2,6,10-trimethylundec-9-enal

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2003

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

The study was performed on a similar substance to the registered substance and as such is considered to be sufficient to address the endpoint by read-across.

Justification for type of information:

In accordance with point 8.6.1 of Annex VIII, of Regulation EC No. 1907/2006, testing for this endpoint should be performed using an appropriate route of exposure. A 14-week oral study was therefore submitted to fulfil the repeated dose toxicity data requirements. Exposure via the oral route is considered a more appropriate route of exposure as the physical chemical properties such as the physical state (liquid at room temperature and pressure) and vapour pressure indicate that exposure via inhalation is unlikely. In addition, although dermal exposure is considered a likely route of exposure, the oral route is expected to provide a higher systemic dose and is therefore representative of a worst case scenario.

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to other study

Reference

Endpoint:

vapour pressure

Type of information:

experimental study

Adequacy of study:

key study

Study period:

13 May 2014 - 17 August 2015

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

EU Method A.4 (Vapour Pressure)

Qualifier:

according to guideline

Guideline:

OECD Guideline 104 (Vapour Pressure Curve)

GLP compliance:

yes (incl. QA statement)

Type of method:

effusion method: Knudsen cell

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Batch No.of test material: SC00010875
- Expiration date of the lot/batch: 9 April 2015

Key result

Test no.:

#1

Temp.:

20 °C

Vapour pressure:

0.311 Pa

Remarks on result:

other: mean value (Test 1; test 2)

Test no.:

#2

Temp.:

25 °C

Vapour pressure:

0.479 Pa

Remarks on result:

other: Mean value (Tes 1, test 2)

Conclusions:

Vapour pressure under the test condition is 0.3112 Pa at 20°C.

Executive summary:

The vapour pressure of ADOXAL has been determined to be 0.3112 Pa at 20°C according to the OECD 104 guideline.

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Reference

Endpoint:

appearance / physical state / colour

Type of information:

other: based on observation

Adequacy of study:

weight of evidence

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: based on observation

Justification for type of information:

No guideline is required according to REACh TGD. Considering that the substance is well characterised and that the data come from a GLP study, full reliability applies.

Reason / purpose for cross-reference:

reference to other study

Qualifier:

no guideline required

Version / remarks:

No guideline is required according to REACh TGD.

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- batch No.of test material: SC00010875
- Expiration date of the lot/batch: 9 April 2015

Physical state at 20°C and 1013 hPa:

liquid

Key result

Form:

liquid

Colour:

Colorless to yellow pale

Odour:

other: Aldehydic, Marine, Powerful and Waxy

Substance type:

organic

Executive summary:

The test substance Adoxal is a liquid, colorless to yellow pale.

No guideline is required according to REACh TGD. Considering that the substance is well characterised and that the data come from a GLP study, full reliability applies.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2003

Report date:

2002

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: http://ntp.niehs.nih.gov/testing/types/cartox/protocols/13week/index.html

Version / remarks:

study was conducted according to National Toxicology Program protocols

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Citral

EC Number:

226-394-6

EC Name:

Citral

Cas Number:

5392-40-5

Molecular formula:

C10 H16 O

IUPAC Name:

3,7-dimethyl-2,6-octadienal

Test material form:

liquid

Specific details on test material used for the study:

Test substance name : Citral
Geometric isomer ratio of 2:1 geranial:neral obtained from Aldrich Chemical Compagny (lot A: 97.6% pure)

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

Animals were obtained from Taconic Laboratories Animals and Services (Germantown, NY). They were approximately six weeks old on the first day of the study. Rats were housed five per cage. Feed and water were available ad Libitum.

Administration / exposure

Route of administration:

other: Microcapsules were combined with feed

Vehicle:

other: empty microcapsules

Details on oral exposure:

Citral was microencapsuled by Midwest Research Institute. Microcapsules loaded with neat citral and placebo (empty capsules) were prepared in several batches by a proprietary process using food-grade sugar and starch to produce dry microspheres.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Dose formulations were analyzed at three timepoints and were within 10% of the target.

Duration of treatment / exposure:

14-weeks

Frequency of treatment:

Daily with feed

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

3 900 other: mg microencapsuled citra/Kg diet (ppm)

Remarks:

Loaded microcapsules were combined with feed to a concentration at 10% microcapsules

Doses / concentrations 2

Dose / conc.:

7 800 other: mg microencapsuled citra/Kg diet (ppm)

Remarks:

Loaded microcapsules were combined with feed to a concentration at 10% microcapsules

Doses / concentrations 3

Dose / conc.:

15 600 other: mg microencapsuled citra/Kg diet (ppm)

Remarks:

Loaded microcapsules were combined with feed to a concentration at 10% microcapsules

Doses / concentrations 4

Dose / conc.:

31 300 other: mg microencapsuled citra/Kg diet (ppm)

Remarks:

Loaded microcapsules were combined with feed to a concentration at 10% microcapsules

No. of animals per sex per dose:

groups of 20 male and female rats

Control animals:

yes, concurrent no treatment

Examinations

Observations and examinations performed and frequency:

Clinical findings were recorded weekly. Feed consumption was recorded twice weekly. The animals were weighted initially, weekly thereafter, and at the end of the study.

Sacrifice and pathology:

Necropsies were performed on all core study animals. The heart, right kidney, liver, lung, right testis, and thymus were weighed. Tissues for microscopic examination were fixed and preserved, processed and trimmed, embedded, sectioned and stained. A complete histopathologic examination was performed on all core study untreated control and vehicle control rats, 15,600 ppm rats, and 31,300 ppm rats.

Other examinations:

Blood was collected from the retroorbital sinus of 10 designated rats from each group under carbon dioxide anesthesia on days 4 and 22 for hematology and clinical pathology and then euthanized with C02. Using the same method, blood was collected from all core study rats surviving to the end of the studies for hematology and clinical chemistry analyses.

Statistics:

The probability of survival was estimated by the product-limit procedure of Kaplan and Meier. Statistical analyses for possible dose-related effects on survival used Cox's method for testing two groups for equality and Tarone's life table test to identify dose-related trends. Organ and body weight data were analyzed with the parametric multiple comparison procedures of Dunnett and Williams. Hematology and clinical chemistry data were analyzed using the nonparametric multiple comparison methods of Shirley and Dunn. Extreme values were identified by the outlier test of Dixon and Massey. Average severity values were analyzed for significance with the Mann-Whitney U-test. The Poly-k test was used to assess neoplasm and nonneoplastic lesion prevalence.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

mortality observed, treatment-related

Description (incidence):

All rats in the 31,300 ppm groups were killed moribund in the second week.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Final mean body weights and body weight gains of males and females were generally significantly less than those of the vehicle controls.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Feed consumption by 15,600 and 31,300 ppm males and females was less than that of the vehicle controls during the first week of the study.

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Nephropathy with renal tubule granular casts was observed in male rats; however, this effect is specific to the male rat and not considered relevant for humans.

Histopathological findings: neoplastic:

no effects observed

Other effects:

not specified

Effect levels

Key result

Dose descriptor:

NOAEL

Effect level:

>= 335 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

body weight and weight gain

Target system / organ toxicity

Key result

Critical effects observed:

no

Applicant's summary and conclusion

Conclusions:

In a 14-week dietary study, the following NOAELs due to effects on body weight gain were observed: 345 mg/kg bw/day in male rats, 335 mg/kg bw/day in female rats.

Executive summary:

A 14 -week citral dietary study was conducted in rats. Mortalities were observed at the highest doses, with renal and body weight gain effects at lower doses. The NOAELs were as follows: 345 mg/kg bw/day in male rats and 335 mg/kg bw/day in female rats.