2,6,10-trimethylundec-9-enal

Endpoint summary

Description of key information

A 14 -week rat study was conducted with the analog, citral, and the NOAEL (based on body weight changes) was 335 mg/kg bw/day in females.

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

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.

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to other study

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

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)

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.

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

Dose / conc.:

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

Remarks:

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

Dose / conc.:

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

Remarks:

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

Dose / conc.:

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

Remarks:

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

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

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.

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

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

Key result

Critical effects observed:

no

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.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

335 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

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

In view of the overall lack of toxicity displayed in the studies available for the test material's structural analogue, citral, no classification in accordance with Regulation (EC) No. 1272/2008 is required for this endpoint.