2-[{6-[(4-amino-6-chloro-1,3,5-triazin-2-yl)(methyl)amino]-1-hydroxy-3-sulfonaphthalen-2-yl}diazenyl]naphthalene-1,5-disulfonic acid, lithium sodium salts

Endpoint summary

Description of key information

The NOAEL of CJ302 was greater than 1000 mg/kg bw/day (OECD TG407).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: oral, other

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From March 21, 2017 to September 28, 2017

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

GLP compliance:

yes

Species:

rat

Strain:

Wistar

Remarks:

Crl:WI

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Source: Charles River Laboratories, Research Models and Services
- Age at study initiation: about 7-8 week old
- Weight at study initiation: Males: 275-313 g, females: 192-224 g.
- Housing: Rodents were housed 2 or 3 animals of the same sex and group/cage.
- Acclimation period: At least 5 days
- Temperature (°C): 19.9-24.9 °C
- Humidity (%): 30-56 %
- Photoperiod: 12 hours daily, from 6.00 a.m. to 6.00 p.m.

Route of administration:

oral: gavage

Vehicle:

water

Remarks:

Distilled water

Duration of treatment / exposure:

28 days

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:

five

Control animals:

yes, concurrent vehicle

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

For the male and female cages of the mid and high doses, red coloured faeces were observed from Day 1 until the end of the study.

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

For female rats:
Statistically significant higher body weight was recorded in mid dose on Day 21 and statistically significant lower body weight gain were noted in low and mid dose between Day 21 and 27.

Food efficiency:

effects observed, non-treatment-related

Description (incidence and severity):

For female rats:
The statistically significant lower food consumption was recorded in mid dose group between Day 7 and 14.

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

For male rats:
The PTT (Prothrombin Time (sec)) was statistically lower in the low (p<0.05), mid (p<0.01) and high dose (p<0.01) group than the control. These statistical differences were in line with the historical control.

Clinical biochemistry findings:

effects observed, non-treatment-related

Description (incidence and severity):

For male rats:
Significant increases when compared to controls were observed in Total Bilirubin (p<0.05), Phosphorus (p<0.05) and Calcium levels (p<0.01) concentration in the high dose group. Significant increases when compared to controls were observed in Cholesterol concentration (p<0.05) and in Calcium level (p<0.05) in the mid dose group.
For female rats:
A significant increase compared to controls was observed in Total Bilirubin (p<0.05) in the low and high dose group and the Bile Acid (p<0.01) was higher in the mid and high dose group. Alanine Aminotransferase (ALT/GPT) (p<0.05) was also higher in the low dose group.

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Description (incidence and severity):

For female rats:
The significantly higher absolute and relative (to body and/or brain weight) Thyroid and Parathyroid weight was recorded in the low and high dose group.

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

The orange discoloration of the digestive content in the stomach (4/5 High dose males and 1/5 High dose female), the pelvic dilatation of the kidney (1/5 High dose male) and the dilatation of the uterine horns (1/5 Control, 1/5 Low dose females) were considered as procedure related or background changes.

Neuropathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

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

Critical effects observed:

no

Conclusions:

According to OECD 407 test method, the NOAEL of CJ302 was greater than 1000 mg/kg bw/day.

Executive summary:

This test using the procedures outlined in the CiToxLAB Study Plan for 16/375-100P 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 CJ302 for the rats was greater than 1000mg/kg bw/day.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Additional information

Repeated dose toxicity: via oral route-systemic effects

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 CJ302 for the rats was greater than 1000 mg/kg bw/day.