Diisopropyl 3,3'-[(2,5-dichloro-1,4-phenylene)bis[iminocarbonyl(2-hydroxy-3,1-naphthylene)azo]]bis[4-methylbenzoate]

Endpoint summary

Description of key information

Pigment Red 221 was tested for acute oral toxicity in male and female rats in four studies:

No mortality at 5000 mg/kg bw (similar to OECD 401, no GLP, 1983)

No mortality at 4640 mg/kg bw (similar to OECD 401, no GLP, 1974)

No mortality at 5000 mg/kg bw (similar to OECD 401, no GLP, 1984)

(No mortality at 10000 mg/kg bw, IBT-study of 1975, therefore disregarded)

Pigment Red 221 was tested for acute inhalation toxicity in male and female rats in one study:

(No mortality at 0.87 mg/m3 (highest attainable concentation), IBT-study of 1975, therefore disregarded)

Assessment by read-across: LC50> 1.7 mg/m3 (dust, highest attainable concentration)

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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

(only four rats used (2 male/2 female animals), no data on body weight gain)

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

yes

Specific details on test material used for the study:

- No. of test material (as cited in study report): 21825
- Physical state: maroon powder

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: in-house breeding
- Age at study initiation: 5-6 weeks
- Weight at study initiation: male average: 174 g, female average: 133 g
- Fasting period before study: 18 hours
- Housing: singly
- Diet (ad libitum): Labsure CRM rat and mouse diet
- Water (ad libitum): filtered water

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 +/- 2
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 25 %
- Amount of vehicle (if gavage): 20 ml/kg bw

Doses:

5 g/kg bw/day

No. of animals per sex per dose:

2

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Necropsy of survivors performed: yes

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: neither mortality nor clinical signs indicative of toxicity were observed during the 14-day observation period.

Mortality:

No mortality occured.

Clinical signs:

other: Piloerection was seen in one female between 3 and 6 hours after compound administration. Red staining of the faeces was seen in all animals between 24 and 72 hours after administration. No abnormalities were noted from day 4 onwards.

Gross pathology:

No abnormalities were noted at necropsy.

Interpretation of results:

practically nontoxic

Remarks:

Migrated information

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

2 000 mg/kg bw

Quality of whole database:

.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

READ ACROSS ANALOGUE APPROACH

The read-across hypothesis is based on the inertness of both read-across (CAS 5580-57-4) and target substance. Both pigments are insoluble, are not irritating to mucous membranes and do not cause toxicity by the oral route up to the limit dose. It is predicted that the target substance does not require classification for acute inhalation toxicity.

Structural similarity/ functional groups
Both substances share the same core structure. The core structure includes all functional groups which might be relevant for metabolism (eg. azo, carboxamide). Structural differences are the substituents on the phenylene or phenyl part. The substituents are non-polar and are therefore predicted to decrease systemic uptake by both increasing the size and the hydrophobicity of the molecule.
Physico-chemical properties and toxicokinetics
The molecular weight of both substances is almost identical, as is their relative density. Both decompose before melting at temperatures above 300 °C. They are of low solubility in water and in octanol. On the basis of the measured solubility in water and octanol, the partitioning coefficient is zero or less.
In a study on solubility (static and dynamic) and on particle reactivity, all disazo concensation red pigments were found to be insoluble and passive (BASF 2021, see attached report).
In acute oral toxicity studies performed with the substances, common clinical signs as dyspnea, exophthalmos, ruffled fur, curved body position, diarrhea and sedation were seen when the substances were applied in high concentrations. These systemic toxic effects were all transient. No indication of a substance specific systemic toxicity can be found in any other study. Therefore, absorption and bioavailability of the test substance after oral administration is not expected.

Consistency of data
Neither substance shows adverse effects at the limit dose in valid acute or subacute studies. For the target substance, an acute inhalation toxicity study showing absence of a hazard is available. As this study was performed at a CRO with unacceptable reputation, it is assigned the validity score of 4 and read-across is applied.

Data quality
The validity scores of the experimental data are provided in the data matrix. Relevant data is at least valid with restriction (K2) or comes from GLP and OECD guideline compliant studies (K1).


Please find the complete Read-across justification text including the data matrix in the attachment.

Reason / purpose for cross-reference:

read-across source

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 1.7 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: No mortality and clinical signs

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating conc.

Value:

1.7 mg/m³ air

Physical form:

inhalation: dust

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Regarding acute inhalation toxicity, a study with whole-body exposure was performed at the CRO which was later sued for having falsified study reports (IBT 1972).  This report itself appears to be plausible, since the findings regarding the focal red discoloration and the particle sizes make sense.The test concentration in testing atmosphere was 2.2 mg/l. Details on analytical verification of test atmosphere concentration are not provided.The method of particle size determination is described as follows: A sample of airborne dust was collected from the test atmosphere for the purpose of conducting a microscopic determination of particle size distribution. Particles were counted with respect to three size ranges, viz. 5 µm or smaller (considered to be respirable), 6-25 µm and >25 µm. The smallest particle which could be detected by the light-field technique employed was approximately one µm. The largest particle observed was also recorded. 55% of the particles were in the range of less than 5 µm and 35% were in the range of 6-25 µm. No deaths were noted during the four-hour exposure period or 14-day observation period which followed. Necropsy, performed on all animals at the end of the two-week observation period, revealed slight to moderate diffuse focal red discoloration of the lungs in six rats. There were no other gross pathologic alterations in any of the other tissues and organs examined.

The reported procedure and findings are plausible and would be expected for red inert pigments that are too large for passive permeation through biological membranes.

The pigments are not have irritating or sensitizing properties and are expected to cause effects via excessive deposition at high doses. Based on experience with inert organic pigments, these do not result in mortality in acute inhalation exposure studies.

Read-across to Pigment Yello 93 is applied (No mortality at 1.7 mg/m3 dust). A study with Pigment Brown 23 is ongoing.

Pigment Red 221 (CAS 71566-54-6, 926 g/mol)

Pigment Red 221 was studied for acute oral toxicity in three studies of which two are reliable and adequate (Ciba-Geigy 1974, Centre de Recherches Biologiques 1983).

The study performed in 1974 has the deficiencies of an observation period of only 7 days. Tested doses were 2150, 3170 and 4640 mg/kg bw/day. Within 2 hours after treatment the rats in all dosage groups showed dyspnoea, exophthalmus, curved position, and ruffled fur. All animals had recovered within 4 to 7 days. No mortality occurred.

The study performed in 1983 had the deficiency that no necropsy was performed at the end of the study. All animals survived the single dose of 5000 mg/kg bw.Immediately following application, piloerection and apathy were observed; these symptoms however disappeared rapidly during the course of the observation period.

 

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance is not considered to be classified for acute oral or dermal toxicity or inhalation toxicity under Regulation (EC) No. 1272/2008.