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Description of key information

Key value for chemical safety assessment

Acute toxicity: via oral route

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Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
02 April 2008 to 18 December 2009
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Compliant to testing guideline; adequate coherence between data, comments and conclusions.
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Janvier (53940 Le Genest-Saint-Isle, France)
- Age at study initiation: about 8 weeks
- Weight at study initiation: 210 ± 6 g
- Fasting period before study: yes
- Housing: polycarbonate cages with stainless steel lid
- Diet (e.g. ad libitum): SSNIFF R/M-H pelleted maintenance diet, ad lib
- Water (e.g. ad libitum): filtered tap water
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C +/-2°C
- Humidity (%): 50% +/-20%
- Air changes (per hr): 12 cycles per hour
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 09 April 2008 To: 07 May 2008
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 30 to 200 g/L
- Amount of vehicle (if gavage): 10 mL/kg
- Justification for choice of vehicle: forms a solution
- Lot/batch no. (if required): not applicable
- Purity: not indicated

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: as no information on the toxic potential of the test item was available, for animal welfare reasons, the starting dose-level of 300 mg/kg was chosen
Doses:
300 and 2000 mg/kg
No. of animals per sex per dose:
3 F
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations made regularly the day of treatment and then at least once a day; weight recorded on the day before administration, on day 1 and then on days 8 and 15.
- Necropsy of survivors performed: yes
Statistics:
Not applicable
Sex:
female
Dose descriptor:
LD0
Effect level:
2 000 mg/kg bw
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
No mortality was observed
Clinical signs:
300 mg/kg: none.

2000 mg/kg: Hypoactivity (all the animals) and piloerection (3/6 animals) were noted within 6 hours of treatment.
Body weight:
300 mg/kg: When compared to CIT historical control animals, a slightly lower body weight gain was noted in 1/3 females between day 8 and day 15, without affecting the mean body weight gain at the end of the study. The body weight gain of the other animals was not affected by treatment with the test item.

2000 mg/kg: When compared to CIT historical control animals, a slightly lower body weight gain was noted in 1/6 females between day 1 and day 8 (returning to normal thereafter). The body weight gain of the other animals was not affected by treatment with the test item.
Gross pathology:
At necropsy, no apparent abnormalities were observed in any animal
Other findings:
None
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the experimental conditions of this study, the oral LD50 of the test item CAE was higher than 2000 mg/kg in rats.

According to the classification criteria laid down in Council Directive 67/548/EEC (and subsequent adaptations), concerning the potential toxicity by oral route, the test item should not be classified.
Executive summary:

The test item CAE was prepared in corn oil and was administered by oral route (gavage), under a volume of 10 mL/kg, to groups of three fasted female Sprague-Dawley rats.

The study design was as follows: 

Dose-level

(mg/kg)

Volume

(mL/kg)

Female

300

10

3

2000

10

3

2000

10

3

 

Clinical signs, mortality and body weight gain were checked for a period of up to 14 days following the single administration of the test item.

All animals were subjected to necropsy.

The interpretation of results was based on the classification critera laid down in Council Directive 67/548/EEC (and subsequent adaptations).

Dose-level of 300 mg/kg (three animals)

No deaths and no clinical signs were observed.

When compared to CIT historical control animals, a slightly lower body weight gain was noted in 1/3 females between day 8 and day 15, without affecting the mean body weight gain at the end of the study. The body weight gain of the other animals was not affected by treatment with the test item.

 

Dose-level of 2000 mg/kg (three females then confirmation on three other females)

No deaths occurred.

Hypoactivity (all the animals) and piloerection (3/6 animals) were noted within 6 hours of treatment.

When compared to CIT historical control animals, a slightly lower body weight gain was noted in 1/6 females between day 1 and day 8 (returning to normal thereafter). The body weight gain of the other animals was not affected by treatment with the test item.

 

At necropsy, no apparent abnormalities were observed in any animal.

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

Acute toxicity: via inhalation route

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Reference
Endpoint:
acute toxicity: inhalation
Type of information:
other: literature review
Adequacy of study:
other information
Study period:
2013
Reliability:
2 (reliable with restrictions)
Principles of method if other than guideline:
Literature review

See executive summary.

An inhalation acute toxicity test should not be required.

Executive summary:

CAE is defined as an UVCB substance (substance of unknown or variable composition). Its detailed chemical characterisation is presented in Table 1 (see PDF document attached).

The final complex is composed of glycerides (46.3%), free fatty acids and unsaponifiables such as alkyl furans, alkyl triols. More particularly alkyl furans are the result of chemical reaction during the heat treatment and are not found naturally in the fruit.

 

CAE was not experimentally tested for all requested toxicological end-points.

Glycerides and free fatty acids are very well-known substances which are not of toxicological concern. On the contrary, alkyl furans and alkyl triols, respectively named fraction H and fraction I, which are less well known, could raise questions about the toxicological profile of CAE.

 

In order to avoid unnecessary experimentation on animals, a literature review was performed for each component to determine their acute inhalation toxicity properties. The results are summarized in Table 2 (see PDF document attached).

 

According to available data, glycerides and free fatty acids have no inhalation acute toxicity. Other components are either of slight acute toxicity like alkyl furans with LC50expected between 1 and 4 mg/L/hr or of unknown toxicity like alkyl triols.

However all of these components have low vapour pressures (alkylfurans: 10-1-10-2 Pa), or extremely low vapour pressures (alkyl triols < 10-6 Pa).

Therefore, according to § 8.5.2. Column 2 in Annex VIII to Regulation (EC) No.1907/2006, testing by the inhalation route is not appropriate as exposure of humans via inhalation is unlikely, taking into account the low vapour pressure of the substance and the reduced possibility of exposure to aerosols, particles or droplets of an inhalable size (confinement during the manufacturing process).

An inhalation acute toxicity test should not be required.

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

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Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
from 26 June to 10 July 2012
Reliability:
1 (reliable without restriction)
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
5 males and 5 females
Age: 7 and 8 weeks for males and females, respectively
Weight at dosing: 220 - 238 g (males) and 188 - 205 g (females)
Acclimation period: at least 5 days

Diet: M2-rat/mouse maintenance
Water: tap-water from public distribution system (Microbiological and chemical analyses of the water were carried out once every six months by IPL, Santé, Environnement Durables - Atlantique, Bordeaux)
Housing: Individually during treatment (24 hours), then 5 rats / cage (clear polycarbonate cages with stainless steel)

Temperature: 19-25°C
Humidity: 30 - 70%
Air changes: fifteen changes per hour
Photoperiod: 12 hours continous light (07:00 to 19:00) and 12 hours darkness
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
Approximately 24 hours before the treatment, fur was removed from the dorsal area of the trunk of the test animals by clipping. At least 10 per cent of the body surface area was clear for the application of the test item.
Then, rats received the test item by topical application, under porous gauze dressing.
Duration of exposure:
After 24-hours exposure period, the gauze dressings were removed and the treated area was rinsed with distilled water.
Doses:
An effective dose of 2000 mg/kg body weight of CAE administered under a volume of 2.19 mL/kg body weight (corresponding to 2 g/kg b.w. according to the calculated density).
No. of animals per sex per dose:
Limit-test: 10 rats treated with a single dose of 2000 mg/kg b.w.
Control animals:
other: control historical data
Details on study design:
Mortality, clinical signs and skin examination were recorded daily for the duration of the study (14 days).
Individual body weights were measured and recorded on days 0 (dosing), 2, 7 and 14. On day 14, all surviving animals were sacrificed and all animals were necropsied for gross pathological changes.
Statistics:
None.
Sex:
male/female
Dose descriptor:
approximate LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
No mortality occurred during the study.
Clinical signs:
No systemic clinical signs related to the administration of the test item were observed. Erythema was noted from 48 hours post-dose in three females and was totally reversible on day 4. Dryness was noted from day 3 in three females and was totally reversible on day 6.
Body weight:
The body weight evolution of the animals remained normal throughout the study.
Gross pathology:
The macroscopical examination of the animals at the end of the study did not reveal treatment-related changes.
Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: OECD GHS
Conclusions:
In conclusion, the LD50 of the test item CAE was higher than 2000 mg/kg body weight by dermal route in the rat.
According to the criteria for classification, packaging and labelling of dangerous substances and preparations in accordance with EEC Directives 67/548, 2001/59 and 99/45, the test item CAE must not be classified. No symbol or risk phrase is required.
In accordance with Regulation EC No.1272/2008 on classification, labelling and packaging of substances and mixtures, the test item must not be classified. No signal word or hazard statement is required.
Executive summary:

In an acute dermal toxicity study, the test item CAE was applied onto the intact skin of 10 Sprague Dawley rats (5 males and 5 females) at the single dose of 2000 mg/kg body weight (limit test) under an occlusive patch, according to the official method as defined in O.E.C.D. guideline No.402 and in test method B.3 of Council Regulation No.440/2008.

All animals were observed for 14 days. Then surviving animals were sacrificed and a necropsy was conducted. Body weights were recorded on days 0 (dosing), 2, 7, 14.

No mortality occurred during the study. No systemic clinical signs related to the administration of the test item were observed. Erythema was noted from 48 hours post-dose in three females and was totally reversible on day 4. Dryness was noted from day 3 in three females and was totally reversible on day 6.

The body weight evolution of the animals remained comparable between treated and control animals throughout the study.

The macroscopical examination of the animals at the end of the study did not reveal treatment-related changes.

In conclusion, the LD50of the test item CAE was higher than 2000 mg/kg body weight by dermal route in the rat.

According to the criteria for classification, packaging and labelling of dangerous substances and preparations in accordance with EEC Directives 67/548, 2001/59 and 99/45, the test item CAE must not be classified. No symbol or risk phrase is required.

In accordance with Regulation EC No.1272/2008 on classification, labelling and packaging of substances and mixtures, the test item must not be classified. No signal word or hazard statement is required.

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

Additional information

Justification for classification or non-classification