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EC number: 219-194-5 | CAS number: 2385-77-5
- 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
![](https://echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Toxicity to reproduction
Administrative data
- Endpoint:
- one-generation reproductive toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Justification for type of information:
- REPORTING FORMAT FOR THE ANALOGUE APPROACH
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
See read across justification document
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See read across justification document
3. ANALOGUE APPROACH JUSTIFICATION
See read across justification document
4. DATA MATRIX
See read across justification document
Cross-reference
- Reason / purpose for cross-reference:
- read-across source
Reference
- Endpoint:
- one-generation reproductive toxicity
- Remarks:
- based on generations indicated in Effect levels (migrated information)
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Study performed according to Guideline 421 with acceptable restrictions: only summary report available; study acceptable for assessment
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- yes
- Remarks:
- (no gross examination of pups)
- GLP compliance:
- yes
- Species:
- rat
- Strain:
- other: Sprague-Dawley Crj:CD(SD)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Japan, Inc.
- Age at study initiation: (P) 10 wks
- Fasting period before study:
- Housing: Metal bracket typed wire mesh floor gauge; stainless tray with floor materials for experimental animals(White flakes Charles River Laboratories Japan, Inc. ), was used for pregnant rats after Day 17 day of their pregnancy.
- Use of restrainers for preventing ingestion (if dermal): yes/no
- Diet: Solid feed (CRF-1, Oriental Yeast Co., Ltd.); ad libitum
- Water: Tap water, ad libitum
- Acclimation period: 14 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23+/-3
- Humidity (%): 55+/-10
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/23 - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
The solution prepared was found to be stable for 5 hours after the preparation. Accordingly, the
solution was prepared everyday at the time of use.
VEHICLE
- Amount of vehicle (if gavage): 5 ml/kg - Details on mating procedure:
- - M/F ratio per cage: 1/1
- After successful mating each pregnant female was caged (how): 1 female rat/cage
- Length of cohabitation: up to 14 days
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy.
Confirmation of pregancy, if implantations were found in the uterus - Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- Premating exposure period: 14 d
Total exposure period: males 46 d, females from 14 d before mating up to day 3 of lactation - Frequency of treatment:
- daily
- Details on study schedule:
- Terminal killing: males on day 47; females on day 4 of lactation
No further data available - Remarks:
- Doses / Concentrations:
40, 200, 1000 mg/kg bw/day
Basis:
actual ingested - No. of animals per sex per dose:
- 12
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:
Dose finding study and literature. - Positive control:
- not applicable
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: yes; daily observations
DETAILED CLINICAL OBSERVATIONS: yes; daily observations
BODY WEIGHT: Yes
- Time schedule for examinations: during 14 day premating period on days 1, 2, 5, 7, 10 and 14; males thereafter weekly and on day 46; females on day 0, 1, 3, 5, 7, 10, 14, 17 and 20 of gestation, and on lactation day 0, 1, and 4.
Body weight change was calculated; males: between Day 1 and Day 46 of administration; females: between Day 1 and Day 14 (premating), Day 0 and Day 20 (gestation), and Day 0 and Day 4 (lactation).
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Time schedule for examinations: on same day as body weight determinations except for Day 0 of pregnancy and Day 0 of lactation. - Oestrous cyclicity (parental animals):
- From all the females, vaginal smear samples were collected on the successive days
from Day 10 before administration to Day of successuful mating and stained with
Giemsa solution to determine their estrous cyclicity phase (Proestrus, early estrus, late
estrus, or anestrum) as well as checking for any irregularity (normal, continuing
anestrum, or irregular) under the light microscope. - Sperm parameters (parental animals):
- not assessed
- Litter observations:
- PARAMETERS EXAMINED:
Number of pups born,
Number of life pups born,
Number of dead pups born,
Sex of pups born
All newborns were observed for its survival or death, general conditions, and appearance once a day from the last day of delivery until the day of necropsy (Day 4 of lactation). Body weight was measured on Days 0, 1 and 4 of nursing and the mean value per litter was obtained respectively for males and females.
GROSS EXAMINATION OF DEAD PUPS:
Dead pups were immediately necropsied. - Postmortem examinations (parental animals):
- SACRIFICE
via exsanguination under ether anesthesia
- Male animals: All surviving animals on day 47.
- Maternal animals: All surviving animals on day 4 of lactation or Day 26 of pregnancy (if no delivery until Day 25 of pregnancy) or immediately
after finding any dead pups.
For males and females with unsuccessful copulation: on the next day after the mating period.
GROSS NECROPSY
no data given
ORGAN WEIGHTS
Absolute and relative weights of testis, epididymis, ovary (each right and left). Absolute weight was divided by the body weight on the necropsy day, and then multiplied by 100 to calculate the relative weight. For pregnant females, the number of implantations and corpus luteum of pregnancy were
counted.
HISTOPATHOLOGY
Main organs and tissues (not further specified), stomach (glandular stomach, forestomach and border), testis, epididymis and ovaries.
Samples were paraffin-embedded and stained with hematoxylin-eosin. - Postmortem examinations (offspring):
- Pups were observed for external body surface (including inside the mouth), and euthanized by CO2 inhalation method on Day 4 of lactation. Organs and tissues throughout the body were macroscopically observed.
- Statistics:
- Bartlett assay. If the results had equal variance, one-way analysis of variance method and Dunnett method was conducted.
If the results had unequal variance, Kruskal-Wallis method and Mann–Whitney U test was performed:
Body weight, increase in body weight and increase rate of body weight, food consumption, absolute organ weight and relative organ weight,
number of corpora lutea, number of implantation sites, implantation index, total number of pups born, number of live pups born, delivery index,live birth index, sex ratio, number of dead pups born, gestation length, number of live pups on Day 4 of nursing, and viability index on day 4.
Kruskal-Wallis method and Mann–Whitney U test was performed:
Histopathology
Multisample X2 test was performed and Two sample X2 test was performed. However, when results failed the Multi-sample X2 test or Two-sample X2 test, then Fisher’s exact test was used:
Estrous cyclicity, copulation index, Fertility index, birth index and nursing index. - Reproductive indices:
- Copulation index [(Number of pairs with sucessful copulation/Number pairs mated) x100]
Fertility index [(Number of pregnant females/Number of pairs with sucessful copulation) x100]
Implantation index [(Number of implantation sites in the uterus/Number of corpora lutea)x100]
Birth index [(Number of females with live pups delivered/Number of corpora lutea)x100]
Delivery index [(Number of pups born/Number of implantation sites)x100],
Live birth index [(Number of live pups born/number of pups born)x100],
Gestation index [(Number of females with live pups delivered/number of pregnant females)*100]
Nursing index [(Number of females with nursing live pups/Number of females with normal delivery)x100]
Sex ratio [Number of male pups/Number of female pups]
Gestation length [Number of days from Day 0 of pregnancy until Day 0 of nursing(last day of delivery)]
For all the mated females, delivery condition and maternal behavior were observed from Day 21 of pregnancy until the last day of delivery. - Offspring viability indices:
- Viability index on day 4 [(Number of live pups on day 4/Number of live pups born) x100]
- Dose descriptor:
- NOAEL
- Remarks:
- parental toxicity
- Effect level:
- 200 mg/kg bw/day
- Sex:
- male/female
- Basis for effect level:
- other: decreased body weight and food consumption, histopathology of forestomach
- Dose descriptor:
- NOAEL
- Remarks:
- Reproductive toxicity
- Effect level:
- 1 000 mg/kg bw/day
- Sex:
- male/female
- Basis for effect level:
- other: NOAEL = highest tested dose
- Dose descriptor:
- NOAEL
- Remarks:
- developmental toxicity
- Generation:
- F1
- Effect level:
- 200 mg/kg bw/day
- Sex:
- male/female
- Basis for effect level:
- other: decreased postnatal body weight gain
- Reproductive effects observed:
- not specified
Males showed no abnormalities in any dose group.
One of the females in the 1000 mg/kg group showed a temporal decrease in locomotor activity on Day 7 of administration. Another female showed temporal salivation on Day 9 and Day 10 of gestation.
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
1000 mg/kg bw/d - males:
- body weight: from day 5 to 46 lower body weight than control group
- mean terminal body weight on day 46: 475.8 g compared to 502.5 g in controls, decrease of 5.3 % (no significant difference)
- A significantly reduced body weight gain was observed (no further data).
- food consumption: significant decrease on day 5 only, on other days comparable or higher than in control group
1000 mg/kg bw/d - females:
- body weight: comparable to control during premating period; lower body weight during gestation and lactation period
- mean terminal body weight on lactation day 4: 313.8 g compared to 325.3 g in controls, decrease of 3.7% (no significant difference)
- A significantly reduced body weight gain was observed during gestation (no further data).
- food consumption: significant decrease on day 5 of the premating period, further non-significant decrease on gestation day 10,
on other days comparable or higher than in control group
Other dose groups - both sexes:
- Body weights: comparable or higher than in the control groups
- Food consumption: Significantly lower food consumption was observed on Day 5 (premating) and Day 4 of lactation. For other timepoints, no consistent trend was observed compared to controls.
REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
During the administration period 1/12 females showed abnormal continuous diestrum in the 40 and 1000 mg/kg-groups; no effects in control or 200 mg/kg-group. Alternations observed are not considered to have any relation to the administration of the test substance.
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
1000 mg/kg bw/d:
- 2/12 females were not pregnant (not significant)
- Number of total dead pups born: 6 (not significant compared to control group, i.e. 14 dead pups born)
40 mg/kg bw/d:
- 3/12 females were not pregnant (not significant)
- Non successful copulation 1/12 females (not significant)
- implantation index significantly increased compared to control
- Number of total dead pups born: 5 (not significant compared to control group, i.e. 14 dead pups born)
Other dose groups and parameters: no significant effects compared to controls
GROSS PATHOLOGY (PARENTAL ANIMALS)
1000 mg/kg group:
2/12 males showed pyelectasia, 1/12 males showed testicular and epididymis atrophy, and 1 infertile male showed yellow-white masses in epididymis. All of which were observed unilaterally.
Partial thickening of the gastric mucosa in 10/12 females and 1/21 showed dark reddening of caudate lobe in the liver.
ORGAN WEIGHTS (PARENTAL ANIMALS)
No significant changes of absolute or relative weights of testis, epididymis or ovaries
HISTOPATHOLOGY (PARENTAL ANIMALS)
- Male reproductive organs:
1000 mg/kg bw/d: testis: 2/12 with tubular atrophy (grading: 1 slight, 1 severe unilateral);
epididymis: 2/12 with decreased intraductal sperm (grading: 1 slight, 1 severe), 1/12 with slight spermatic granuloma
Controls: testis: 1/12 with tubular atrophy (grading: slight);
Other dose groups: no adverse effects observed
- Findings in forestomach:
1000 mg/kg bw/d - males: 2/12 with slight squamous hyperplasia
1000 mg/kg bw/d - females: 10/12 with squamous hyperplasia (4/12 slight, 6/12 moderate effect), control 1/12 with slight effect;
2/12 with ulceration, 2/12 with neutrophil cellular infiltration and 6/12 with granulation in the lamina propria,
Other dose groups and controls: no changes
- Findings in liver:
1000 mg/kg bw/d - females: 1/1 with centrilobular necrosis (no further females examined) confirmation of necropsy findings, i.e. dark reddening of caudate lobe in the liver
All groups - males: no adverse effects observed
Viability index in dosed animals was slightly higher than in controls (not significant)
BODY WEIGHT (OFFSPRING)
1000 mg/kg bw/d - both sexes: significant decrease on day 0, 1, 4 after birth compared to control (see Table 1)
GROSS PATHOLOGY (OFFSPRING)
200 mg/kg bw/day: 1 case of pyelectasia and 2 cases of ureter dilatation
40 mg/kg bw/day: 2 cases with injuries to the tail and dark reddening
Table 1: Body weights of pups
Sex |
Day after birth |
Dose group |
|||
0 |
40 |
200 |
1000 |
||
male |
0 |
6.81 ± 0.48 |
6.62 ± 0.64 |
6.43 ± 0.82 |
5.88 ± 0.56 a |
1 |
7.52 ± 0.58 |
7.50 ± 0.71 |
7.08 ± 1.11 |
6.31 ± 0.77 a |
|
4 |
10.77 ± 0.80 |
10.88 ± 1.34 |
10.24 ± 1.87 |
8.77 ± 0.84 a |
|
female |
0 |
6.33 ± 0.61 |
6.34 ± 0.63 |
6.04 ± 0.80 |
5.34 ± 0.70 a |
1 |
7.09 ± 0.71 |
7.07 ± 0.69 |
6.61 ± 1.13 |
5.69 ± 0.97 a |
|
4 |
10.08 ± 0.99 |
10.32 ± 1.50 |
9.71 ± 1.81 |
7.98 ± 1.15 a |
significantly different from control group: a P < 0.01
Data source
Materials and methods
Test material
- Reference substance name:
- Citronellal
- EC Number:
- 203-376-6
- EC Name:
- Citronellal
- Cas Number:
- 106-23-0
- Molecular formula:
- C10H18O
- IUPAC Name:
- 3,7-dimethyloct-6-enal
Constituent 1
Results and discussion
Results: P0 (first parental generation)
Effect levels (P0)
open allclose all
- Dose descriptor:
- NOAEL
- Remarks:
- parental toxicity
- Effect level:
- 200 mg/kg bw/day
- Sex:
- male/female
- Basis for effect level:
- other: decreased body weight and food consumption, histopathology of forestomach
- Dose descriptor:
- NOAEL
- Remarks:
- Reproductive toxicity
- Effect level:
- 1 000 mg/kg bw/day
- Sex:
- male/female
- Basis for effect level:
- other: NOAEL = highest tested dose
Results: F1 generation
Effect levels (F1)
- Dose descriptor:
- NOAEL
- Remarks:
- developmental toxicity
- Generation:
- F1
- Effect level:
- 200 mg/kg bw/day
- Sex:
- male/female
- Basis for effect level:
- other: decreased postnatal body weight gain
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Applicant's summary and conclusion
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.
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