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Description of key information

The NOAEL is considered to be 1000 mg/kg bw/day based on the outcome of a 28-day repeated dose oral toxicity study,

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reason / purpose:
read-across source
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
50 mg/kg bw/day (nominal)
Dose / conc.:
200 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
0 mg/kg bw/day : 5 males and 5 females
0 mg/kg bw/day (recovery): 5 males and 5 females
50 mg/kg bw/day: 5 males and 5 females
200 mg/kg bw/day : 5 males and 5 females
1000 mg/kg bw/day : 5 males and 5 females
1000 mg/kg bw/day (recovery): 5 males and 5 females
Female: 10 animals at 0 mg/kg bw/day
Female: 5 animals at 50 mg/kg bw/day
Female: 5 animals at 200 mg/kg bw/day
Female: 10 animals at 1000 mg/kg bw/day
Control animals:
yes, concurrent vehicle
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Description (incidence and severity):
The findings recorded were considered to be within the range of normal background lesions, which may be seen in rats of this strain and age in oral toxicity studies.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
liver:
minimal to slight hepatocellular hypertrophy, accompanied by finely-granular to floccular cytoplasmic basophilia was noted after four weeks treatment in two males treated with 200 mg/kg/day and four males treated with 1000 mg/kg/day. This finding was not evident in any animals after the recovery period.
Details on results:
Clinical observations:
MORTALITY / VIABILITY:

All animals survived until scheduled necropsy.


CLINICAL SIGNS:

No clinical signs were noted during weekly observations (weeks 1-3).


FUNCTIONAL OBSERVATIONAL BATTERY:

No clinical signs were observed during the functional observation battery (week 4).

Grip Strength:

Significantly decreased mean fore limb grip strength was noted in males (p<0.05) and in females (p<0.01) treated with 1000 mg/kg/day of the test item compared with controls, and significantly decreased (p<0.05) mean hind limb grip strength was noted also in females of the same dose group. It cannot be excluded that this effect is test item related.

No further test item-related differences were observed in mean fore- or hind limb grip strength.

Locomotor Activity:

Significantly decreased mean locomotor activity recorded from 30-45 minutes (p<0.01) and recorded from 45-60 minutes (p<0.05) was observed in males treated with 50 mg/kg/day of the test item.

This was considered to be incidental because it was not seen in any further dose group and not in females.


FOOD CONSUMPTION

No test item related differences in the mean daily and relative food consumption of the test item treated animals were observed compared with controls.


BODY WEIGHT

No changes in mean body weights and mean body weight gain of test item treated animals were observed compared with control animals.

Laboratory findings:
CLINICAL LABORATORY INVESTIGATIONS:

Hematology:

No test item-related differences in parameters of hematology were observed in test item treated females or males after 4 or 6 weeks compared with controls.

Clinical Biochemistry:

No test item-related differences in parameters of clinical biochemistry were noted in test item treated females or males after 4 or 6 weeks compared with controls.

Urinalysis:

No test item-related differences in parameters of urinalysis were observed in test item treated females or males after 4 or 6 weeks compared with controls.

Effects in organs:
ORGAN WEIGHTS:

No test item-related differences in organ weights were noted in test item treated animals after 4 or 6 weeks when compared with the control animals.


MACROSCOPIC / MICROSCOPIC FINDINGS:

The findings recorded were considered to be within the range of normal background lesions, which may be seen in rats of this strain and age in oral toxicity studies. The following microscopic findings were considered to be test item-related lesions:

Liver:
Minimal to slight hepatocellular hypertrophy, accompanied by finely-granular to floccular cytoplasmic basophilia was noted after four weeks treatment in two males treated with 200 mg/kg/day and four males treated with 1000 mg/kg/day. This finding was not evident in any animals after the recovery period.
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Dose descriptor:
NOEL
Effect level:
50 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Critical effects observed:
not specified
Conclusions:
Based on the results of this study with FAT 41034/A, 50 mg/kg bw/day was established as the no-observed-effect-level (NOEL) and 1000 mg/kg bw/day as the no-observed-adverse-effect-level (NOAEL).
Executive summary:

Currently, no short term toxicity studies are available with Solvent Yellow 163, however a structurally similar substance, FAT 41034/A was tested in a 28 day oral toxicity study. In this subacute toxicity study, FAT 41'034/A was administered daily by oral gavage to SPF-bred Wistar rats of both sexes at dose levels of 50, 200 and 1000 mg/kg body weight/day for a period of 28 days. A control group was treated similarly with the vehicle, PEG 300, only. The groups comprised 5 animals per sex which were sacrificed after 28 days of treatment. Additional 5 rats per sex and group were used at 0 and 1000 mg/kg. These animals were treated for 28 days and then allowed a 16-day treatment-free recovery period after which they were sacrificed. Clinical signs, outside cage observation, food consumption and body weights were recorded periodically during pretest, the treatment and recovery periods. Functional observational battery, locomotor activity and grip strength were performed during week 4. At the end of the dosing and the treatment-free recovery period, blood samples were withdrawn for hematology and plasma chemistry analyses. Urine samples were collected for urinalyses. All animals were killed, necropsied and examined post mortem. Histological examinations were performed on organs and tissues from all control and high dose animals, and all gross lesions from all animals. From the animals of the low and middle dose groups, additionally, slides of the liver of the animals treated with 50 or 200 mg/kg bw/day, respectively were evaluated to establish a no effect level. Oral administration of FAT 41'034/A to Wistar rats at doses of 50, 200 and 1000 mg/kg/day, for 28 days resulted in no changes in: mortality, body weights, food consumption and absolute or relative organ weights. No clinical signs, changes of parameters of hematology or clinical biochemistry of toxicological relevance were evident. Significantly decreased mean forelimb grip strength was noted in males (p<0.05) and in females (p<0.01) treated with 1000 mg/kg/day of the test item compared with controls, and significantly decreased (p<0.05) mean hind limb grip strength was noted also in females of the same dose group. It cannot be excluded that this effect is test item related. No further test item-related differences were observed in mean fore- or hind limb grip strength. Significantly decreased mean locomotor activity recorded from 30-45 minutes (p<0.01) and recorded from 45-60 minutes (p<0.05) was observed in males treated with 50 mg/kg/day of the test item. This was considered to be incidental because it was not seen in any further dose group and not in females. Treatment-related findings were generally restricted to minimal to slight hepatocellular hypertrophy along with a fine-granular to floccular cytoplasmic basophilia in two males treated with 200 mg/kg/day and four males treated with 1000 mg/kg/day. This finding was not evident in any animals after the recovery period. Based on the results of this study, 50 mg/kg body weight/day of FAT 41'034/A was established as the no-observed-effect-level (NOEL) and 1000 mg/kg body weight/day of FAT41'034/A as the no-observed-adverse-effect-level (NOAEL).

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 guideline study

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local 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: 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

Oral:

Currently, no short-term toxicity studies are available with Solvent Yellow 163, but data from the read-across substance, Disperse Red 381 (FAT 41034/A) are available from a 28-day oral toxicity study. In this subacute toxicity study, Disperse Red 381 (FAT 41'034/A) was administered daily by oral gavage to SPF-bred Wistar rats of both sexes at dose levels of 0, 50, 200 and 1000 mg/kg bw/day for a period of 28 days. Recovery groups were included at 0 and 1000 mg/kg bw/day, these were treated for 28 days and then allowed a 16-day treatment-free recovery period after which they were sacrificed. Oral administration of FAT 41'034/A for 28 days resulted in no changes in: mortality, body weights, food consumption and absolute or relative organ weights. No clinical signs, changes of parameters of hematology or clinical biochemistry of toxicological relevance were evident. Significantly decreased mean forelimb grip strength was noted in males (p<0.05) and in females (p<0.01) treated with 1000 mg/kg bw/day of the test item compared with controls, and significantly decreased (p<0.05) mean hind limb grip strength was noted also in females of the same dose group. It cannot be excluded that this effect is test item related. No further test item-related differences were observed in mean fore- or hind limb grip strength. Significantly decreased mean locomotor activity recorded from 30-45 minutes (p<0.01) and recorded from 45-60 minutes (p<0.05) was observed in males treated with 50 mg/kg bw/day of the test item. This was considered to be incidental because it was not seen in any further dose group and not in females. Treatment-related findings were generally restricted to minimal to slight hepatocellular hypertrophy along with a fine-granular to floccular cytoplasmic basophilia in two males treated with 200 mg/kg bw/day and four males treated with 1000 mg/kg bw/day. This finding was not evident in any animals after the recovery period. Based on the results of this study, 50 mg/kg bw/day of FAT 41'034/A was established as the no-observed-effect-level (NOEL) and 1000 mg/kg bw/day of FAT41'034/A as the no-observed-adverse-effect-level (NOAEL). Based on the outcome of this study and using the principles of read across, Solvent Yellow 163 is also expected to not lead to adverse effects on repeated oral exposure. The above consideration that the repeated oral administration of Solvent Yellow 163 will not lead to systemic toxicity was also supported from the findings of a reproduction and developmental toxicity screening test with Solvent Yellow 163. In this study, four groups of male and female Wistar rats received the test substance at 0, 100, 300 and 1000 mg/kg bw/day for at least 28 days. There were no clinical signs of toxicological relevance in the dose groups, when compared to the control group. However, the skin of all male and female animals of the low, mid and high dose groups was observed to be slightly discoloured yellowish from approximately the third week of treatment until the end of the study due to the properties of the coloured test item. Histomorphologically observed renal changes (secondary changes including tubular degeneration/regeneration, granular casts and/or tubular dilatation) with eosinophilic substance deposition without clear dose relationship in severity were not considered to be adverse. Hence, based on the findings of the study, the NOAEL for systemic toxicity was set at 1000 mg/kg bw/day.

Inhalation:

Currently no study to assess the repeated dose inhalation toxicity potential of Solvent Yellow 163 is available. However, the vapour pressure for the substance can be considered low owing to the high melting point (>350 °C). Hence the substance is considered to have low volatility. Based on column 2, ‘Specific rules for adaptation from column 1’ of the table given in REACH Annex VII, 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 a structurally similar substance, FAT 41034/A was administered upto 1000 mg/kg bw/day to Wistar rats in a 28 day repeated dose toxicity study. 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 Solvent Yellow 163 has a low toxicity potential via inhalation route and thus the study on repeated inhalation toxicity study is considered scientifically not necessary.

Dermal:

Currently no study to assess the repeated dose dermal toxicity of Solvent Yellow 163 is available. However, the molecular weight of the chemical is 424.534 g/mol, indicating it being large for dermal absorption. Hence, the dermal uptake for the chemical is expected to be limited. Furthermore, no systemic toxicity was observed when a structurally similar substance, FAT 41034/A was administered upto 1000 mg/kg bw/day to Wistar rats in a 28 day oral toxicity study. Similarly, absence of systemic toxicity in skin irritation and sensitisation studies, further supports the conclusion that low toxicity is expected for the chemical via the 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 Solvent Yellow 163 is considered to be scientifically not necessary.

Justification for classification or non-classification

No classification is warranted for the repeated dose toxicity according to CLP Regulation, as NOAEL value was determined as 1000 mg/kg bw/day.