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EC number: 203-766-6 | CAS number: 110-42-9
- 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
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Toxicity to reproduction
Administrative data
- Endpoint:
- screening for reproductive / developmental toxicity
- Remarks:
- based on test type (migrated information)
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- supporting study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: see 'Remark'
- Remarks:
- GLP - Guideline study, tested with the source substance methyl laurate (CAS 111-82-0). According to the ECHA guidance document ¿Practical guide 6: How to report read-across and categories (March 2010)¿, the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 000
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Methyl laurate
- EC Number:
- 203-911-3
- EC Name:
- Methyl laurate
- Cas Number:
- 111-82-0
- IUPAC Name:
- methyl laurate
- Details on test material:
- - Name of test material (as cited in study report): Methyl dodecanoate
- CAS-No. of test material (as cited in study report): 111-82-0
- Purity: 99.2 %
- Physical state: colorless liquid
- Lot/batch No.: GD01
- Stability under test conditions: verified
- Storage condition of test material: sealed at room temperature
Constituent 1
Test animals
- 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., Atsugi, Japan
- Age at study initiation: 10 weeks
- Weight at study initiation: males: 354 - 386 g, femalrs: 216 - 241 g
- Housing: stainless steel cage
- Diet (e.g. ad libitum): NMF from Oriental Yeast Co., Ltd
- Water (e.g. ad libitum): tap water
- Acclimation period: 15 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 ± 2 °C
- Humidity (%): 55 ± 10%
- Air changes (per hr): 15 times/hour
- Photoperiod (hrs dark / hrs light): 12/12 (light intensity 150 - 300 lux)
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
test substance was dsolved in corn oil. Dosing solutions ware prepared once or more a week, kept under seal, cool and dark until use and used within 7 days after preparation. 5 (w/v)% was confirmed to be stable for at least 8 days under cool and dark condition. - Details on mating procedure:
- - M/F ratio per cage: 1/1
- Length of cohabitation: max. 2weeks
- Proof of pregnancy: vaginal plug and sperm in vaginal smear referred to as day 0 of pregnancy
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): after 18 days of pregnancy, females wered caged in stainless cage with a nursing tray and nesting stuff (alfa dry).
- Any other deviations from standard protocol: - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analysis of the concentration was conducted using a sample by random-choice from each batch. Since 98.6 - 104% was shown as a result, it was confirmed that given amount of dodecanoic acid methyl ester was included.
- Duration of treatment / exposure:
- Females: 14 days before mating until day 3 of lactation (41 - 55 days)
Males: 45 days - Frequency of treatment:
- Daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 250, 500 and 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:
- - The animals were mated.
- Terminal kill was on day 45 for males and on day 4 of lactation for females.
- Dose selection rationale: A preliminary test was performed to determin dose. Dose group were 0, 250, 500, 750 and 1000 mg / kg for 14 consecutive days in males and females, and the general condition showed no effect relevant to test substance, deaths were also not observed. No change were observed in weight, food consumption, autopsy findings, organ weights, blood chemistry test and hematology test.
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily
BODY WEIGHT: Yes
- Time schedule for examinations: Males on days 1, 8, 15, 22, 29, 36 and 43 of administration; Females on days 1, 8 and 15 before mating, on days 0, 7, 14 and 21 of gestation and on days 0 and 4 of Lactation
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No
- Time schedule: days 1-8, 8-15, 22-29, 29-36, 36-43 and 43-45 in male animals; days 1-8, 8-15 before mating, days 0-7, 7-14 and 14-21 of gestation and during days 0-4 of lactation in females.
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: At autopsy
- Anaesthetic used for blood collection: Yes (ether):
- Animals fasted: Yes (16 hours)
- How many animals: 12 males per dose
- Parameters checked: Hct, Hgb, RBC, MCV, MCH, MCHC, PLT, WBC, Differential leukocyte counts.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At autopsy
- Animals fasted: Yes (16 hours)
- How many animals: 12 males per dose
- Parameters checked: Total protein, albumin, A/G, glucose, BUN, creatinine, total cholesterol, GOT, GPT, gamma-GTP, total bilirubin, pottasium, chloride, calcium, inorganic phosphorus
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
ORGAN WEIGHTS: Yes, absolute and relative weights
- How many animals: 10- 12 animals per dose
- Organs: Thymus, Liver, Kidneys, testes, epididymides, ovaries, lung - Oestrous cyclicity (parental animals):
- observed
- Sperm parameters (parental animals):
- not observed
- Litter observations:
- PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain
GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was/was not determined for pups born or found dead. - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals on day 45.
- Maternal animals: All surviving animals at day 4 of lactation.
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
HISTOPATHOLOGY / ORGAN WEIGHTS
Males in control and highest dose group, successful pregnancy: brain, thymus, heart, lungs, liver, kidney, spleen, testis and adrenal gland
Females in control and highest dose group at day 4 of lactation: brain, thymus, heart, lungs, liver, kidney, spleen, adrenal and ovarian
Non-pregnancy females and not fertile males: brain, thymus, heart, lungs, liver, kidney, spleen, adrenal glands, vagina, uterus, ovary, testis, epididymis, seminal vesicles, prostate and pituitary gland
Females with all dead pups: skin, breast, lymph nodes, salivary glands, sternum, femur (including marrow), thymus, trachea, bronchi and lungs, heart, thyroid and parathyroid glands, tongue, esophagus, stomach, duodenum, small intestine, large intestine, liver, pancreas, spleen, kidney, adrenal gland, bladder, ovaries, uterus, vagina, eye, Harderian gland, brain, spinal cord and pituitary gland - Postmortem examinations (offspring):
- SACRIFICE
- Four days after birth
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
HISTOPATHOLOGY
- Performed but detail information is not stated. - Statistics:
- Barlett test, One-way ANOVA, Kruskal-Wallis test, Dunnett test, Scheffe test, chi-square test
- Reproductive indices:
- coupulation index, fertility index, gestation index, implantation index, delivery index
- Offspring viability indices:
- live birth index, viability index on day 4, type and incidence of external anomalies
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Other effects:
- not specified
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- not specified
- Reproductive performance:
- no effects observed
Details on results (P0)
Mortality were not observed in either group throughout the treatment period both sexes. The anomaly of a tooth in a male of the control group (fracture of incisors) was observed in 5-7 days administered, alopecia on a neck of a male in 250 mg/kg on days 10-19 and crusting in the same male on days 20 - 21, alopecia on a neck of another male in 250 mg/kg on days 2 - 46 and trauma on the same male on days 4 - 13 and crusting on the same male on days 14 - 46. For females, any abnormal were not observed throughout treatment. But this change was regarded as non-relevant effect.
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Difference between treatment groups and the control group throughout the treatment period was not observed in both sexes.
REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
No defference was observed.
REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
Not determined.
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
Reproductive performance displayed no significant changes between treatment groups and controls (estrous cycle, copulation index, fertility index, gestation length, gestation index, delivery conditions, or implantation index). In control group and 1000 mg / kg, since there was bias of the number of male and female infants, sex ratio was defference between in these groups. Since many pups died before day four of lactation in the control group, number of total live female pups were significant different between the control group and 1000 mg/kg group. But no difference was found in delivery, pregnant duration, the number of corpora lutea, number of implantation scars, and fetal birth of live or dead pups, the birth rate, implantation rate, delivery percentage and fertility rate.
ORGAN WEIGHTS (PARENTAL ANIMALS)
In males 1000 mg/kg group, actual weight of the thymus was heavier compared to control group. But this change was regarded as non-relevant effect because no difference was observed in female groups.
GROSS PATHOLOGY (PARENTAL ANIMALS)
In fertile males, lung colored spots / areas (gray) and white spots / areas were oberved in two animals in control group, the red spots / areas in the lung in a few cases including the control group and administration group, the thymus red spot / area was observed in 2 animals in 500 mg/kg, skin colored spots / areas (gray) was observed in one animal in 250 mg/kg, respectively. In naturally delivered females, atrophy of the thymus, spots of color / area (brown) in the lungs, changing into black and atrophy of the large intestine, white spots / areas in the liver, cysts of the ovary and scarring of the kidney were found in each administration including the control group. These changes were considered to be not toxicologically relevant, since these were regarded as natural change due to frequency. Two animals in 250 mg/kg in both sexes were not successfully pregnancy but showed no abnormal findings. The two animals, whose all pups died before day 4 of lactation, were observed in control group and one case showed red eye in the retina.
HISTOPATHOLOGY (PARENTAL ANIMALS)
In the fertile male, granuloma of the liver lesion, basophilic tubules of the kidney, acidophilic bodies appearance in the kidney and vacuolate adrenal glands were observed. No abonormality was observed in thymus in 1000 mg/kg, where increase of organ weights was obsereved. In females delivered naturally, pigmented spleen, aggregated macrophages in the lungs, focal granulomas in the liver, basophilic tubules and vacuolation of the kidney were observed in each group.
In two cases in the control group, whoses pups were dead before day 4 of lactation, mammary gland hyperplasia, accumulations of macrophages, blood vessel expansion arteritis of the uterus were observed. One case had bleeding in the retina of the eye locally.
A non-reproducible male in 250 mg/kg showed sperm granulomas of the epididymis.
These changes were considered to be not toxicologically relevant, since there were no difference of the number of occuarance between each group.
Effect levels (P0)
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no effects on: estrous cycle, copulation index, fertility index, gestation length, number of corpora lutea or implantation, implantation index, delivery index or parturition.
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- not specified
Details on results (F1)
no difference was observed.
CLINICAL SIGNS (OFFSPRING)
2 case of hypodermic hmorrhage, 1 case of imperforate anus and 1 case of rudiment tail were observed in control group, 1 case of nanooffspring was in 250 mg/kg, 1 case of short tail was in 500 mg/kg.
BODY WEIGHT (OFFSPRING)
Rgarding weight, no difference was observed.
SEXUAL MATURATION (OFFSPRING)
not determined
ORGAN WEIGHTS (OFFSPRING)
not determined
GROSS PATHOLOGY (OFFSPRING)
At autopsy, thymic remnant in the neck was observed in control group, 250 mg/kg and 1000 mg/kg, diaphragmatic hernia was observed in two dead pups in 500 mg/kg.
HISTOPATHOLOGY (OFFSPRING)
not performed
Effect levels (F1)
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no effects on live birth index, viability index on day 4,
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
Table 1:
Summary of reproductive performance in rats treated orally with Methyl dodecanoate in the combined repeated dose and reproductive/developmental toxicity screening test
Dose level |
0 mg/kg |
250 mg/kg |
500 mg/kg |
1000 mg/kg |
No. of pairs mated |
12 |
12 |
12 |
12 |
No. of pairs copulated |
12 |
12 |
12 |
12 |
No. of pregnant females |
12 |
10 |
12 |
12 |
Copulation index (%) |
100 % |
100 % |
100 % |
100 % |
Fertility index (%) |
100 % |
100 % |
100 % |
100 % |
Estrus cycle (days, mean) |
4.5 |
4.6 |
4.5 |
4.7 |
Table 2
Findings of delivery in dams treated orally with Methyl dodecanoate and observations on their pups (F1) in the combined repeated dose and reproductive/developmental toxicity screening test
Dose level |
0 mg/kg |
250 mg/kg |
500 mg/kg |
1000 mg/kg |
No. of dams observed |
12 |
10 |
12 |
12 |
No. of dams delivered live newborns |
12 |
10 |
12 |
12 |
Duration of gestation (mean) |
22.9 |
22.6 |
22.6 |
22.4 |
No. of corpora lutea (mean) |
221 (18.4) |
168 (16.8) |
204 (17.0) |
209 (17.4) |
No. of total implants (mean) |
188 (15.7) |
161 (16.1) |
173 (14.4) |
180 (15.0) |
No. of total pups born (mean) |
171 ( 14.3) |
147 (14.7) |
157 (13.1) |
163 (13.6) |
No. of total live pups born (mean) |
170 (14.2) |
146 (14.6) |
156 (13.0) |
163 (13.6) |
No. of total live pups on day 4 |
|
|
|
|
Male |
84 (7.0) |
72 (7.2) |
71 (5.9) |
64 (5.39 |
Female |
57 (4.8) |
61 (6.1) |
81 (7.4) |
97 (8.1)* |
No. of total dead pups born |
1 (0.1) |
1 (0.1) |
1 (0.1) |
0 (0.0) |
stillbirth |
0 (0.0) |
1 (0.1) |
1 (0.1) |
0 (0.0) |
cannibalism |
1 (0.1) |
0 (0.0) |
0 (0.0) |
0 (0.0) |
Gestation index (%) |
100 % |
100 % |
100 % |
100 % |
Implantation index (%) |
84.0 |
95.9 |
85.2 |
86.7 |
Delivery index (%) |
89.8 |
91.2 |
88.9 |
90.6 |
Live birth index (%) |
99.5 |
99.4 |
99.5 |
100.0 |
Viability index on day 4 |
|
|
|
|
Male |
76.7 |
91.3 |
97.8 |
95.1 |
Female |
78.2 |
94.5 |
97.5 |
100.0 |
* Significantly different from control p < 0.05
Applicant's summary and conclusion
- Conclusions:
- In the Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test an oral NOAEL of 1000 mg/kg bw/day was found for male and female rats. There were no effects of the test substance on the oestrous cycle, copulation index, fertility index, gestation length, number of corpora lutea or implantation, implantation index, delivery index or parturition.
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