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EC number: 229-114-0 | CAS number: 6413-10-1
- 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)
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 21 February 2013 to 6 June 2013
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 013
- Report date:
- 2013
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- other: OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- Ethyl 2-methyl-1,3-dioxolane-2-acetate
- EC Number:
- 229-114-0
- EC Name:
- Ethyl 2-methyl-1,3-dioxolane-2-acetate
- Cas Number:
- 6413-10-1
- Molecular formula:
- C8H14O4
- IUPAC Name:
- ethyl 2-(2-methyl-1,3-dioxolan-2-yl)acetate
- Details on test material:
- - Name of test material (as cited in study report): Methyl Dioxolan
- Appearance: colourless liquid
- Storage condition of test material: room temperature protected from light
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Strain: Crl CD®(SD) IGS BR
- Age at study initiation: 10 weeks old (males); 9 weeks old (females)
- Weight at study initiation: 323 - 409 g (males); 204 - 277 g (females)
- Housing: Individually housed (except during mating) in polycarbonate cages with stainless steel lids and containing autoclaved sawdust.
- Diet: ad libitum
- Water: filtered tap water (0.22 µm filter), ad libitum.
- Acclimation period: 6 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2 °C
- Humidity (%): 50 ± 20 %
- Air changes (per hr): approximately 12 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours dark / 12 hours light
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Remarks:
- drinking water treated by reverse osmosis
- Details on exposure:
- PREPARATION AND ADMINISTRATION OF DOSING SOLUTIONS
Test material was formulated in vehicle at the required concentrations. The quantity of dose formulation administered to each animal was adjusted according to the most recently recorded body weight.
A constant dose volume of 10 mL/kg/day was used.
Control animals (group 1) received vehicle only. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The concentration of test material in the dose formulations was analysed by GC-FID.
- Instrumentation: Varian Gas Chromatography system with FID detector
- Chromatographic conditions:
Column: HP-ULTRA (Agilent) 50 m x 0.32 mm (0.52 µm)
Mobile phase: hydrogen
Sensitivity: 12
Column temperature: from 70°C to 300°C at 10°C/min
Constant flow rate: 2 mL/min
Split rate: 10
Software: Empower 2 (Waters)
Detector temperature: 300°C
Injector temperature: 250°C
Injected volume: 2 µL
Detector gas flows: 30 mL/min for make up; 30 mL/min for hydrogen and 300 µL/min for air
Retention time: 8.4 min (test material); 8.8 min (internal standard)
Standard solutions of test material were prepared. An internal standard (1,4 diisopropylbenzene) was used to correct the injection variability.
- Preparation of Standard Solutions
Stock solutions of test material in diluent were prepared at 0.2, 0.02 and 0.0015 mg/mL.
- Preparation of Internal Standard
A solution of 1,4-diisopropylbenzene in methanol was prepared at 10 µg/mL.
ANALYTICAL METHOD
1 mL of dose formulation was diluted with diluent to reach the nominal concentration for injection. The diluted samples were analysed by GC-FID, bracketed by standard solutions and quantified by the mean response factors calculated for the standard solutions. The internal standard was used to correct the injection variability.
ANALYSIS OF DOSE FORMULATIONS
The test material concentrations in the administered dose formulations analysed in weeks 1, 4 and 6 remained within an acceptable range of -4.4 to +8.69 % when compared to the nominal values. Test material was not detected in the control samples. - Details on mating procedure:
- Females were paired with males from the same dose level group. One female was placed with one male, in the latter's cage, during the night. Sibling pairings were avoided.
Confirmation of mating was made in the morning by checking for the presence of a vaginal plug or for sperm in a vaginal lavage. The day of confirmed mating was designated day 0 post coitum.
Each female was placed with the same male until mating occurred or 14 days had elapsed. - Duration of treatment / exposure:
- Males received dose formulations for 2 weeks before pairing, during the 2 week pairing period, until sacrifice (at least 5 weeks in total). Females received dose formulations for 2 weeks before mating, during the 2 week pairing period, during gestation, and during lactation until day 5 post partum inclusive (or until sacrifice).
- Frequency of treatment:
- Daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0 (vehicle control), 100, 300, 1000 mg/kg bw/day
Basis:
actual ingested
- No. of animals per sex per dose:
- 10 males and 10 females per dose.
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: the selected dose levels were based on results of previous studies 2 acute oral studies where the LD50 values were > 5000 mg/kg and a 2-week preliminary toxicity study, by the oral route, in rats in which no animals died at dose levels up to 1000 mg/kg bw/day, however, some clinical signs were noted.
- Rationale for animal assignment: during the acclimation period, the required number of animals was selected according to body weight and/or clinical condition. The animals were allocated to groups (by sex) according to a computerised stratification procedure based on body weight, so that the average body weight of each group was similar.
Therefore, 1000 mg/kg/day was selected as the high dose-level for this study. Mid and low dose-levels were selected in order to cover approximately 3-fold intervals.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: mortality and morbidity was checked once daily before the treatment period and at least twice a day during the treatment period. General clinical observations were performed once a day after treatment at approximately the same time.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once before the beginning of the treatment period and weekly thereafter, observations were performed on all animals outside the home cage in a standard arena.
- Observations included (but were not limited to): changes in fur, skin, eyes, mucous membranes, occurrence of secretions and excretions and autonomic activity (e.g. lacrimation, piloerection, pupil size, unusual respiratory pattern). Changes in gait, posture and response to handling as well as the presence of clonic or tonic movements, stereotypes (e.g. excessive grooming, repetitive circling) or bizarre behaviour (e.g. self-mutilation, walking backwards) were also recorded.
BODY WEIGHT: Yes
- Time schedule for examinations: males were weighed on the first day of treatment and weekly thereafter until sacrifice. Females were weighed on the first day of treatment then weekly until mated (or until sacrifice) and on days 0, 7, 14 and 20 post coital and days 1 and 5 post partum.
Bodyweight gain was calculated for selected intervals and for the overall study.
FOOD CONSUMPTION: Yes
- Food consumption by each male was measured once a week, over a 7-day period, from the first day of treatment until the start of the pairing period. The measures coincided with body weight measurements.
The quantity of food consumed by each female was measured once a week, over a 7-day period, from the first day of treatment until the start of the pairing period, during pregnancy at the intervals days 0-7, 7-14 and 14-20 p.c. and during lactation for interval days 1-5 post partum.
During the pairing period, the food consumption was measured for neither males nor females.
Food intake per animal and per day was calculated by noting the difference between the food given and that remaining in the food-hopper at the next filling.
WATER CONSUMPTION: No
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 6
> Macroscopic examination: A complete macroscopic examination was performed. This included examination of the external surfaces, all orifices, the cranial cavity, the external surfaces of the brain and spinal cord, the thoracic, abdominal and pelvic cavities/muscles with their associated organs and tissues and the neck with its associated organs and tissues. All gross lesions were recorded and preserved.
> Organ Weight: The body weight of each animal sacrificed as scheduled was recorded before sacrifice.The wet weights of the following were recorded as soon as possible after dissection: adrenals, brain (including medulla/pons cerebellar and cereebral cortex), epidiymides, heart, kidneys, liver, ovaries (with oviducts), prostate, seminal vesicles, spleen, testes, thymus, thyroids with parathyroids and uterus (horns and cervix).
The ratio of organ weight to body weight (recorded immediately before sacrifice) was calculated.
> Histopathology: All tissues listed below were from the first five sacrificed as scheduled males and the first five females which delivered and were sacrificed on day 6 post partum of the control and high groups (groups 1 and 4) and for the female sacrificed prematurely:
adrenals, brain, cecum, colon, duodenum, epididymides, esophagus, gut-associated lymphoid tissue, heart, ileum, jejunum, kidneys, liver, lungs with bronchi, lymph nodes, ovaries, prostate, rectum, sciatic nerves, seminal vesicles, spinal cord, spleen, sternum with marrow bone, stomach with forestomach, testes, thymus, thyroids with parathyroids, trachea, urinary bladder, uterus and vagina.
Microscopic examination was also performed on all lesions of all the animals of the low- and intermediate-dose groups sacrificed on completion of the treatment period.
OTHER: haematology parameters, blood biochemistry parameters and neurobehaviour were also tested. - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes. the number of corpora lutea and implantation sites were recorded for females sacrificed as scheduled on day 6 post partum.
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: No
- Skeletal examinations: No
- Head examinations: No
The total litter size and numbers of each sex were recorded as soon as possible after birth. Any gross malformations in pups were noted.
The litters were observed daily in order to note the number of live, dead and cannibalised pups; clinical signs or abnormal behaviour were also recorded daily.
Furthermore, the body weight of each pup was recorded on days 1 and 5 post partum.
Pups found dead and pups sacrificed on day 5 post partum were carefully examined externally for gross external abnormalities. No macroscopic examination was performed and no tissues were preserved. - Statistics:
- Data was compared by one-way analysis of variances and Dunnett test or by Fischer exact probability test. PathData software was used to perform the statistical analysis of organ weight data.
- Indices:
- The following indices were calculated: pre-implantation loss, post-implantation loss (manually calculated), mating index, fertility index, gestation index, live birth index, viability index and lactation index.
Results and discussion
Results: maternal animals
Maternal developmental toxicity
- Details on maternal toxic effects:
- Maternal toxic effects:no effects
Details on maternal toxic effects:
There were no unscheduled deaths that could be attributed to treatment during the study. In the 100 mg/kg/day group, one female was prematurely sacrificed on day 0 post coitum due to its poor clinical conditions (piloerection, round back, swollen on left forelimb and chromorhinorrhea). At necropsy, a pouch was observed in the subcutaneous tissue of the left axillary region with a brown thick content which correlated histologically with acute inflammation. Inflammation with hemorrhage was seen in the larynx and particularly in surrounding tissues with edema and hemorrhage. There was no histological correlation with the perforation of the larynx noted at necropsy. Inflammation in tissues adjacent to the thymus was also observed. Additional changes consisted of a moderate hemorrhage in the left adrenal which correlated with a red discoloration at necropsy. Moderate increased apoptotic cell numbers was seen in the thymus along with decreased periarteriolar lymphoid sheaths (PALS) in the spleen. These observations in the lymphoid tissue were considered to be non specific, probably stress related. All these changes were suggestive of a gavage trauma due to the technical procedures (gavage error).
Ptyalism (hypersalivation) was recorded in males receiving 300 mg/kg/day (2/10 males) and in most males and females dosed at 1000 mg/kg/day during the premating period (9/10 males and 5/10 females) and in all females during the gestation and lactation period. This finding was considered to be related to the test material and a sign of discomfort but not an adverse effect.
A treatment-related effect was considered to be unlikely for the few other clinical signs as they are commonly observed in this species and strain or observed with no dose-level relationship.
There were no treatment-related effects in mean body weights and mean body weight changes. There were no biologically significant effects on mean food consumption associated with treatment with the test material.
There were no changes at necropsy which were indicative of a test material-related effect. Any changes observed were considered to be part of the normal background commonly seen in rats.
There were no changes in the mean organ weights which were suggestive of a test material-related effect. The small differences observed between groups were considered to reflect normal variations and were not considered to be due to treatment with the test material.
There were no changes at histopathological examination which were suggestive of a test material-related effect.
In the mandibular lymph nodes, presence of sinusal red blood cells was seen at a higher incidence in females given 1000 mg/kg/day than in controls. As this observation is commonly seen in rats, was observed unilaterally in 3/5 treated females and in the absence of a similar trend in males, any relationship with the test material was excluded.
Tubular basophilia was seen in the kidneys of 2/5 females given 1000 mg/kg/day but not in controls. As this observation was focal and unilateral, in the absence of a similar trend in males, any relationship with the test material was excluded.
Other changes observed were considered to be part of the normal background commonly seen in rats and without relationship with the test material.
Careful examination of testes, epididymides and ovaries did not reveal any treatment related changes.
There were no treatment related effects on functional observation battery observations or on the heamatology and blood chemistry parameters investigated.
Effect levels (maternal animals)
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: developmental toxicity
Results (fetuses)
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
At 1000 mg/kg/day, there was a tendency towards an increased number of pups found dead (2.6% vs. 0.7% in controls) and cannibalised pups (3.2% vs 1.4% in controls). However, when compared with Historical Control Data (2009-2012), it is unclear whether this was a test material-related effect.
No treatment-related clinical signs were observed at pup examination.
There were no toxicologically significant effects on live birth, viability and lactation indexes associated with treatment with the test material.
At 1000 mg/kg/day, there was a tendency towards a decrease in mean pup body weight and mean body weight changes. This finding was considered to be test material-related but of minor toxicological significance as the difference was of low magnitude and remained within the range of 2009-2012 Historical Control Data.
There were no treatment-related effects on sex-ratio.
Furthermore, no macroscopically malformed pups were observed.
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- reduction in number of live offspring
- fetal/pup body weight changes
- changes in litter size and weights
- changes in postnatal survival
- skeletal malformations
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
- Lowest effective dose / conc.:
- 1 000 mg/kg bw/day
- Treatment related:
- no
Any other information on results incl. tables
Table 1: Delivery and Litter Data
Dose level (mg/kg bw/day) |
0 |
100 |
300 |
1000 |
No. of pregnant females |
10 |
9 |
10 |
10 |
No. of females which delivered |
10 |
9 |
10 |
10 |
Mean duration of gestation (days) |
21.3 |
21.3 |
21.6 |
21.5 |
Mean no. of corpora lutea |
16.4 |
15.1 |
16.4 |
16.9 |
Mean no. of implantations |
16.4 |
15.1 |
16.4 |
16.9 |
Mean pre-implantation loss (%) |
0.0 |
0.0 |
0.0 |
0.0 |
Mean no. of pups delivered |
14.5 |
14.2 |
15.0 |
15.4 |
Mean post-implantation loss (%)* |
11.0 |
5.7 |
8.0 |
9.0 |
Viability index on day 4 post partum (%) |
97.9 |
97.7 |
97.3 |
94.2 |
* manually calculated, no statistics performed
Table 2: Mortality Data
Dose level (mg/kg bw/day) |
0 |
100 |
300 |
1000 |
No. of pups found dead |
1 |
3 |
3 |
4 |
No. of pups cannibalised |
2 |
2 |
1 |
5 |
No. of pups delivered |
145 |
128 |
150 |
154 |
Table 3: Clinical Signs and Gross External Examination
Dose level (mg/kg bw/day) |
0 |
100 |
300 |
1000 |
No. of pups examined |
145 |
128 |
150 |
154 |
Thin appearance |
2 |
1 |
1 |
|
Cold to the touch |
2 |
1 |
1 |
|
Necrosis (tail/hind limb) |
1/1 |
4/4 |
3/3 |
2/2 |
Dehydration |
1 |
1 |
4 |
|
Dyspnea |
1 |
|||
Heamatoma (head/back/abdomen) |
4 |
4 |
8 |
Clinical signs/gross external observation
Table 4: Pup Viability
Dose level (mg/kg bw/day) |
0 |
100 |
300 |
1000 |
Live birth index (%) |
100 |
100 |
100 |
100 |
Pups dying, missing and/or cannibalised (days 1-4 p.p., %) |
2.1 |
2.3 |
2.7 |
5.8 |
Viability index (day 4 p.p., %) |
97.9 |
97.7 |
97.3 |
94.2 |
Lactation index (day 5 p.p., %) |
100 |
98.4 |
100 |
100 |
p.p. = post partum
Table 5: Pup Body Weights (g)
Sex |
Male |
Female |
||||||
Dose level (mg/kg/day) |
0 |
100 |
300 |
1000 |
0 |
100 |
300 |
1000 |
Day 1 p.p. |
7.0 |
7.1 |
7.1 |
6.7 |
6.5 |
6.5 |
6.7 |
6.4 |
Day 5 p.p. |
11.3 |
11.7 |
11.4 |
10.7 |
10.9 |
11.1 |
11.0 |
10.3 |
Body weight change (g) |
+4.4 |
+4.6 |
+4.3 |
+4.0 |
+4.3 |
+4.6 |
+4.2 |
+4.0 |
p.p. = post partum
Table 6: Summary of Male Body/Organ Weights
Organ |
Dose Group (mg/kg/day) n = 10 |
||||
0 |
100 |
300 |
1000 |
||
Final Body Weight (n = 10) |
Mean Weight (g) |
417.3 |
432.0 |
447.1 |
443.8 |
Adrenal Glands (n = 5) |
Mean Weight (g) |
0.07580 |
0.07700 |
0.07740 |
0.08400 |
Mean % Body |
0.01766 |
0.01708 |
0.01768 |
0.01799 |
|
Brain (n = 5) |
Mean Weight (g) |
2.09 |
20.3 |
2.08 |
2.09 |
Mean % Body |
0.48609 |
0.45047 |
0.47657 |
0.44759 |
|
Epididymides (n = 10) |
Mean Weight (g) |
1.44 |
1.40 |
1.41 |
1.46 |
Mean % Body |
0.34573 |
0.32473 |
0.31715 |
0.33084 |
|
Heart (n = 5) |
Mean Weight (g) |
134 |
1.39 |
1.36 |
1.45 |
Mean % Body |
0.31160 |
0.30831 |
0.31112 |
0.31067 |
|
Kidneys (n = 5) |
Mean Weight (g) |
3.03 |
3.13 |
3.21 |
3.34 |
Mean % Body |
0.70657 |
0.69605 |
0.73149 |
0.71510 |
|
Liver (n = 5) |
Mean Weight (g) |
10.94 |
11.48 |
10.82 |
12.04 |
Mean % Body |
2.53 |
2.55 |
2.46 |
2.58 |
|
Prostate (n = 5) |
Mean Weight (g) |
1.52 |
1.31 |
1.33 |
1.58 |
Mean % Body |
0.34868 |
0.28918 |
0.30124 |
0.33704 |
|
Seminal Vesicles (n = 5) |
Mean Weight (g) |
1.66 |
1.84 |
1.84 |
1.77 |
Mean % Body |
0.38802 |
0.40978 |
0.42236 |
0.37840 |
|
Spleen (n = 5) |
Mean Weight (g) |
0.74700 |
0.84560 |
0.74560 |
0.91000 |
Mean % Body |
0.17333 |
0.18777 |
0.16988 |
0.19573 |
|
Testes (n = 10) |
Mean Weight (g) |
3.43 |
3.36 |
3.50 |
3.47 |
Mean % Body |
0.82614 |
0.78212 |
0.78701 |
0.78876 |
|
Thymus (n = 5) |
Mean Weight (g) |
0.26860 |
0.33920 |
0.33340 |
0.29420 |
Mean % Body |
0.06193 |
0.07543 |
0.07644 |
0.06293 |
|
Thyroid Gland (n = 5) |
Mean Weight (g) |
0.2380 |
0.02460 |
0.02840 |
0.02400 |
Mean % Body |
0.00550 |
0.00548 |
0.00648 |
0.00513 |
Dunnett's Test: No statistically significant weight differences noted between treated groups and controls.
Table 7: Summary of Female Body/Organ Weights
Organ |
Dose Group (mg/kg/day) n = 10 |
||||
0 |
100 |
300 |
1000 |
||
Final Body Weight (n = 10) |
Mean Weight (g) |
297.6 |
302.0 |
302.0 |
302.0 |
Adrenal Glands (n = 5) |
Mean Weight (g) |
0.08740 |
0.09440 |
0.09200 |
0.09280 |
Mean % Body |
0.03114 |
0.03150 |
0.03013 |
0.03166 |
|
Brain (n = 5) |
Mean Weight (g) |
1.93 |
2.02 |
1.98 |
1.95 |
Mean % Body |
0.68916 |
0.67280 |
0.66057 |
0.67211 |
|
Heart (n = 5) |
Mean Weight (g) |
0.96380 |
0.99780 |
0.96700 |
1.05 |
Mean % Body |
0.34367 |
0.33247 |
0.32203 |
0.35673 |
|
Kidneys (n = 5) |
Mean Weight (g) |
1.97 |
2.13 |
2.10 |
2.18 |
Mean % Body |
0.70297 |
0.71120 |
0.69474 |
0.74038 |
|
Liver (n = 5) |
Mean Weight (g) |
9.34 |
9.29 |
10.07 |
9.74 |
Mean % Body |
3.33 |
3.10 |
3.34 |
3.31 |
|
Ovaries (n = 5) |
Mean Weight (g) |
0.17900 |
0.22650# |
0.21900 |
0.21320 |
Mean % Body |
0.06380 |
0.07521 |
0.07289 |
0.07279 |
|
Spleen (n = 5) |
Mean Weight (g) |
0.67280 |
0.65440 |
0.72060 |
0.65580 |
Mean % Body |
0.23993 |
0.21818 |
0.23827 |
0.22277 |
|
Thymus (n = 5) |
Mean Weight (g) |
0.22160 |
0.22260 |
0.31440 |
0.23500 |
Mean % Body |
0.07896 |
0.07465 |
0.10615 |
0.07945 |
|
Thyroid Gland (n = 5) |
Mean Weight (g) |
0.01820 |
0.01700 |
0.01860 |
0.01620 |
Mean % Body |
0.00649 |
0.00569 |
0.00613 |
0.00550 |
|
Uterus (n = 5) |
Mean Weight (g) |
0.79540 |
0.74700 |
0.70380 |
0.71460 |
Mean % Body |
0.28343 |
0.25007 |
0.23378 |
0.24407 |
# Significant in the Dunn’s test at 5%
Applicant's summary and conclusion
- Conclusions:
- Under the conditions of the study the No Observed Adverse Effect Level was determined to be 1000 mg/kg bw/day for both maternal toxicity and developmental toxicity based on the absence of findings at this level.
- Executive summary:
The developmental toxicity of the test material was determined in a study which was conducted under GLP conditions and in accordance with the standardised guideline OECD 422.
During the study groups of 10 male and 10 female animals received daily doses of test material at dose levels of 0 (vehicle control), 100, 300 or 1000 mg/kg bw/day for 2 weeks before mating, during mating and, for the females, throughout gestation until day 5 post partum. During the study animals were observed for mortality and clinical effects, and bodyweights and food consumption were recorded. The animals were paired for mating after 2 weeks of treatment and the dams were allowed to litter and rear their progeny until day 5 post partum. The total litter size and numbers of pups of each sex were recorded after birth. The pups were observed daily for clinical signs of toxicity and pup body weights were recorded on days 1 and 5 post partum. A functional observational battery was performed and blood biochemistry and haematology parameters were examined in parental animals. Dams were sacrificed on day 6 post partum. Body weights and selected organ weights were recorded and a complete macroscopic post mortem examination was performed. Pups, including those found dead before study termination, were also submitted for macroscopic post mortem examination.
There were no unscheduled deaths in parental animals that could be attributed to treatment during the study. In the 100 mg/kg/day group, one female was prematurely sacrificed on day 0 post coitum due to its poor clinical conditions which were considered to be due to a gavage trauma. There were no treatment-related effects on body weight, food consumption, functional observation battery, blood biochemistry or haematology parameters. Furthermore, there were no treatment-related findings noted at necropsy.
There were no treatment-related effects on the distribution of pups found dead and/or cannibalised and there were no treatment-related findings at pup examinations. Furthermore, there were no toxicologically significant effects on live birth, viability and lactation indexes. Although there was a tendency towards a decrease in mean body weight and mean body weight changes in pups at 1000 mg/kg/day, this finding was considered to be test material-related but of minor toxicological significance.
Therefore, under the conditions of the study the No Observed Adverse Effect Level was determined to be 1000 mg/kg bw/day for both maternal toxicity and developmental toxicity.
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