (nominal)
Remarks:
Low Dose
Dose / conc.:
300 mg/kg bw/day (nominal)
Remarks:
Mid Dose
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Remarks:
High Dose
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle

Results and discussion

Results of examinations

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
Blue coloured faeces were observed from Day 1 until the end of the study in the male and female cages in the Low, Mid and High doses. This observation was considered to be related to the blue nature of the test item and is not considered to be an adverse effect.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Slightly increased body weight gain was noted in males and females of all dose groups without any statistical significance compared to the control group as shown in Figures 1-2. In summary, there were no effects on body weight or on body weight gain that were ascribed to the test item.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
Statistically significant higher food consumption was recorded in Mid and High dose male groups between Day 7 and 14 but there was no dose-response relationship.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Description (incidence and severity):
There was no visible change in the water consumption of any dose groups, therefore it was not considered necessary to measure the water consumption during the study.
Ophthalmological findings:
not specified
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Variations were noted in one parameter in the treated animals, with statistically significant lower Mean Cell Haemoglobin Concentration (MCHC) levels in High dose males compared to the control. As the recorded values are within the historical control range, these statistical differences were considered to not reflect any adverse effects of the test item.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
For male rats:
Significant increases when compared to controls were observed in the Glucose level in the Mid dose group (p<0.01). Significant decreases were observed in the Cholesterol level in Low (p<0.05) and High dose (p<0.01) groups and in the Chloride ion level in the Mid (p<0.01) and High (p<0.05) dose groups.
For female rats:
A significant increase compared to controls was observed in Bile Acid (p<0.01) in the High dose group.
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
The significantly higher absolute and relative (to body and brain weight) Thyroid and Parathyroid weight in the male High dose group was recorded.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
In the animals test item-related macroscopic changes, as blue discoloration of the digestive content of the stomach, small and large intestine, the kidney, the mandibular and the mesenteric lymph node and urinary bladder (4/5 males in the High dose group) (correlated with the dark blue colour of the test item) were observed at the necropsy. In one High dose male rat in the enlargement of the spleen were observed, as incidental.
Neuropathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Effect levels

Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
clinical biochemistry
clinical signs
food efficiency
gross pathology
haematology
histopathology: non-neoplastic
mortality
neuropathology
organ weights and organ / body weight ratios

Target system / organ toxicity

Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
According to OECD 407 test method, the NOAEL of CJ303 was greater than 1000 mg/kg bw/day.
Executive summary:

This test using the procedures outlined in the CiToxLAB Study Plan for 16/376-100P and OECD 407 (OECD, 2008). The test article was administered to the three treatment groups by oral gavage in a dose of 100, 300 and 1000 mg/kg bw for 28 consecutive days. There were five male and five female Wistar rats in each group. The examinations included clinical signs, mortality, body weights, food consumption, neurological assessment, clinical pathology, vaginal smears, gross pathology, organ weights, histopathology. The observations of clinical signs, body weights, food consumption, clinical pathology, gross pathology and organ weights were not associated with any adverse effects that could be ascribed to treatment. On the basis of the test results given above, the NOAEL of CJ303 for the rats was greater than 1000mg/kg bw/day.