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EC number: 226-394-6 | CAS number: 5392-40-5
- Life Cycle description
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- Endpoint summary
- Appearance / physical state / colour
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- Stability: thermal, sunlight, metals
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- Additional physico-chemical properties of nanomaterials
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- Endpoint summary
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- Environmental data
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- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
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- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data

Repeated dose toxicity: oral
Administrative data
- 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:
- other: Comparable to guideline study with minor restrictions
Cross-referenceopen allclose all
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to other study
Data source
Referenceopen allclose all
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 003
- Reference Type:
- publication
- Title:
- Toxicology and Carcinogenesis Studies of Microencapsulated Citral in Rats and Mice
- Author:
- Ress NB, Hailey JR, Maronpot RR, Bucher JR, Travlos GS, Haseman JK, Orzech DP, Johnson JD, Hejtmancik MR
- Year:
- 2 003
- Bibliographic source:
- Toxicol. Sci., 71, 198-206
- Reference Type:
- other: abstract
- Title:
- TR-505 Toxicology and Carcinogenesis Studies of Citral (Microencapsulated) (CAS No. 5392-40-5) in F344/N Rats and B6C3F1 Mice (Feed Studies) - Draft Abstract
- Author:
- National Toxicology Program NTP
- Year:
- 2 003
- Bibliographic source:
- http://ntp-server.niehs .nih .gov/htdocs/LT-studies/tr505 .html
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- yes
- Remarks:
- (exposure 98 days, partly other organ weights and other clinical chemistry parameters, no urinalysis or ophthalmological examination)
- GLP compliance:
- yes
- Remarks:
- FDA GLP regulations
Test material
- Reference substance name:
- Citral
- EC Number:
- 226-394-6
- EC Name:
- Citral
- Cas Number:
- 5392-40-5
- Molecular formula:
- C10H16O
- IUPAC Name:
- 3,7-dimethylocta-2,6-dienal
- Reference substance name:
- (Z)-3,7-dimethylocta-2,6-dienal
- EC Number:
- 203-379-2
- EC Name:
- (Z)-3,7-dimethylocta-2,6-dienal
- Cas Number:
- 106-26-3
- Molecular formula:
- C10H16O
- IUPAC Name:
- (2Z)-3,7-dimethylocta-2,6-dienal
- Details on test material:
- - Name of test material (as cited in study report): Citral
- Physical state: colourless liquid
- Analytical purity: ca. 97.6%
- Impurities (identity and concentrations): seven substances corresponding to 2.4 % in total
- Isomers composition: ratio geranial:neral = 2:1
- Lot/batch No.: 06930PG
- Expiration date of the lot/batch: no data
- Stability under test conditions: no degradation of the neat chemical after storage for 2 weeks at temperatures up to 60°C when protected from light; no loss of citral from the microcapsules during 14 weeks
Constituent 1
Constituent 2
Test animals
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Taconic Laboratory Animals and Services, Germantown, N.Y.
- Age at study initiation: ca. 6 weeks
- Weight at study initiation: ca. 80 g
- Fasting period before study: no
- Housing: 5 per cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 11 to 12 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 °C (calculated from 72° +- 3° F)
- Humidity (%): 50% +- 15%
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 / 12
IN-LIFE DATES: From: June 5 or 6, 1995 To: September 5 or 6, 1995
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- other: microcapsules loaded with citral
- Details on oral exposure:
- DIET PREPARATION
- Rate of preparation of diet (frequency): every 2 to 4 weeks
- Mixing appropriate amounts with nonirradiated NTP-2000 feed: final concentrations of 3900, 7800, 15600, or 31300 ppm citral were achieved by adding loaded and/or placebo microcapsules at a total concentration of 10% microcapsules
- Storage temperature of food: room temperature
VEHICLE
- Justification for use and choice of vehicle: microcapsules prepared from food-grade sugar and starch were loaded with citral to prevent loss of test substance
- Concentration in vehicle: 31.3 % citral (analytical method GC)
- Lot/batch no.: 20295 - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- periodic verification by GC
- Duration of treatment / exposure:
- 14 weeks
- Frequency of treatment:
- continuously
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
3900, 7800, 15600, 31300 ppm
Basis:
nominal in diet
- Remarks:
- Doses / Concentrations:
ca. 345, 820, 1785, and 1586 mg/kg bw
Basis:
other: actual ingested by male rats
- Remarks:
- Doses / Concentrations:
ca. 335, 675, 1330, and 1215 mg/kg bw
Basis:
other: actual ingested by female rats
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:based on pre-study of Dieter et al., 1993
- Positive control:
- not necessary
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly
BODY WEIGHT: Yes
- Time schedule for examinations: initially, weekly, and at termination of study
FOOD CONSUMPTION AND COMPOUND INTAKE : weekly
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: day 4, 22 and after 14 weeks of treatment
- Anaesthetic used for blood collection: Yes (carbon dioxide)
- Animals fasted: No data
- How many animals: 10 per dose
- Parameters: erythrocyte, reticulocyte, platelet counts, hematocrit, hemoglobin concentration, erythrocyte morphology, mean cell volume, mean cell hemoglobin, mean cell hemoglobin concentration, leukocyte counts and differentials
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: day 4, 22 and after 14 weeks of treatment
- Anaesthetic used for blood collection: Yes (carbon dioxide)
- Animals fasted: No data
- How many animals: 10 per dose
- Parameters: urea nitrogen, creatinine, total protein, albgumin, alanine aminotransferase, alkaline phosphatase, creatinine kinase, sorbitol dehydrogenase, bile acids
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
ORGAN WEIGHTS: Yes
heart, right kidney, liver, lung, right testis, thymus
HISTOPATHOLOGY: Yes
Complete histopathology performed on untreated controls, vehicle controls, dose groups with food concentrations of 15,600, or 31,300 ppm;
examined tissues: gross lesions and tissue masses, adrenal gland, bone with marrow, brain, clitoral gland, esophagus, heart and aorta, large intestine, small intestine, kidney, liver, lung and mainstem bronchi, lymph nodes , mammary gland, nose, ovary, pancreas, parathyroid gland, pituitary gland, preputial gland, prostate gland, salivary gland, skin, spleen, stomach, testis with epididymis and seminal vescicles, thymus, thyroid gland, trachea, urinary bladder, uterus
In addition, examination of bone marrow and forestomach (both sexes) and of kidney (male rats) of lower dose groups to find a NOEL.
Specific staining of hyaline droplets in renal tubules with H&E and Mallory Heidenhain stains - Statistics:
- Body weights: Williams' or Dunnett's test
Hematology or clinical chemistry data: Dunn's or Shirley's test
Results and discussion
Results of examinations
- Details on results:
- CLINICAL SIGNS AND MORTALITY
31300 ppm: all rats killed moribund in second week of treatment; clinical signs were listlessness, hunched posture, absent or slow paw reflex, dull eyes
other dose groups: all animals survived to the end of the study, no clinical signs reported
BODY WEIGHT AND WEIGHT GAIN (for details see Table 1)
all dose groups: significant decrease of final mean body weight; signifcant decrease of body weight gain in all dosed males
from 7800 ppm: signifcant decrease of body weight gain in females
FOOD CONSUMPTION AND COMPOUND INTAKE (for details see Table 1)
from 15600 ppm: decreased food consumption during first study week resulting in lowered average daily doses of the rats of the 31,300 ppm-group which were killed untimely
HAEMATOLOGY
Changes tended to be transient and to improve with increased duration of exposure. They were in general not observed after day 22:
day 4: from 7800 ppm significant increases in hematocrit values, hemoglobin concentrations, erythrocyte and platelet counts; significant decreases in mean cell volumes, mean cell hemoglobin values, reticulocyte and nucleated erythrocyte counts
day 22: 15600 ppm significant decreases in mean cell volumes and mean cell hemoglobin values
week 14: male rats: significant increase of mean cell volume; female rats: significant decrease of mean cell volumes, significant increase of erythrocyte counts
Evaluation - no effects: Changes in erythrocyte and platelet counts were consistent with known physiologic responses related to decreased food and water consumption, and were not considered to be a direct cause of a toxic action of citral.
CLINICAL CHEMISTRY
Generally, the changes tended to be transient and to improve with increased duration of exposure:
day 4: from 3900 ppm: both sexes: significant increase of urea nitrogen; male rats: significant increase of albumin
from 15600 ppm: both sexes: significant decrease of alkaline phosphatase; male rats: significant increase of total protein;
female rats: significant increase of bile acids
day 22: from 3900 ppm: male rats: significant increase of urea nitrogen
from 7800 ppm: female rats: significant increase of alkaline phosphatase
15,600 ppm: both sexes: significant increase of albumin; female rats: significant increase of urea nitrogen and bile acids
week 14: 7800 ppm: male rats: significant increase of albumin
from 7800 ppm: female rats: significant increase of alkaline phosphatase
15600 ppm: male rats: significant increase of urea nitrogen
Evaluation - no effects: Decreased food consumption (see Table 1) and possibly water consumption (no data available) were discussed as causes of physiological responses leading to the changes of serum biochemical parameters. Alterations in albumin, total protein, and urea nitrogen concentrations may be related to possible dehydration or to decreased glomerular filtration rates due to renal damage. The decreases in alkaline phosphatase activity may reflect a loss of circulating intestinal isoenzyme fraction related to decreased feed consumption. In females, bile acid concentration and alkaline phosphatase were increased at 15600 ppm and 31300 ppm. In general, these parameters are considered indicators of bile stasis and would suggest that a cholestatic event may have occurred. However, alterations were of minimal severity and transient, and there was no histopathologic evidence of cholestasis, suggesting that these changes were not biologically significant.
ORGAN WEIGHTS (for details see Table 1)
Evaluation - no effects: Changes were minor with significant decreases of absolute organ weights and significant increases of relative organ weights. These were considered to be related to the significant decreases of final body weight and to be of no biological relevance or toxicologically significance.
GROSS PATHOLOGY
No exposure-related changes
HISTOPATHOLOGY: NON-NEOPLASTIC
Forestomach:
at 31300 ppm after premature sacrifice in the second week epithelial hyperplasia (2/10 m, 4/10 f) and hyperkeratosis (2/10 m, 4/10 f) , with thickening of stratified squamous epithelium and of the cornified superficial layer of the mucosa were observed, no signs of inflammation; significant increase in f, p<=0.01
Bone marrow:
at 15600 ppm increased incidence of minimal grade of atrophy in 7/10 m and 8/10 f, p<=0.01;
31,300 ppm: all males showed atrophy and hemorrhage; incidences in f: atrophy 4/10, p<=0.05, hemorrhage 9/10, p<=0.01
Thymus:
at 31300 ppm atrophy in 5/10 m and 4/10 f, p<=0.05
Kidney:
minimal to mild nephropathy present in males of all dose groups with incidences of 3/10, 10/10, 8/10, 0/10 (premature termination of high dose group), vehicle control 0/10, with significant increases at 7800 and 15600 ppm, p<=0.01; changes characterized by foci of regenerative epithelium, occasional eosinophilic casts, peritubular mononuclear inflammation, and dilated tubules;
Granular casts in renal tubules in males of all dose groups with incidences of 3/10, 10/10, 10/10, 0/10 (premature termination of high dose group), vehicle control 0/10, with significant increases at 7800 and 15600 ppm, p<=0.01; changes characterized by few and scattered granular casts within the outer strip of the medulla, dilated tubules filled with granular eosinophilic material presumed to be proteinacious material and cellular debris; no apparent increase in the amount of hyaline droplets.
Testes:
aspermia in all males at 31000 ppm
Evaluation: Findings in the forestomach, thymic atrophy, and aspermia in the testes were limited to the high dose group that had to be sacrificed in the second study week due to moribundity. It was not clear if the bone marrow lesions in the same dose group were a direct effect of citral toxicity or due to inanition. At the lower dose of 15600 ppm minimal atrophy of bone marrow without accompanying hemorrhage was considered a borderline lesion. Concerning the renal changes in male rats of all dose groups, the presence of granular casts and exacerbation of spontaneous nephropathy would be suggestive of an alpha2µ globulin nephropathy. However, it was considered that renal lesions were not mediated by alpha2µ globulin as there was no increased incidence of hyaline droplets.
Effect levels
open allclose all
- Dose descriptor:
- LOAEL
- Effect level:
- 345 mg/kg bw/day (actual dose received)
- Sex:
- male
- Basis for effect level:
- other: decrease of final body weight and body weight change / dose corresponds to 3900 ppm in diet
- Dose descriptor:
- LOAEL
- Effect level:
- 335 mg/kg bw/day (actual dose received)
- Sex:
- female
- Basis for effect level:
- other: decrease of final body weight / dose corresponds to 3900 ppm in diet
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Table 1: Survival, body and organ weight data, and feed consumption in the 14-day feeding study with citral
Concentration | Survival | Final body weight (g) | Weight change (g) | Feed consumption (g/animal/d) | Organ weight changes e | ||
Week 1 | Week 14 | absolute | relative | ||||
Males | |||||||
Vehicle control | 10/10 | 336 +-6 | 255 +-6 | 15.4 | 18.7 | - | - |
3900 ppm | 10/10 | 318 +-6a | 238 +-5b | 15.9 | 19.9 | - | kidneyctestisc |
7800 ppm | 10/10 | 292 +-4b | 208 +-3b | 15.1 | 20.1 | heartblungathymusb | kidneycliverctestisc |
15600 ppm | 10/10 | 247 +-4b | 163 +-4b | 8.4 | 15.6 | heartbliverblungbthymusb | kidneycliverc testisc |
31300 ppm | 0/10 | - | - | 4.0 | - | - | - |
Females | |||||||
Vehicle control | 10/10 | 190 +-4 | 108 +-4 | 12.8 | 10.7 | - | - |
3900 ppm | 10/10 | 180 +-4a | 101 +-4 | 11.6 | 9.6 | - | kidneyc |
7800 ppm | 10/10 | 181 +-2a | 97 +-2a | 11.8 | 10.8 | - | kidneyc |
15600 ppm | 10/10 | 166 +-2b | 82 +-2b | 6.5 | 10.2 | heartc | kidneycliverd |
31300 ppm | 0/10 | - | - | 4.7 | - | - | - |
Significant changes in comparison to vehicle control:
a significant decrease, p<=0.05; b significant decrease, p<=0.01; c significant increase, p<=0.01; d significant increase, p<=0.05
e The relevance of observed organ weight changes is discussed in "Details on results"
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