Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 943-438-6 | CAS number: 90063-59-5
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- 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
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- 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
Endpoint summary
Administrative data
Description of key information
Chronic oral toxicity (similar to OECD TG
453, Read across from Citral)
Rat: NOAEL 100 mg/kg bw/day
Mouse: LOAEL 60 mg/kg bw/day
Subchronic oral toxicity (similar to OECD TG 408, Read across from Citral)
Rat: LOAEL 335 mg/kg bw/day
Mouse: LOAEL 745 mg/kg bw/day
Subchronic inhalation toxicity (Weight of evidence, Read across from Citral: Gaworski 1992,1993)
rat: NOAEC 34 ppm = 215 mg/m3
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- June 1995 - September 1995
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Comparable to guideline study with minor restrictions.
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- yes
- Remarks:
- (partly other organ weights and clinical chemistry parameters, no urinalysis or ophthalmological examination)
- GLP compliance:
- yes
- Remarks:
- FDA GLP regulations
- Species:
- mouse
- Strain:
- B6C3F1
- 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: 6 weeks
- Weight at study initiation: males ca. 20 g, females ca. 16.5 g
- Fasting period before study: no
- Housing: males inidividually, females 5 per cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 13 to 14 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 7 or 8, 1995 To: September 7 or 8, 1995 - 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 3,900, 7,800, 15,600, or 31,300 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
- Remarks:
- Doses / Concentrations:
3900, 7800, 15600, or 31300 ppm
Basis:
nominal in diet - Remarks:
- Doses / Concentrations:
745, 1840, 3915, and 8110 mg/kg bw/d
Basis:
other: actual ingested by male mice - Remarks:
- Doses / Concentrations:
790, 1820, 3870, and 7550 mg/kg bw/d
Basis:
other: actual ingested by female mice - 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
- 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, gallbladder, heart and aorta, large intestine, small intestine, kidney, liver, lung and mainstem bronchi, lymph nodes , mammary gland (females only), 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 forestomach and of ovaries of lower dose groups to find a NOEL - Statistics:
- Body weights: Williams' or Dunnett's test
Hematology or clinical chemistry data: Dunn's or Shirley's test - Details on results:
- CLINICAL SIGNS AND MORTALITY
31300 ppm: 4 males killed moribund in second week of treatment
clinical signs: at 15600 and 31300 ppm animals were generally thin and appeared lethargic; at 7800 ppm few males were also thin
other dose groups: all animals survived to the end of the study
BODY WEIGHT AND WEIGHT GAIN (for details see Table 1)
all dose groups: significant dose-dependent decreases of final mean body weight and of body weight gain
31300 ppm: final weight < initial weight
FOOD CONSUMPTION AND COMPOUND INTAKE (for details see Table 1)
from 7800 ppm: females showed decreased food consumption during first study week
all doses: by the end of the study, food consumption was greater than by vehicle control
Evaluation: increased food consumption may have been due to the mice scattering feed, an indication of poor palatability
HAEMATOLOGY
week 14: from 15600 ppm: significant dose-dependent decreases of leukocyte and lymphocyte counts; in male mice lymphocyte counts were already decreased at 3900 and 7800 ppm without a dose-dependency, however, some other parameters were increased at single dosages showing no biological relevance.
Evaluation: These changes together with marked suppression in mean body weights may reflect a physiological response consistent with a stress-related and/or corticosteroid-induced lymphopenia.
ORGAN WEIGHTS
Significant decreases of absolute organ weights, increases of relative organ weights (for details see Table 1)
Evaluation: differences in organ weights between exposed mice and vehicle controls reflected body weight differences and were not toxicologically significant
GROSS PATHOLOGY
No exposure-related changes
HISTOPATHOLOGY: NON-NEOPLASTIC
Forestomach:
from 15,600 ppm: wall of forestomach of many males and females (incidences not given) variably thickened (2 to 5times normal), mucosa (squamous epithelium) and submucosa were often rugose; additionally, minimal hyperkeratosis of epithelium being insignificant
Evaluation: Although thickened, all three main components (mucosa, submucosa, and muscle) appeared proportional to each other and to those of control animals. Therefore alteration considered to be the result of a contradicted stomach rather than a pathological alteration.
Ovaries:
from 15,600 ppm: increased incidences of ovarian atrophy characterized by absence of or reduction in the number of corpora lutea with no effect on primary, secondary, or antral follicles; incidences 0/10, 0/10, 7/10, 10/10, vehicle control 0/10
Evaluation: NTP Pathology Working group considered these lesions most probably to represent hypoplasia being most likely a secondary effect due to the poor condition of female mice in these dose groups. - Dose descriptor:
- LOAEL
- Effect level:
- 745 mg/kg bw/day (actual dose received)
- Sex:
- male
- Basis for effect level:
- other: reduced final body weight and body weight change / dose corresponds to 3900 ppm in diet
- Dose descriptor:
- LOAEL
- Effect level:
- 790 mg/kg bw/day (actual dose received)
- Sex:
- female
- Basis for effect level:
- other: reduced final body weight and body weight change / dose corresponds to 3900 ppm in diet
- Critical effects observed:
- not specified
- Conclusions:
- Based on the results of the study, the LOAELs of Citral were set at 745 and 790 mg/kg bw/day (3900ppm) in males and females respectively (based on decreased body weight).
- Executive summary:
The substance Citral (Reaction mass of (E)-3,7-dimethylocta-2,6-dienal and (Z)-3,7-dimethylocta-2,6-dienal) has been tested in a study similar to OECD TG 453. Groups of male and female B6C3 mice were exposed to microencapsulated citral (greater than 96% pure) in feed for 14 weeks. The concentration of Citral in the diet was equivalent to average daily doses of approximately 745 - 8,110 mg/kg to males and 790 - 7,550 mg/kg to females.
Effects observed:In the second week of the study, four males in the high dose group were killed moribund. Lower mean body weights. Mice in the mid and high dose groups were generally thin and lethargic. The incidences of ovarian atrophy were significantly increased in females exposed to mid and high doses.
The LOAELs at 14 weeks were determined at 745 and 790 mg/kg bw/day (3900ppm) in males and females respectively (based on decreased body weight).
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- June 1995 - September 1995
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Comparable to guideline study with minor restrictions
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- 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
- 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 - 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
- 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
- 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 - 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. - 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
- Critical effects observed:
- not specified
- Conclusions:
- Based on the results of the study, the LOAELs of Citral were set at 345 and 335 mg/kg bw (3900ppm) for male and female rats based on decreased body weight.
- Executive summary:
The substance Citral (Reaction mass of (E)-3,7-dimethylocta-2,6-dienal and (Z)-3,7-dimethylocta-2,6-dienal) has been tested in a study similar to OECD TG 408. Groups of male and female F344/N rats were exposed to microencapsulated citral (greater than 96% pure) in feed for 14 weeks. Dose used in rats were equivalent to 345-1,585 mg citral/kg body weight for males and 335- 2,125 mg/kg for females.
Effects observed: Lower mean body weights, and feed consumption. Males and females in the high dose group exhibited listlessness, hunched posture, absent or slow paw reflex, and dull eyes. Some evidence of forestomach epithelial hyperplasia and hyperkeratosis, bone marrow atrophy and hemorrhage, and nephrotoxicity was observed.
Based on these results the LOAEL of rats at 14 weeks was set at 345 and 335 mg/kg bw (3900ppm) based on decreased body weight.
- Endpoint:
- chronic toxicity: oral
- Remarks:
- combined repeated dose and carcinogenicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- June 1995 - September 1995
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Comparable to guideline study with acceptable restrictions.
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
- Deviations:
- yes
- Remarks:
- (complete histopathology for all dose groups; no parameters of hematology, clinical chemistry or urinalyses measured)
- GLP compliance:
- yes
- Remarks:
- FDA GLP regulations
- Species:
- mouse
- Strain:
- B6C3F1
- 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: 6 weeks
- Weight at study initiation: males ca. 20 g, females ca. 16.5 g
- Fasting period before study: no
- Housing: males inidividually, females 5 per cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 13 to 15 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 19 or 20, 1996 To: June 15-19 (males) or June 22-24 (females), 1998 - Route of administration:
- oral: feed
- Vehicle:
- other: microcapsules loaded with citral
- Details on oral exposure:
- DIET PREPARATION
- Rate of preparation of diet (frequency): every 4 weeks
- Mixing appropriate amounts with nonirradiated NTP-2000 feed: final concentrations of 0, 500, 1000, or 2000 ppm citral were achieved by adding loaded and/or placebo microcapsules at a total concentration of 1.25% 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: 31.9 % citral (analytical method GC)
- Lot/batch no.: MRI 020196MC - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- periodic verification by GC
- Duration of treatment / exposure:
- 104-105 weeks
- Frequency of treatment:
- continuously
- Remarks:
- Doses / Concentrations:
0, 500, 1000, 2000 ppm
Basis:
nominal in diet - Remarks:
- Doses / Concentrations:
ca. 0, 60, 120, 260 mg/kg bw/d
Basis:
actual ingested - No. of animals per sex per dose:
- 50
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: based on 14-week pre-study described in same study report
- Positive control:
- Not necessary
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: day 8, 36, and every 4 weeks thereafter, at end of study
BODY WEIGHT: Yes
- Time schedule for examinations: day 0, 8, 36, and every 4 weeks thereafter, at end of study
FOOD CONSUMPTION AND COMPOUND INTAKE : weekly
- Food consumption for each cage determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes, approximately every 4 weeks for a 1-week period
- 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: No
CLINICAL CHEMISTRY: No
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Complete histopathology performed on all mice:
examined tissues: gross lesions and tissue masses, adrenal gland, bone with marrow, brain, clitoral gland, esophagus, gallbladder, heart and aorta, large intestine, small intestine, kidney, liver, lung and mainstem bronchi, lymph nodes , mammary gland (females only), 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 - Statistics:
- Probability of survival: product-limit procedure of Kaplan and Meier
dose-related effects on survival: Cox's method, Tarone's life table test
Body weight data: parametric multiple comparison procedures of Dunnett and Williams
Incidences of non-neoplastic lesions: Poly-3 test (Bailer and Portier, 1988) - Details on results:
- CLINICAL SIGNS AND MORTALITY
Survival of all dosed groups similar to vehicle control groups; no clinical findings attributable to citral exposure
BODY WEIGHT AND WEIGHT GAIN (for details see Table 1)
Mean body weights were generally less compared to those of the vehicle controls in the following dose groups and study periods:
females: at 500 ppm from week 30-102, at 1000 ppm from week 14-102, at 2000 ppm during whole study period;
males: at 1000 ppm from year 2, at 2000 ppm during whole study period.
Final body weights (101 w): females: 91%, 88% and 78% of controls; males: 93%, 91% and 84% of controls for 500, 1000, 2000 ppm respectively.
FOOD CONSUMPTION AND COMPOUND INTAKE (for details see Table 1)
Comparable to vehicle control
PATHOLOGY: NON-NEOPLASTIC
- Oral mucosa: Inflammation and ulceration
Incidences: present in all groups including vehicle controls with significantly increased incidences in all exposed female mice and 2000 ppm male mice (for incidences see Table 2)
Location: areas of inflammation and ulceration directly medial to the molar teeth in most cases; ulceration almost always located at the points were hair shafts penetrated the oral mucosa
Characterization of inflammation: minimal to mild severity (see Table 2), accumulation of mixed inflammatory cells within and just beneath the oral mucosa adjacent to the medial aspect of the teeth; in a majority of cases hair shafts present in the inflamed areas and appeared to have penetrated the tooth socket
Characterization of ulceration: minimal to mild severity (see Table 2), focal areas with loss of mucosa
Evaluation: inflammation and ulceration were considered to be secondary to embedded hair shafts. The same lesions, with similar severity, were present in vehicle controls. Thus, lesions in the oral mucosa were considered probably not a direct toxic effect of citral, but citral may have exacerbated the secondary inflammatory response in females. The significance of this effect is unknown.
- Adrenal cortex: focal hyperplasia, significant increase in 2000 ppm male mice (for incidences see Table 2)
Evaluation: Incidences were very low for this common background lesion and are therefore not considered to reflect a toxic response to citral exposure.
- Bone: fibrosis, significant increase in 500 and 1000 ppm female mice (see Table 2)
Evaluation: The significance of this effect without dose-relationship is unknown.
- Kidney: minimal nephropathy with significant increase in 2000 ppm females and minimal renal tubule mineralization with significant increase in 500 and 1000 ppm females (for incidences see Table 2)
Evaluation: The toxicological significance of increased incidences of these minimal changes also present in vehicle controls is unclear.
PATHOLOGY: NEOPLASTIC
Equivocal evidence of treatment-related induction of malignant lymphoma in female mice: Findings are presented in Section 7.7 in detail. - Dose descriptor:
- LOAEL
- Effect level:
- 60 mg/kg bw/day (actual dose received)
- Sex:
- female
- Basis for effect level:
- other: reduction of body weights / dose corresponding to 500 ppm in diet
- Dose descriptor:
- LOAEL
- Effect level:
- 120 mg/kg bw/day (actual dose received)
- Sex:
- male
- Basis for effect level:
- other: reduction of body weights/ dose corresponding to 1000 ppm in diet
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 60 mg/kg bw/day (actual dose received)
- Sex:
- male
- Basis for effect level:
- other: dose corresponding to 500 ppm in diet
- Critical effects observed:
- not specified
- Conclusions:
- Based on the results of the study, the LOAELs of Citral were set at 120 and 60 mg/kg bw/day (1000 and 500 ppm) for male and female rats based on decreased body weight.
- Executive summary:
The substance Citral (Reaction mass of (E)-3,7-dimethylocta-2,6-dienal and (Z)-3,7-dimethylocta-2,6-dienal) has been tested in a study similar to OECD TG 453. Groups of male and female B6C3 mice were exposed to microencapsulated citral (greater than 96% pure) in feed for 2 years. Dose used in the 2 year study were 60 - 260 mg/kg to males and females.
Effects observed: Lower mean body weights in the treated group. The incidences of malignant lymphoma occurred with a positive trend in female mice, and the incidence in 2,000 ppm females was significantly greater than that in the vehicle control group. Tissues most commonly affected by malignant lymphoma were the spleen, mesenteric lymph node, thymus, and, to a lesser extent, the ovary.
Based on these results the LOAELs were determined to be 120 and 60 mg/kg bw/day (1000 and 500 ppm) for males and females respectively, based on reduced body weights.
- Endpoint:
- chronic toxicity: oral
- Remarks:
- combined repeated dose and carcinogenicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- June 1995 - September 1995
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
- Deviations:
- yes
- Remarks:
- (complete histopathology of all dose groups; no parameters of hematology, clinical chemistry or urinalyses measured)
- GLP compliance:
- yes
- Remarks:
- FDA GLP regulations
- 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: males ca. 120 g, females ca. 100 g
- Fasting period before study: no
- Housing: 2 or 3 males, or 5 females per cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 14 to 15 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 6 or 7, 1996 To: June 1-5 (males) or June 8-10 (females), 1998 - Route of administration:
- oral: feed
- Vehicle:
- other: microcapsules loaded with citral
- Details on oral exposure:
- DIET PREPARATION
- Rate of preparation of diet (frequency): every 4 weeks
- Mixing appropriate amounts with nonirradiated NTP-2000 feed: final concentrations of 0, 1000, 2000 or 4000 ppm citral were achieved by adding loaded and/or placebo microcapsules at a total concentration of 1.25% 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: 31.9 % citral (analytical method GC)
- Lot/batch no.: MRI 020196MC - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- periodic verification by GC
- Duration of treatment / exposure:
- 104-105 weeks
- Frequency of treatment:
- continuously
- Dose / conc.:
- 0 ppm
- Remarks:
- 0 mg/kg bw/day
- Dose / conc.:
- 1 000 ppm
- Remarks:
- 50 mg/kg bw/day (nominal)
- Dose / conc.:
- 2 000 ppm
- Remarks:
- 100 mg/kg bw/day (nominal)
- Dose / conc.:
- 4 000 ppm
- Remarks:
- 210 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 50
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: based on 14-week pre-study described in same study report
- Positive control:
- not necessary
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: day 8, 33, and every 4 weeks thereafter, at end of study
BODY WEIGHT: Yes
- Time schedule for examinations: day 0, 8, 33, and every 4 weeks thereafter, at end of study
FOOD CONSUMPTION AND COMPOUND INTAKE : weekly
- Food consumption for each cage determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes, approximately every 4 weeks for a 1-week period
- 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: No
CLINICAL CHEMISTRY: No
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
ORGAN WEIGHTS: No
HISTOPATHOLOGY: Yes
Complete histopathology performed on untreated controls, vehicle controls, and all dosed animals:
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 - Statistics:
- Probability of survival: product-limit procedure of Kaplan and Meier
dose-related effects on survival: Cox's method, Tarone's life table test
Body weight data: parametric multiple comparison procedures of Dunnett and Williams
Incidences of non-neoplastic lesions: Poly-3 test (Bailer and Portier, 1988) - Dose descriptor:
- LOAEL
- Effect level:
- 210 mg/kg bw/day (actual dose received)
- Sex:
- male/female
- Basis for effect level:
- other: decrease of mean body weight; dose corresponds to 4000 ppm in diet
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 100 mg/kg bw/day (actual dose received)
- Sex:
- male/female
- Basis for effect level:
- other: dose corresponds to 2000 ppm in diet
- Critical effects observed:
- not specified
- Conclusions:
- Based on the results of the study, the LOAEL and NOAEL were set at 210 mg/kg bw (4000 ppm) and 100 mg/kg bw (1000ppm) for males and females respectively, based on decreased body weight.
- Executive summary:
The substance Citral (Reaction mass of (E)-3,7-dimethylocta-2,6-dienal and (Z)-3,7-dimethylocta-2,6-dienal) has been tested in a study similar to OECD TG 453. Groups of male and female F344/N rats were exposed to microencapsulated citral (greater than 96% pure) in feed for 2 years. Doses used in rats in the 2 year study were 50 - 210 mg/kg to males and females.
Effects observed: Higher survival of all exposed groups of males compared to controls. Lower mean body weights in exposed groups. No neoplasms or non-neoplastic lesions were attributed to exposure to citral.
Based on these results the LOAEL and NOAEL were set at 210 mg/kg bw (4000 ppm) and 100 mg/kg bw (1000ppm) respectively for males and females, based on decreased body weights.
Referenceopen allclose all
Table 1: Survival, body weights, feed consumption, and organ weights of mice in the 14-week feed study of 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 | 33.2 +- 0.8 | 12.6 +- 0.7 | 4.4 | 4.5 | - | - |
3900 ppm | 10/10 | 28.1 +- 0.6b | 7.9 +- 0.6b | 4.6 | 5.0 | - | kidneyclivercthymusd |
7800 ppm | 10/10 | 25.6 +- 0.6b | 5.2 +- 0.4b | 4.3 | 5.9 | kidneybthymusa | heartckidneycliverclungd |
15600 ppm | 10/10 | 21.3 +- 0.6b | 1.3 +- 0.5b | 4.0 | 6.2 | kidneybliverbtestisbthymusa | heartckidneycliverc lungcthymusc |
31300 ppm | 6/10 | 17.1 +- 0.4b | -2.9 +- 0.4b | 4.1 | 6.2 | kidneybliverblungbtestisbthymusb | heartckidneycliverc lungcthymusd |
Females | |||||||
Vehicle control | 10/10 | 29.8 +- 0.7 | 13.4 +- 0.8 | 3.4 | 3.6 | - | - |
3900 ppm | 10/10 | 26.1 +- 0.4b | 9.5 +- 0.4b | 3.3 | 5.1 | - | heartckidneycliverc thymusd |
7800 ppm | 10/10 | 21.2 +- 0.4b | 4.2 +- 0.4b | 2.3 | 6.4 | - | heartckidneycliverc lungcthymusc |
15600 ppm | 10/10 | 18.2 +-0.2b | 1.4 +- 0.3b | 2.3 | 6.5 | kidneyb | heartckidneycliverc lungcthymusc |
31300 ppm | 10/10 | 16.2 +- 0.2b | -0.2 +- 0.2b | 2.1 | 5.3 | kidneybliverblunga | heartckidneycliverc lungcthymusc |
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"
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"
Table 1: Body weight data for mice in the 2-year feed study of citral
Sex |
Timepoint |
Vehicle control |
500 ppm |
1000 ppm |
2000 ppm |
|||
Av wt (g) |
Av wt (g) |
Rel wt (%)a |
Av wt (g) |
Rel wt (%)a |
Av wt (g) |
Rel wt (%)a |
||
m |
Mean w 1-13 |
25.3 |
25.2 |
100 |
24.7 |
98 |
24.2 |
96 |
Mean w 14-52 |
40.0 |
39.2 |
98 |
38.2 |
96 |
36.7 |
92 |
|
Mean w 53-101 |
46.6 |
44.9 |
96 |
43.5 |
93 |
40.5 |
87 |
|
Final w 102 |
45.9 |
42.8 |
93 |
41.6 |
91 |
38.6 |
84 |
|
f |
Mean w 1-13 |
21.1 |
20.9 |
99 |
21.0 |
100 |
20.5 |
97 |
Mean w 14-52 |
35.3 |
33.1 |
94 |
32.7 |
93 |
30.7 |
87 |
|
Mean w 53-101 |
44.3 |
41.1 |
93 |
39.6 |
89 |
36.3 |
82 |
|
Final w 101 |
47.1 |
42.9 |
91 |
41.4 |
88 |
36.6 |
78 |
a weight as % of control group’s weight
Table 2: Incidences of selected non-neoplastic lesions of the oral mucosa in mice in the 2 -year feed study of citral
Type of lesion | Vehicle control | 500 ppm | 1000 ppm | 2000 ppm | ||||
Incidence | Severity gradec | Incidence | Severity gradec | Incidence | Severity gradec | Incidence | Severity gradec | |
Males | ||||||||
Oral mucosa, inflammation | 12/50 | 1.8 | 16/50 | 1.9 | 21/50 | 1.9 | 21/50a | 1.5 |
Oral mucosa, ulcer | 9/50 | 1.8 | 8/50 | 1.6 | 12/50 | 1.4 | 10/50 | 1.6 |
Adrenal cortex, focal hyperplasia | 0/50 | 3/50 | 2/50 | 5/50d | ||||
Females | ||||||||
Oral mucosa, inflammation | 14/49 | 1.4 | 32/50b | 1.9 | 35/50b | 1.8 | 32/50b | 1.5 |
Oral mucosa, ulcer | 6/49 | 1.2 | 15/50b | 1.9 | 22/50b | 1.6 | 15/50a | 1.5 |
Bone, fibrosis | 11/49 | 22/50d | 21/50d | 18/50 | ||||
Kidney, nephropathy | 9/49 | 1.0 | 16/50 | 1.0 | 15/50 | 1.2 | 17/50a | 1.0 |
Kidney, renal tubule mineralization | 4/50 | 1.0 | 14/50a | 1.0 | 18/50b | 1.0 | 6/50 | 1.2 |
Significant changes in comparison to vehicle control: a significant increase, p<=0.05; b significant increase, p<=0.01; d significant increase, p not specified; relevance of findings is discussed in "Details on results"
c Grading of severity: 1=minimal, 2=mild
Table 1: Body weight data for rats in the 2-year feed study of citral
Sex |
Timepoint |
Vehicle control |
1000 ppm |
2000 ppm |
4000 ppm |
|||
Av wt (g) |
Av wt (g) |
Rel wt (%) |
Av wt (g) |
Rel wt (%) |
Av wt (g) |
Rel wt (%) |
||
m |
Mean w 1-13 |
249 |
248 |
100 |
244 |
98 |
241 |
97 |
Mean w 14-52 |
440 |
436 |
99 |
429 |
98 |
418 |
95 |
|
Mean w 53-101 |
483 |
478 |
99 |
473 |
98 |
453 |
94 |
|
Final w 101 |
479 |
470 |
98 |
461 |
96 |
440 |
92 |
|
f |
Mean w 1-13 |
157 |
155 |
99 |
155 |
99 |
151 |
96 |
Mean w 14-52 |
232 |
227 |
98 |
227 |
98 |
216 |
93 |
|
Mean w 53-101 |
311 |
301 |
97 |
299 |
96 |
270 |
87 |
|
Final w 101 |
335 |
326 |
97 |
323 |
96 |
298 |
89 |
Av wt: average weight
Rel wt: relative weight as % of the control group's weight
Table 2: Incidences of non-neoplastic lesions in the 2 -year feeding study with citral
Vehicle control | 1000 ppm | 2000 ppm | 4000 ppm | |
Type of lesion |
Incidence | Incidence | Incidence | Incidence |
Males | ||||
Kidney, renal tubule mineralization | 42/50 | 45/50 | 48/50 | 50/50 |
Females | ||||
Adrenal cortex, angiectasis | 1/50 | 1/50 | 3/50 | 10/50* |
Significant changes in comparison to vehicle control:
* significant increase, level of significance not specified
The evaluation of observed effects is discussed in "Details on results"
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- LOAEL
- 60 mg/kg bw/day
- Study duration:
- chronic
- Species:
- mouse
- Quality of whole database:
- comparable to guideline study with acceptable restrictions
- System:
- other: Body weight effects
- Organ:
- not specified
Repeated dose toxicity: inhalation - systemic effects
Link to relevant study records
- Endpoint:
- repeated dose toxicity: inhalation, other
- Remarks:
- inhalation during developmental toxicity study (GD 6-15)
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Remarks:
- Developmental toxicity study comparable to guideline study (OECD Guideline 414) with sufficient documentation, well documented
- Reason / purpose for cross-reference:
- reference to other study
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- other: OECD414
- Deviations:
- yes
- Remarks:
- Mortalities, clinical signs of intoxication, body weight gains and gross lesions were investigated as signs of maternal toxicity during a developmental toxicity study.
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratory, Inc. (Raleigh, NC, USA)
- Age at study initiation: 9-11 w
- Weight at study initiation: females ca. 230 g
- Fasting period before study: no
- Housing: individually
- Diet: ad libitum during non-exposure periods
- Water: ad libitum during non-exposure periods
- Acclimation period: 2 w
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +- 1
- Humidity (%): 31 +- 8
- Photoperiod (hrs dark / hrs light): 12/12 - Route of administration:
- inhalation
- Type of inhalation exposure:
- whole body
- Vehicle:
- other: nitrogen
- Remarks on MMAD:
- no data
- Details on inhalation exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Rochester-type stainless steel inhalation chambers of 1 cubic meter volume
- Method of conditioning air: filtered through coarse particulate and HEPA filters and an activated carbon cartridge
- System of generating particulates/aerosols: aerolization of liquid citral with a DeVilbiss Model 41 nebulizer using nitrogen as a carrier gas to prevent degradation, which had been observed during nebulization in the presence of air
- Temperature, humidity, pressure in air chamber: no data
- Air flow rate: not data
- Air change rate: 15 +- 3 changes/hr
- Method of particle size determination: cascade impactor; MMAD 4.2 µm, geometric standard deviation 1.9; about 90% of the aerosol with aerodynamic diameter < 10 µm
- Treatment of exhaust air: no data
TEST ATMOSPHERE
- Brief description of analytical method used: gas chromatography with flame ion detection
- Samples taken from breathing zone: not specified
VEHICLE
- Justification for use and choice of vehicle: to prevent degradation of citral
- Composition of vehicle: nitrogen - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analysis of vapour and aerosol samples indicated that citral purity degraded less than 5% with nitrogen nebulization, with only a slight entrichment of the neral isomer (< 3%) in the vapour phase Chamber vapour atmospheres sampled by cryogenic trapping. Sampling was performed at a flow rate of 400 mL/min for 25 min through two all-glass and teflon traps immersed in a dry-ice methanol bath. The tubes were rinsed with 10 mL of isopropanol containing n-octanol as internal standard. Analysis performed by gas chromatography and flame ion detection.
- Duration of treatment / exposure:
- 6 h/d, gestation day 6-15
- Frequency of treatment:
- daily
- Dose / conc.:
- 10 ppm
- Remarks:
- nominal conc. corresponding to 63 mg/m3 (=MW*ppm/24.1*1000); MW=152,2 g/mol
- Dose / conc.:
- 34 ppm
- Remarks:
- nominal conc. corresponding to 215 mg/m3 (=MW*ppm/24.1*1000); MW=152,2 g/mol
- Dose / conc.:
- 68 ppm
- Remarks:
- nominal conc. corresponding to 430 mg/m3 (=MW*ppm/24.1*1000); MW=152,2 g/mol
- No. of animals per sex per dose:
- 25
- Control animals:
- yes, sham-exposed
- Details on study design:
- - Dose selection rationale: highest selected to produce maternally toxic effects
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily
BODY WEIGHT: Yes
- Time schedule for examinations: days 0, 2 4, 6, 8 (exposure), 12, 16, 20 (post-exposure)
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: No
CLINICAL CHEMISTRY: No
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
FOOD CONSUMPTION: No data
WATER CONSUMPTION: No data - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: No data - Statistics:
- Maternal body weights and body-weight gains were analysed by a one-way analysis of variance (ANOVA), followed by a Dunnett's when applicable ( Steel and Torrie, 1960).
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Ocular opacity, difficulty in breathing during the exposure phase of the study indicating stress of severe respiratory tract irritation; normal breathing returned in most of affected animals by gestation day 20; other frequently observed clinical signs: nasal discharge, salivation, redness around eyes, discolored facial fur, scrubby hair coat
However, after completion of the exposure period recovery clinical signs of toxicity occurred. - Mortality:
- mortality observed, treatment-related
- Description (incidence):
- 68 ppm: moribund condition of 1/25 animals (killed on gestation day 17);
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- 68 ppm:
- Body weight loss during exposure period from gestation day (GD) 6 to 15; after exposure period body weight gain was comparable to other groups;
- Overall mean body weight (GD 20) significantly decreased
- Body weight gain (GD0-20) decreased by 39% compared to controls.
However, after completion of the exposure period recovery of body weight occurred. - Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Dose descriptor:
- NOAEC
- Effect level:
- 34 ppm
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- body weight and weight gain
- Remarks on result:
- other: corresponds to 215 mg/m3
- Dose descriptor:
- LOAEC
- Effect level:
- 68 ppm
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: severe respiratory tract irritation with reduced body weight gain and clinical signs as secondary effects in pregant rats; corresponds to 430 mg/m3
- Critical effects observed:
- not specified
- Conclusions:
- The results of the present study revealed no significant maternal toxicity or adverse developmental effects in rats exposed to citral vapour at concentrations up to 34 ppm (NOAEL: 215 mg/m3).
- Executive summary:
- The repeated dose inhalation toxicity of citral was evaluated based on maternal toxicity data from a OECD TG 414 developmental toxicity inhalation study in rats. Exposure atmospheres contained citral concentrations of 1, 3, 10 and 34 ppm (both as vapour), or 68 ppm (aerosol/vapour mixture) corresponding to 6, 19, 63, 215, 430 mg/m3. The exposure condition at 68 ppm comprised an aerosol/vapour mixture with the intention to produce signs of toxicity. Maternal toxicity was indicated at 68 ppm (430 mg/m3) by decreased body weights and by clinical signs as ocular opacity, breathing difficulty, nasal discharge and salivation. These signs of maternal toxicity were secondary to the stress produced by severe respiratory tract irritation, as recovery of body weight and clinical signs of toxicity occurred after completion of the exposure period. At 10 and 34 ppm, findings were incidental and not siginficantly different from control animals.
- Endpoint:
- sub-chronic toxicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Study period:
- 1993
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: See remarks:
- Remarks:
- Although this investigation has only been published as an abstract, additional data on the test conditions are available from a valid developmental toxicity study (Gaworski et al., 1992) from the same working group. The results on maternal toxicity in the developmental toxicity study confirm the test results of the repeated dose inhalation toxicity study. Acceptable restrictions in documentation are: number of exposed animals not given, no details on test results given; study acceptable for derivation of a NOAEL for local and systemic effects based on weight of evidence approach
- Reason / purpose for cross-reference:
- reference to other study
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- F344/N rats were expo 6 hrs/day for either 21 consecutive days at concentrations of 10 & 34 ppm, or 68 ppm, or for 13 weeks at concentrations of 1, 3, or 10 ppm. No mortalities occurred during the 21 day study. Investigated endpoints were mortality, body weight, organ weigths (13 week study only), signs of ocular, nasal and oral irritation, and histological examination of nose tissues, larynx, trachea and lungs. Reversibility was investigated after a 5-week recovery period.
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- not specified
- Route of administration:
- other: exposure to vapours for low concentrations; exposure to vapour/aerosol mixtures to achieve higher concentrations
- Type of inhalation exposure:
- whole body
- Vehicle:
- other: nitrogen
- Remarks on MMAD:
- MMAD / GSD: no data
- Details on inhalation exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION (Information taken from Gaworski et al., 1992)
- Exposure apparatus: Rochester-type stainless steel inhalation chambers of 1 cubic meter volume
- Method of conditioning air: filtered through coarse particulate and HEPA filters and an activated carbon cartridge
- System of generating particulates/aerosols: aerolization of liquid citral with a DeVilbiss Model 41 nebulizer using nitrogen as a carrier gas to prevent degradation, which had been observed during nebulization in the presence of air
- Temperature, humidity, pressure in air chamber: no data
- Air flow rate: not data
- Air change rate: 15 +- 3 changes/hr
- Method of particle size determination: cascade impactor; MMAD 4.2 µm, geometric standard deviation 1.9; about 90% of the aerosol with aerodynamic diameter < 10 µm
- Treatment of exhaust air: no data
TEST ATMOSPHERE
- Brief description of analytical method used: gas chromatography with flame ion detection
- Samples taken from breathing zone: not specified
VEHICLE
- Justification for use and choice of vehicle: to prevent degradation of citral
- Composition of vehicle: nitrogen - Analytical verification of doses or concentrations:
- yes
- Remarks:
- (Information taken from Gaworski et al., 1992)
- Details on analytical verification of doses or concentrations:
- Analysis of vapour and aerosol samples indicated that citral purity degraded less than 5% with nitrogen nebulization, with only a slight entrichment of the neral isomer (< 3%) in the vapour phase
Chamber vapour atmospheres sampled by cryogenic trapping. Sampling was performed at a flow rate of 400 mL/min for 25 min through two all-glass and teflon traps immersed in a dry-ice methanol bath. The tubes were rinsed with 10 mL of isopropanol containing n-octanol as internal standard. Analysis performed by gas chromatography and flame ion detection. - Duration of treatment / exposure:
- 21 days or 13 weeks
- Frequency of treatment:
- Daily for 21 days, 6 h/d
13 w, 5 d/w, 6 h/d
additional group with 5 week recovery period after the 13 week treatment - Dose / conc.:
- 10 ppm
- Remarks:
- 63 mg/m3
21 Days exposure - Dose / conc.:
- 34 ppm
- Remarks:
- 215 mg/m3
21 Days exposure - Dose / conc.:
- 68 ppm
- Remarks:
- 430 mg/m3
21 Days exposure - Dose / conc.:
- 1 ppm
- Remarks:
- 6 mg/m3, 13 week exposure
- Dose / conc.:
- 3 ppm
- Remarks:
- 19 mg/m3, 13 week exposure
- Dose / conc.:
- 10 ppm
- Remarks:
- 63 mg/m3, 13 week exposure
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice a day
BODY WEIGHT: Yes
- Time schedule for examinations: not specified
FOOD CONSUMPTION: No data
WATER CONSUMPTION: No data
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: No
CLINICAL CHEMISTRY: No
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No - Key result
- Dose descriptor:
- NOAEC
- Remarks:
- subchronic inhalation
- Effect level:
- 34 ppm
- Based on:
- test mat.
- Sex:
- not specified
- Remarks on result:
- other: 215 mg/m3
- Key result
- Dose descriptor:
- LOAEC
- Effect level:
- 68 ppm
- Based on:
- act. ingr.
- Sex:
- not specified
- Basis for effect level:
- body weight and weight gain
- clinical signs
- Remarks on result:
- other: 430 mg/m3
- Critical effects observed:
- not specified
- Conclusions:
- Based on the results of the present study the NOAEC for Citral is set to 34 ppm or 215 mg/m3 based on evident local irritation and systemic effects, i.e. body weight changes, observed at 68 ppm or 430 mg/m3.
- Executive summary:
To evaluate the potential toxic effects of inhaled citral, F344/N rats were expo 6 hrs/day for either 21 consecutive days at concentrations of 10 & 34 ppm, or 68 ppm, or for 13 weeks at concentrations of 1, 3, or 10 ppm. No mortalities occurred during the 21 day study. Rats exposed to 68 ppm citral displayed signs of severe ocular, oral & nasal irritation and had significantly reduced body weight gains compared to controls. Treatment related lesions consisted of dose-related chronic-active inflammation, hyperplasia, squamous metaplasia & goblet cell atrophy of the nasal respiratory epithelium. Animals exposed to 68 ppm citral also developed changes indicative of irritation in the tracheas and lungs, as well as corneal inflammation & ulceration. Exposure to citral for 13 wk at concentrations up to 10 ppm did not produce mortality or treatment related signs of tox. Body weight gains, clinical pathology indices and organ weight were not adversely affected by exposure. Rats exposed to 10 ppm citral developed minimal hyperplasia and squamous metaplasia of the laryngeal epithelium; however, these changes were completely reversed during a 5-wk recovery period. No significant lesions were observed in the rats exposed to 1 or 3 ppm citral.
Referenceopen allclose all
Table: Overview on findings in a subacute and a subchronic inhalation study
Exposure time |
Concen- tration (ppm) |
Mortality |
Body weight gain |
Organ weights |
Signs of irritation |
Histological findings |
|
Nasal respiratory epithelium |
Other |
||||||
21 d |
10a |
no |
No effect |
No data |
No effect |
Dose related increase of chronic active inflammation, hyperplasia, squamous metaplasia and goblet cell atrophyc |
No data |
34a |
no |
No effect |
No data |
No effect |
No data |
||
68b |
no |
Significant reduction |
No data |
Severe nasal, oral and ocular irritation; corneal inflammation and ulceration |
Signs of irritation in trachea and lungs |
||
13 w |
1a |
no |
No effect |
No effect |
No effect |
No effect |
No effect |
3a |
no |
No effect |
No effect |
No effect |
No effect |
No effect |
|
10a |
no |
No effect |
No effect |
No effect |
No effect |
Minimal hyperplasia and squamous metaplasia of the laryngeal epithelium |
|
13 w + 5 w recovery |
10 |
Effect in laryngeal epithelium fully reversible |
avapour concentration
bconcentration of vapour/aerosol mixture
cno information given from which concentration up effects have to be considered as significant and biologically relevant
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEC
- 215 mg/m³
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- Although the subchronic investigation has only been published as an abstract, additional data on the test conditions are available from a valid developmental toxicity study (Gaworski et al., 1992) from the same working group. The results on maternal toxicity in the developmental toxicity study confirm the test results of the repeated dose inhalation toxicity study. Acceptable restrictions in documentation are: number of exposed animals not given, no details on test results given; study acceptable for derivation of a NOAEL for local and systemic effects based on weight of evidence approach
- System:
- other: Body weight effects
- Organ:
- not specified
Additional information
Oral toxicity (similar to OECD TG 453 and OECD TG 408, Read across from Citral)
The source substance Citral (Reaction mass of (E)-3,7-dimethylocta-2,6-dienal and (Z)-3,7-dimethylocta-2,6-dienal) has been tested in a study similar to OECD TG 453. Groups of male and female F344/N rats and B6C3 mice were exposed to microencapsulated citral (greater than 96% pure) in feed for 14 weeks or 2 years. Dose used in rats were equivalent to 345-1,585 mg citral/kg body weight for males and 335- 2,125 mg/kg for females in the 14 week study and in the 2 year study 50 - 210 mg/kg to males and females. For mice the concentration of Citral in the diet was equivalent to average daily doses of approximately 745 - 8,110 mg/kg to males and 790 - 7,550 mg/kg to females in the 14 week study, and in the 2 year study 60 - 260 mg/kg to males and females.
2 Year study in mice and rats: Effects observed in the 2 year study in rats: higher survival of all exposed groups of males compared to controls. Lower mean body weights in exposed groups. No neoplasms or non-neoplastic lesions were attributed to exposure to citral. Effects observed in the 2 year study in mice: Lower mean body weights in treated group. The incidences of malignant lymphoma occurred with a positive trend in female mice, and the incidence in 2,000 ppm females was significantly greater than that in the vehicle control group. Tissues most commonly affected by malignant lymphoma were the spleen, mesenteric lymph node, thymus, and, to a lesser extent, the ovary. In the 2 year study, LOAELs were determined to be 120 and 60 mg/kg bw/day (1000 and 500 ppm) for males and females respectively, based on reduced body weights. The NOAEL was set at 60 mg/kg bw/day.
14 week study in mice and rats: Effects observed in 14 week study in rats: Lower mean body weights, and feed consumption. Males and females in the high dose group exhibited listlessness, hunched posture, absent or slow paw reflex, and dull eyes. Some evidence of forestomach epithelial hyperplasia and hyperkeratosis, bone marrow atrophy and hemorrhage, and nephrotoxicity was observed.
Effects observed in the 14 week study in mice:In the second week of the study, four males in the high dose group were killed moribund. Lower mean body weights. Mice in the mid and high dose groups were generally thin and lethargic. The incidences of ovarian atrophy were significantly increased in females exposed to mid and high doses.
Based on these results the LOAEL of rats at 14 weeks was set at 745 and 790 mg/kg bw (3900ppm) based on decreased body weight. At 2 years the LOAEL and NOAEL were set at 210 mg/kg bw (4000 ppm) and 100 mg/kg bw (1000ppm) respectively for males and females, based on decreased body weights. In mice the LOAELs at 14 weeks were determined at 345 and 335 mg/kg bw/day (3900ppm) in males and females respectively (based on decreased body weight).
Subchronic inhalation toxicity (Weight of evidence, Read across from Citral: Gaworski 1992,1993)
The repeated dose inhalation toxicity of Litsea Cubeba was evaluated based on Read across from the source substance Citral. A weight of evidence approach was used, including data from a 21-day and 13-week inhalation toxicity study (Gaworski 1993) and maternal toxicity data from a developmental toxicity study (Gaworski 1992).
Groups of F344 rats were exposed for 6 hrs/day for 21 days at concentration of 10 and 34 ppm (both as vapour, corresponding to 63 and 215 mg/m3 or 68 ppm (aerosol/vapour mixture, 430 mg/m3), or for 13 w, 5 days per week, at concentrations of 1, 3, or 10 ppm (all vapour atmospheres, corresponding to6, 19, 63 mg/m3). During the 21 day study, no mortalities occurred. Rats in the 68 ppm-dose group displayed some clinical signs such as: severe ocular, oral and nasal irritation (dose-related chronic-active inflammation, hyperplasia, squamous metaplasia and goblet cell atrophy of the nasal respiratory epithelium), and significantly reduced body weights. In the subchronic inhalation toxicity study there was no mortality and no treatment related signs of toxicity
These findings were supported by a developmental toxicity study, in which maternal toxicity was indicated at 68 ppm (430 mg/m3) by decreased body weights and by clinical signs as ocular opacity, breathing difficulty, nasal discharge and salivation. The maternal toxicity was considered secondary to the stress produced by severe respiratory tract irritation, as recovery of body weight and clinical signs of toxicity occurred after completion of the exposure period. Overall, the NOAEC has been set to 34 ppm or 215 mg/m3 based on evident local irritation and systemic effects, i.e. body weight changes, observed at 68 ppm or 430 mg/m3.
Justification for classification or non-classification
Based on the available read-across data for repeated dose toxicity, Litsea cubeba does not need to be classified for STOT-RE according to the classification criteria outlined in Annex I of 1272/2008/EC (CLP).
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.