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Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
according to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:
not specified
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
Strain: Wistar
HanIbm: WIST (SPF)
Body weight males: mean 141 g (123-163 g)
Body weight females: mean 123 g (98-143 g)

Route of administration:
oral: gavage
Vehicle:
other: water + 1% CMC
Duration of treatment / exposure:
7 days per week for at least 13 weeks
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
0
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
2.5 mg/kg bw
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
5 mg/kg bw
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
10 mg/kg bw
Basis:
nominal in diet
No. of animals per sex per dose:
10 male and 10 females for each concentration
Control animals:
yes, concurrent no treatment
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
No mortality and no clinical signs were observed.
Mortality:
mortality observed, treatment-related
Description (incidence):
No mortality and no clinical signs were observed.
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
see "details on results"
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
see "details on results"
Details on results:
Changes in haematology were evident in males treated with 5 and 10 mg/kg bw/day.
Changes in haematological parameters like increased methemoglobin levels in males up to 2.5 mg/kg bw/day and females up to 5 mg/kg bw/day, decreased haemoglobin levels in males (5 and 10 mg/kg bw/day) increased reticulocyte counts (relative and absolute) in all test article treated males and a general shift towards high fluorescent reticulocytes in high dosed males.
The changes noted in methemoglobin levels and reticulocte counts in males treated with 2.5 mg/kg bw/day were within the upper levels of the historical control data.
When compared with similarly high values at 5 mg/kg bw/day, there was no correlation to pathomorphological (extramedullary hemopoiesis in the spleen) or other haematological parameters at 2.5 mg/kg bw/day.
In males treated with 10 mg/kg bw/day, increased organ/body weight ratio in the spleen was noted, which correlated to microscopic findings (extramedullary hemopoiesis in the spleen in all animals treated with 5-10 mg/kg bw/day.
No test article related macroscopic findings were observed during necropsy.
With regard to the results obtained this, especially to changes in haematological parameters of males, the No Observed Adverse Effect Level (NOAEL) of Acid Orange 7 was considered to be in the general range around 2.5 mg/kg bw/day.
This dose led to borderline effects on met-hemoglobin and reticulocytes counts without concurrent effects on the spleen.
The NOAEL for females was set to 2.5 mg/kg bw/ day by the study authors.
Dose descriptor:
NOAEL
Effect level:
2.5 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
Critical effects observed:
not specified
Conclusions:
The value of NOAEL for repeated dose toxicity was established at 2.5 mg/kg bw/day both for males and females.
Based on the test result, Acid Orange 7 needs to be considered as toxic for oral repeated dose with classiifcation under CLP as Cat. 1 STOT RE, H372: Causes damage to organs through prolonged or repeated exposure
Executive summary:

The value of NOAEL for repeated dose toxicity was established at 2.5 mg/kg bw/day both for males and females.

It should be noted that at this dose, some slight early haematological effects (increased met-haemoglobin levels in males and increased reticulocytes count) are already observed.

Even if there are in the upper limits of the historical control values, this finding could be test article related. Therefore, the dose of 2.5 mg/kg bw /day is considered as the LOAEL. Based on the test result, Acid Orange 7 needs to be considered as toxic for oral repeated dose with classification under CLP as Cat. 1 STOT RE, H372: Causes damage to organs through prolonged or repeated exposure.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
2.5 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

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:
sub-chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
according to guideline
Guideline:
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
Deviations:
not specified
GLP compliance:
not specified
Limit test:
no
Species:
rabbit
Strain:
not specified
Sex:
not specified
Type of coverage:
open
Vehicle:
other: water as well as USP White Oitment
Details on exposure:
Daily applications on intact and abraded skin
Duration of treatment / exposure:
21 days on abraded skin
90 days on intact skin
Frequency of treatment:
Daily application
Remarks:
Doses / Concentrations:
0.1 %
Basis:
no data
Remarks:
Doses / Concentrations:
1 %
Basis:
no data
No. of animals per sex per dose:
3 animals each group
Control animals:
not specified
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
No mortality and no evidence of systemic toxicity
Dermal irritation:
no effects observed
Mortality:
mortality observed, treatment-related
Description (incidence):
No mortality and no evidence of systemic toxicity
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Normal
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
No dose-related findings
Details on results:
There was no mortality or any evidence of systemic toxicity. Haematological values, growth responses and urinary components were normal. Gross autopsies disclosed no dose-related findings.
Dose descriptor:
conc. level:
Effect level:
1 other: %
Based on:
test mat.
Sex:
not specified
Critical effects observed:
not specified
Conclusions:
The tested item does not have any effects for a repeated dose dermal toxicity.
Executive summary:

Based on the results, there was no evidence of systemic toxicity.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
4 mg/kg bw/day
Study duration:
chronic
Species:
mouse

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Based on the results both for subchronic oral repeated dose toxicity and for chronic dermal repeaded dose toxicity, the tested substance cause adverse effects at the dose of the test.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:

Daily dermal application for 18 months.

Justification for classification or non-classification

The tested substance needs to be classified as Cat. 1 STOT RE, H372: Causes damage to organs through prolonged or repeated exposure

under CLP Regulation (Ec n. 1272/2008).