7-[{4-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]-2-(carbamoylamino)phenyl}diazenyl]naphthalene-1,3,6-trisulfonic acid, lithium sodium salts

Endpoint summary

Description of key information

Acute toxicity: via oral route

The harmonized LD50cut-off valueof CJ312 was 5000 mg/kg or Unclassified (OECD TG423).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From December 21, 2015 to December 15, 2016

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

GLP compliance:

yes

Test type:

acute toxic class method

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

- Source: BioLASCO Taiwan Co., Ltd (Taipei, Taiwan)
- Age at study initiation: 8-10 week old
- Housing: one or two animals per cage
- Diet: ad libitum
- Water: ad libitum
- Temperature (°C): 20.2-22.1 °C
- Humidity (%): 41.0-68.4%
- Photoperiod (hrs dark / hrs light): 12-hrs dark / 12-hrs light cycle

Route of administration:

oral: gavage

Vehicle:

water

Remarks:

water for injection

Doses:

Dose Step 1: 2000 mg/kg
Dose Step 2: 2000 mg/kg

No. of animals per sex per dose:

Dose Step 1: three female
Dose Step 2: three female

Sex:

female

Dose descriptor:

LD50 cut-off

Effect level:

5 000 mg/kg bw

Based on:

test mat.

Respectively, the mortalities andclinical observations in Dose Step 1 and 2 as below:

In Dose Step 1

No mortality occurred within the first three dayspost-dose. All dose animals tolerated the dose well and survived to termination on Day 15. Two animals (ID No. 0032 and 0033) were seen to have mild decreased activity in the first three days post dose. Two animals (ID No. 0031 and 0033) excreted orange colored urine and then no abnormal excretion was reported after Day 3. Hair loss of the forelimb was noted for one animal (ID No. 0031) on Day 6 and persistent to study completion.

In Dose Step 2

All dose animals tolerated the dose well and survived to termination on Day 15. Two animals (ID No. 0034 and 0036) excreted orange colored urine and then two animals (ID No. 0034 and 0035) excreted red colored feces. No abnormal excretion was reported after Day 3. Red stained hair over the ano-genital area was noted for one animal (ID No. 0034) on Day 1 through Day 3. There were no records of animal observations on Day 12 and Day 13.

 

In Dose Step 1 and 2, body weights increased throughout the study period and gross examination at termination revealed no remarkable changes or lesions in all dose animals.

Interpretation of results:

Category 5 based on GHS criteria

Remarks:

or Unclassified

Conclusions:

According to OECD 423 test method a, the harmonized LD50 cut-off value of CJ312 was 5000 mg/kg. Therefore, CJ312 was Category 5 or Unclassified based on GHS criteria.

Executive summary:

This test using the procedures outlined in the QPS Taiwan Study Plan for T65315006-GN which is based on the SOP for the OECD 423 and OECD 423 (OECD, 2002).A total of 6 female Sprague-Dawley rats were orally dosed with CJ312 in two dose steps of three animals each, at 2000 mg/kg b.w. for both Dose Step 1 and Dose Step 2. All animals in the two dose steps tolerated the test article well with increasing body weights and no mortality or moribundity reported. The only remarkable clinical signs observed were mild decrease in activity in the first three days post dose in Dose Step 1; and excretion of orange urine in both dose steps and red feces in Dose Step 2, both within the first three days post dose. Isolated instances of forelimb hair loss were also noted for one animal in Dose Step 1. In absence of mortality, moribund state, or other significant clinical and gross signs of toxicity, these results place CJ312 in the GHS Category 5 or Unclassified, with harmonized LD50 cut-off value at 5,000 mg/kg or Unclassified.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

Limited exposure evisaged.

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Principles of method if other than guideline:

Methods not always explicit in reviews, but OECD testing principles appear to have been followed in most cases.

GLP compliance:

not specified

Test type:

other: Review of various studies

Limit test:

no

Species:

rat

Sex:

male/female

Details on test animals or test system and environmental conditions:

Mostly rat data, but dermal effects on guinea pigs and rabbits also examined (non-maximised sensitisation studies and dermal irritation)

Type of coverage:

not specified

Vehicle:

not specified

Doses:

Up to 2000 mg/kg

Control animals:

not specified

Sex:

male/female

Dose descriptor:

discriminating dose

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality reported

Clinical signs:

other: Other than discolouration, no clinical signs

Gross pathology:

No adverse systemic effects reported.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Based on reliable review of literature and assessment of similar sulphonated azo dyes.
No further animal testing is justified.

Executive summary:

From assessment of similar sulphonated azo dyes, none are noted as being acutely toxic and there is no evidence of dermal absorption. From various data sources, it is considered unlikely that the substance will be acutely toxic by the dermal route. Most azo dyes have acute toxicity discriminating dose > 2000 mg/kg and the similar substances reviewed fall into this category.

 

The impact of lithium is not likely to impact on the toxicity when comparing with sodium salts as dermal toxicity of lithium substances are reported to be low and in view of the minimal % w/w content of lithium, this is not significant in the classification of toxicity.

 

Studies on guinea pigs and rabbits for sensitising and irritancy assessment have not revealed any evidence of adverse systemic effects. Only the maximised sensitising studies (ie injected) appear to give positive results with some azo dyes, confirming low levels of dermal absorption. Discolouration of skin will occur and the colour is difficult to wash off.

 

It is not considered justifiable to perform dermal toxicity testing on CJ312 in view of the similarity with other dyes assessed. It should also be noted that some other registrations have indicated waivers for this endpoint.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

This class of substance considered to be of low toxicity and not likely to be absorbed dermally.

Additional information

Acute toxicity: via oral route

A total of 6 female Sprague-Dawley rats were orally dosed with CJ312 in two dose steps of three animals each, at 2000 mg/kg b.w. for both Dose Step 1 and Dose Step 2. All animals in the two dose steps tolerated the test article well with increasing body weights and no mortality or moribundity reported. The only remarkable clinical signs observed were mild decrease in activity in the first three days post dose in Dose Step 1; and excretion of orange urine in both dose steps and red feces in Dose Step 2, both within the first three days post dose. Isolated instances of forelimb hair loss were also noted for one animal in Dose Step 1. In absence of mortality, moribund state, or other significant clinical and gross signs of toxicity, these results place CJ312 in the GHS Category 5 or Unclassified, with harmonized LD50 cut-off value at 5,000 mg/kg or Unclassified.

Justification for selection of acute toxicity – dermal endpoint

Based on reliable review of literature and assessment of similar sulphonated azo dyes.

No further animal testing is justified.