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Description of key information

LD50 >2000 mg/kg for oral study.

LD50 >10000 ml/kg for dermal study.

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:
The study was conducted between 11 July 2000 and 25 July 2000
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Ace Animals, Inc., Boyer Town, PA, USA
- Age at study initiation: 8-9 weeks
- Weight at study initiation: 182-194 g males and 146-170 g females
- Fasting period before study: 18 hours; feed was returned to the cages approximately 3.5 hours after dosing
- Housing: singly in suspended stainless steel cage with mesh floor
- Diet (e.g. ad libitum): ad libitum Purina Rodent Chow #5012 (except during fasting)
- Water (e.g. ad libitum): ad libitum access to filtered tap water
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-24
- Humidity (%): 40-54
- Air changes (per hr): no details
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 11 July 2000 To: 25 July 2000
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Individual doses were calculated based on initial body weight and were in the range of 0.28 to 0.38 mL. The specific gravity of the undiluted test substance was stated to be 1.028 g/mL

Doses:
Animals were gavaged with a single dose of 2000 mg/kg bw
No. of animals per sex per dose:
Five
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed at 1 and 3 hours post-dosing and at least once daily thereafter for 14 days. Body weights were recorded on Day 0 (shortly before dosing) and on Days 7 and 14 (termination)
- Necropsy of survivors performed: Yes, at study termination (Day 14)
- Other examinations performed: Clinical signs (mortality, signs of gross toxicity and behavioural changes), body weight
Statistics:
Not required.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No mortality at the limit dose
Mortality:
There were no mortalities.
Clinical signs:
One rat appeared hypoactive at 1 hour post dosing. No other clinical signs were observed and all other rats appeared active and healthy during the observation period.
Body weight:
All rats gained weight throughout the observation period
Gross pathology:
No gross abnormalities were observed at terminal necropsy.
Other findings:
No other findings.

The acute oral LD50 of the test material was found to be greater than 2000 mg/kg bw.

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute oral LD50 was >2000 mg/kg bw.
Executive summary:

The acute oral toxicity of ST 30 C 00 (aurantiol pure) was evaluated in Sprague-Dawley rats, according to OECD Guideline 401. Five males and five female rats were administered the undiluted test substance by gavage, at a dose of 2000 mg/kg bw. The animals were observed for mortality, signs of reaction to treatment and behavioural changes at least once daily for 14 days. Bodyweights were recorded on the day of administration and again on Days 7 and 14. All rats were euthanised on Day 14 and gross necropsies were performed. All rats survived and all gained weight during the study. With the exception of one rat that appeared hypoactive 1 hour post-dosing, all animals appeared active and healthy during the study. No abnormalities were detected at necropsy. Under the conditions of the study, the acute oral LD50 of aurantiol pure was found to be > 2000 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Acute toxicity: via inhalation route

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:
experimental study
Adequacy of study:
weight of evidence
Study period:
No data
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Older proprietary study conducted prior to development of GLP and test guideline. Reporting is considered minimal, and the methodology is not comparable to the recommended guideline.
Qualifier:
no guideline followed
Principles of method if other than guideline:
The study was conducted prior to adoption of the current test guidelines. Four rabbits (2/sex) were exposed to a limit dose of the test substance for 24 hours. The application site in 1 rabbit/sex was abraded prior to application.
GLP compliance:
no
Remarks:
Conducted prior to development of GLP
Test type:
standard acute method
Limit test:
yes
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: No data
- Age at study initiation: No data
- Weight at study initiation: 1.9 to 3.3 kg

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: A single application of test material was made to the clipped intact and abraded skin of the backs and flanks of each animal, at a dose of 10 mL/kg bw. The application site of one male and one female from each group was prepared by making epidermal abrasions every 2-3 cm longitudonally over the exposure area. The abrasions penetrated the stratum corneum, but not the dermis.
- Type of wrap if used: The test substance was applied beneath dental dam binders which were placed around the trunk of each animal. The trunk was then covered with a gauze and adhesive bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Test sites were sponged with warm tap water
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 10 mL/kg bw
- Concentration (if solution): Applied undiluted
Duration of exposure:
24 hours
Doses:
10 mL/kg bw (equivalent to approximately 10000 mg/kg bw)
No. of animals per sex per dose:
2/sex
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days.
- Frequency of observations and weighing: Observations for signs of toxicity, mortality and dermal irritation were made once daily following removal of the dental dam, for 14 days. Body weights were recorded prior to dosing, and again at 14 days.
- Necropsy of survivors performed: Yes (Day 14).
- Other examinations performed: Clinical signs, body weight, dermal irritation.
Statistics:
Not required.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 10 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: Based on a dose of 10 mL/kg bw
Mortality:
No mortalities occurred.
Clinical signs:
No clinical signs were noted during the study.
Body weight:
Body weight gain averaged 0.5 kg over the 14 day observation period.
Gross pathology:
No abnormalities were detected at necropsy.
Other findings:
Dermal irritation was observed at the test sites. Well-defined to moderate erythema and very slight to slight oedema were noted 24 hours after test substance removal, at the intact skin sites. The oedema cleared by Day 4 and the erythema cleared by Day 10. Well-defined to moderate erythema and slight oedema were noted at the abraded test sites, persisting until study termination; slight to well-defined erythema and slight oedema were noted at the final observation.

The acute dermal LD50 of the test material was reported to be > 10 mL/kg bw, equivalent to approximately >10000 mg/kg bw.

Interpretation of results:
GHS criteria not met
Conclusions:
Under the conditions of the study, the acute dermal LD50 was estimated to be greater than 10 mL/kg bw, equivalent to approximately 10000 mg/kg bw.
Executive summary:

The acute dermal toxicity of aurantiol pure (RIFM 71 -32) was investigated in a group of two male and two female New Zealand White rabbits. The test substance was applied to the clipped back skin of each rabbit and held in place under an occlusive dressing for 24 hours. A dose of 10 mL/kg bw was applied to each rabbit. The test site was abraded on 1 male and 1 female prior to application. The rabbits were observed for signs of toxicity, mortality and dermal irritation daily for 14 days following application. Gross necropsies were performed on all animals at study termination (Day 14). There were no mortalities, and no clinical signs of toxicity were observed during the study. Well-defined to moderate erythema and slight to moderate oedema was observed in all rabbits. Dermal irritation had cleared by Day 10 in the intact sites, but persisted to Day 14 in the abraded test sites. No abnormalities were detected at necropsy.

Under the conditions of the study, the acute dermal LD50 was estimated to be greater than 10 mL/kg bw, equivalent to approximately 10000 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
10 000 mg/kg bw

Additional information

Oral

An acute oral toxicity test was carried out on groups of young adult rats at dose levels of 2 gms/kg bodyweight. No deaths and no overt signs of toxicity were observed during the fourteen day observation periods. No toxicity was observed in the study at the limit of 2 gms/kg bw. The LD50 was therefore greater than 2 gms/kg bodyweight.

In a separate supporting oral toxicity study testing was carried out on groups of young adult rats at dose levels of 5 ml/kg bodyweight. Again, no deaths and no overt signs of toxicity were observed during the fourteen day observation periods.

Dermal

In the study, 4 animals (two male and two female) were dosed at 10 ml/kg bodyweight and observed for 14 days. No toxicity was seen in the 4 animals during the 14 day observation period.

Symptomatology: Mild erythema on rabbits lasting 24 hours. No toxicity was observed in the study at the limit of 10 ml/kg bw. The LD50 was therefore greater than 10 ml/kg bodyweight.

Justification for classification or non-classification