1-amino-4-({3-[(4-chloro-6-{[(3 or 4)-sulfophenyl]amino}-1,3,5-triazin-2-yl)amino]-2,4,6-trimethyl-5-sulfophenyl}amino)-9,10-dioxo-9,10-dihydroanthracene-2-sulfonic acid, lithium sodium salts

Endpoint summary

Description of key information

Acute toxicity: via oral route

The harmonized LD50 cut-off valueof CJ304 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.

Clinical signs:

other:

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. For one animal (ID No. 0014), pilo-erection was noted for three days post dose and then mild general weakness and abnormally colored mucus membrane (blue) were also noted on Day 1 through Day 3. All study animals were seen to excrete blue colored feces for the first seven days post dose. Two animals (ID No. 0013 and 0014) were also seen to excrete blue colored urine and the signs then persisted through the first three to five days post dose. Blue stained hair over the ano-genital area, forelimbs, forepaws, hindpaws, and/or head was noted on Day 1 through Day 7.

In Dose Step 2

All dose animals tolerated the dose well and survived to termination on Day 15. Pilo-erection was noted on two animal (ID No. 0016 and 0018) for two days post dose. All study animals were seen to excrete blue colored feces for the first three days post dose. All animals were also seen to excrete blue colored urine and the signs then persisted on the first three days post dose. Blue stained hair over the ano-genital area, forelimbs, forepaws, hindpaws, and/or head was noted on Day 1 through Day 7. 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 diffused, dark brown discoloration in both kidneys of one animal (ID No. 0014). No other remarkable changes or lesions were noted in the remaining study animals.

Interpretation of results:

GHS criteria not met

Conclusions:

According to OECD 423 test method a, the harmonized LD50 cut-off value of CJ304 was 5000 mg/kg. Therefore, CJ304 was Category 5 or Unclassified based on GHS criteria.

Executive summary:

This test using the procedures outlined in the QPS Taiwan Study Plan for T65315003-GN which is based on the SOP for the OECD 423 (OECD, 2002). A total of 6 female Sprague-Dawley rats were orally dosed with CJ304 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 pilo-erection, excretion of blue colored urine, and excretion of blue colored and watery feces within the first week post dose. For one animal in Dose Step 1, transient general weakness and abnormally colored mucus membrane (blue) was also observed and gross examination revealed dark brown discoloration of the kidneys. In absence of mortality, moribund state, or other significant clinical signs of toxicity, these results place CJ304 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

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size

Endpoint conclusion

Endpoint conclusion:

no study available

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 anthraquinone dyes.
No further animal testing is justified.

Executive summary:

From assessment of similar 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. All anthraquinone dyes reviewed 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, 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 further acute dermal toxicity testing on CJ304 in view of the similarity with other dyes assessed in this report. It should also be noted that some other registrations have indicated waivers for this endpoint.

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute toxicity: via oral route

A total of 6 female Sprague-Dawley rats were orally dosed with CJ304 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 pilo-erection, excretion of blue colored urine, and excretion of blue colored and watery feces within the first week post dose. For one animal in Dose Step 1, transient general weakness and abnormally colored mucus membrane (blue) was also observed and gross examination revealed dark brown discoloration of the kidneys. In absence of mortality, moribund state, or other significant clinical signs of toxicity, these results place CJ304 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 – inhalation endpoint

Based on Column 2 of the table given in REACH Annex VIII, the study on acute inhalation toxicity only needs to be conducted if an exposure via inhalation is to be expected, based on vapour pressure and/or the likelihood of an exposure to aerosols, particles or droplets. Referring to the very low vapour pressure of the substance, the fact that the substance is imported into the EU in a formulated form as a dust-free powder or as a granulate, the inhalation route of exposure is considered to be unlikely, thus the study on acute inhalation toxicity is being waived.

Justification for selection of acute toxicity – dermal endpoint

Further analysis of our substance does not indicate any harm upon oral exposure and neither the chemical structure of the substance nor any toxicokinetic results raise any concern about the toxic behavior of the substance upon dermal absorption, we will not perform any test on this endpoint in in vitro or in vivo test systems.