CJ303

Repeated dose toxicity: oral

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

Test material information

Constituent 1

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

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 / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day (nominal)

Remarks:

Control

Doses / concentrations 2

Dose / conc.:

100 mg/kg bw/day (nominal)

Remarks:

Low Dose

Doses / concentrations 3

Dose / conc.:

300 mg/kg bw/day (nominal)

Remarks:

Mid Dose

Doses / concentrations 4

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.