1,8-dihydroxy-4-nitro-5-(phenylamino)anthraquinone

Endpoint summary

Description of key information

The ‘No Observed Adverse Effect Level’ (NOAEL) for systemic toxicity was 1000 mg/kg bw/day for either sex.

Key value for chemical safety assessment

Toxic effect type:

concentration-driven

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: oral, other

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

Refer chapter 13 for the detailed read across justification.

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Remarks:

systemic toxicity

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No significant toxicological effects

Key result

Dose descriptor:

NOEL

Remarks:

reproductive toxicity

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No significant toxicological effects

Key result

Critical effects observed:

no

Conclusions:

The oral administration of the source substance, FAT 92504/C, to rats by gavage, at dose levels of 100, 300 and 1000 mg/kg bw/day, did not result in any significant toxicological effects. The ‘No Observed Adverse Effect Level’ (NOAEL) for systemic toxicity was therefore considered to be 1000 mg/kg bw/day for either sex.

Executive summary:

The source substance, Disperse Blue 054/077, has been assessed in a high quality study for potential to cause toxicity on repeated exposure via oral route. The study was designed to investigate the systemic toxicity and potential adverse effects of the test item on reproduction (including offspring development) and is designed to be compatible with the requirements of the OECD Guidelines for Testing of Chemicals No. 422 “Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test” (adopted 22 March 1996). The test item was administered by gavage to three groups, each of twelve male and twelve female Wistar Han™:RccHan™:WIST strain rats, for up to eight weeks (including a two week pre-pairing phase, pairing, gestation and early lactation for females), at dose levels of 100, 300 and 1000 mg/kg bw/day. A control group of twelve males and twelve females was dosed with vehicle alone (Polyethylene glycol 400). Clinical signs, behavioral assessments, body weight change and food and water consumption were monitored during the study. Pairing of animals within each dose group was undertaken on a one male: one female basis within each treatment group on Day 15 of the study, with females subsequently being allowed to litter and rear their offspring to Day 5 of lactation. During the lactation phase, daily clinical observations were performed on all surviving offspring, together with litter size and offspring weights and assessment of surface righting reflex. Extensive functional observations were performed on five selected males from each dose group after the completion of the pairing phase, and for five selected parental females from each dose group on Day 4 post partum. Hematology and blood chemistry were evaluated prior to termination on five selected males and females from each dose group.  Adult males were terminated on Days 43 and 44, followed by the termination of all females and offspring on Day 5 post partum. Any female which did not produce a pregnancy was terminated on or after Day 25 post coitum. All animals were subjected to a gross necropsy examination and histopathological evaluation of selected tissues was performed. The oral administration of FAT 92504/C to rats by gavage, at dose levels of 100, 300 and 1000 mg/kg bw/day, did not result in any significant toxicological effects. The ‘No Observed Adverse Effect Level’ (NOAEL) for systemic toxicity was therefore considered to be 1000 mg/kg bw/day for either sex. The ‘No Observed Effect Level’ (NOEL) for reproductive toxicity was considered to be 1000 mg/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

Quality of whole database:

High quality GLP compliant guideline study

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Data waiving:

other justification

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

Data waiving:

other justification

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated dose toxicity: oral

Disperse Blue 077, was evaluated for short-term repeated dose toxicity by METI, Japan (2011) in a study conducted according OECD 422. In this study, four groups of rats (males and females) received the test substance at 0, 40, 200 and 1000 mg/kg/day via gavage for 42 days.No animal died in any test article group. In clinical signs, test article-colored feces were observed in all test article groups, and colored aqueous solution and retention of content was observed in the gastrointestinal tract at necropsy. In the 1000 and 200 mg/kg groups, discoloration (test article-like color) was observed in the mucosa in the stomach, ileum, cecum, and colon.lnblood chemistry, low total protein, low albumin, and high alpha-2-globulin were noted after dosing in males in the 1000 mg/kg group. However, these changes were judged to be toxicologically insignificant because no differences from the control group were noted in any examination after the completion of the recovery period, and no changes were noted in any female.In urine analysis, in males, changes in urine color which were considered lo have reflected the color of the test article or its metabolite were noted in all animals in the 1000 and 200 mg/kg groups. No test article-related changes were noted in detailed observations, grip strength, locomotor activity, body weight, food consumption, hematology, organ weight, necropsy, or histopathology in any group.From these results, under the conditions of  this study,  the no-observed-effect  level (NOEL) of Disperse Blue 077 was judged to be 40 mg/kg/day for general toxicity in consideration of the discoloration of the mucosa! surface of the gastrointestinal tract andabnormal urine color observed in the 200 mg/kg group. The no-observed-adverse-effect level (NOAEL) of Disperse Blue 077 was judged to be 1000 mg/kg/day for general toxicity because changes observed in parental animals were toxicologically insignificant.

The repeated dose toxicity potential of the source substance, Disperse Blue 054/077, was assessed in a study (2017) conducted according to OECD TG 422. This study was designed to investigate the systemic toxicity and potential adverse effects of the test item on reproduction. The test item was administered by gavage to three groups, each of twelve male and twelve female Wistar Han™:RccHan™:WIST strain rats, for up to eight weeks (including a two week pre-pairing phase, pairing, gestation and early lactation for females), at dose levels of 100, 300 and 1000 mg/kg bw/day. A control group of twelve males and twelve females was dosed with vehicle alone (Polyethylene glycol 400). Clinical signs, behavioral assessments, body weight change and food and water consumption were monitored during the study. Pairing of animals within each dose group was undertaken on a one male: one female basis within each treatment group on Day 15 of the study, with females subsequently being allowed to litter and rear their offspring to Day 5 of lactation. During the lactation phase, daily clinical observations were performed on all surviving offspring, together with litter size and offspring weights and assessment of surface righting reflex. Extensive functional observations were performed on five selected males from each dose group after the completion of the pairing phase, and for five selected parental females from each dose group on Day 4post partum. Hematology and blood chemistry were evaluated prior to termination on five selected males and females from each dose group.  Adult males were terminated on Days 43 and 44, followed by the termination of all females and offspring on Day 5 post partum. Any female which did not produce a pregnancy was terminated on or after Day 25 post coitum. All animals were subjected to a gross necropsy examination and histopathological evaluation of selected tissues was performed. The oral administration of FAT 92504/C to rats by gavage, at dose levels of 100, 300 and 1000 mg/kg bw/day, did not result in any significant toxicological effects. The ‘No Observed Adverse Effect Level’ (NOAEL) for systemic toxicity was therefore considered to be 1000 mg/kg bw/day for either sex. The ‘No Observed Effect Level’ (NOEL) for reproductive toxicity was considered to be 1000 mg/kg bw/day.

Repeated dose toxicity: inhalation

Currently no study to assess the repeated dose inhalation toxicity of Disperse Blue 077 is available. However, as the melting point >230 °C indicates low volatility, the substance may not be available for inhalation as a vapour. Based on column 2, ‘Specific rules for adaptation from column 1’ of the table given in REACH Annex VIII, the study on repeated dose inhalation toxicity only needs to be conducted if 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 expected low volatility 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 exposure via inhalation is considered to be unlikely. Furthermore, no systemic toxicity was observed when Disperse Blue 077 was administered upto 1000 mg/kg bw/day in a combined repeated dose toxicity study with reproductive/developmental toxicity screening. Experience with similar chemical substances has demonstrated that it is very unlikely that toxicity related to the intrinsic properties of the chemical only show up upon inhalation exposure and not after systemic application. Hence, considering all the above arguments, it is considered that Disperse Blue 077 has a low toxicity potential via inhalation route and thus, the study on repeated inhalation toxicity is considered scientifically not necessary.

Repeated dose toxicity: dermal

Currently no study to assess the repeated dose dermal toxicity of Disperse Blue 077 is available.However, the molecular weight (376.3 g/mol), indicates limited dermal absorption can be expected for it. Further, low water solubility (<0.85 µg/L) , indicate the substance may not be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Hence, the dermal uptake for the substance is expected to be low. No systemic toxicity was observed when Disperse Blue 077 was administered upto 1000 mg/kg bw/day via gavage in a combined repeated dose toxicity study with reproductive/developmental toxicity screening. Similarly, absence of systemic toxicity in skin irritation as well as sensitization studies, further supports the conclusion that low toxicity is expected for the chemical via dermal route. Further, experience with similar chemical substances has demonstrated that it is very unlikely that toxicity related to the intrinsic properties of the chemical only show up upon dermal exposure and not after systemic application. Taking into consideration the above arguments, low toxicity potential is expected on repeated exposure via dermal route and safety for human health can be estimated using the principles of route to route extrapolation. Hence, the conduct of repeated dose toxicity study via dermal route for Disperse Blue 077 is considered to be scientifically not necessary.

Justification for classification or non-classification

Based on the above discussion, Disperse Blue 077 does not warrant classification according to CLP (Regulation EC No. 1272/2008) criteria.