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EC number: 226-641-8 | CAS number: 5444-75-7
- 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
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 27 September 2017 to 24 November 2017
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 018
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- 2001
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.31 (Prenatal Developmental Toxicity Study)
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
- Qualifier:
- according to guideline
- Guideline:
- other: Japanese Ministry of Agriculture, Forestry and Fisheries, Test Data for Registration of Agricultural Chemicals, 12 Nohsan No. 8147, Agricultural Production Bureau, November 24, 2000.
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- 2-ethylhexyl benzoate
- EC Number:
- 226-641-8
- EC Name:
- 2-ethylhexyl benzoate
- Cas Number:
- 5444-75-7
- Molecular formula:
- C15H22O2
- IUPAC Name:
- 2-ethylhexyl benzoate
- Test material form:
- liquid
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Strain: RccHan™;WIST rat.
- Source: Envigo RMS Limited.
- Age at study initiation: 76 - 82 days
- Weight at study initiation: 180-208 g
- Housing: individually in polycarbonate cages with a stainless steel mesh lid
- Diet: SDS VRF1 Certified pelleted diet ad libitum
- Water: tap water ad libitum
- Acclimation period: 5 days before pairing and during pairing until evidence of mating
ENVIRONMENTAL CONDITIONS
- Temperature: 20-24ºC
- Humidity (%): 40-70%
- Air changes: Filtered fresh air which was passed to atmosphere and not recirculated
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- CMC (carboxymethyl cellulose)
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: weekly
The required amount of substance was weighed and then mixed with the vehicle (approximately 50% of the final volume). The mixture was magnetically stirred until the test material was uniformly mixed. The remaining vehicle was added to achieve the required volume and the formulation was mixed using a magnetic stirrer until homogeneous.
VEHICLE: 1% w/v methylcellulose
- Amount of vehicle (if gavage): 10 mL/kg - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The first and last freshly prepared test formulations were sampled (4 × 1 mL,accurately weighed) and submitted for analysis. Duplicate samples were analyzed. The samples were dissolved using ultrasonic vibration and swirling in a suitable volume of diluent (Methanol / water 80/20 v/v). The extract was diluted using diluent (where necessary) to provide a solution containing the substance at an expected concentration within the range 2 µg/mL to 4 µg/mL.
Method:
High performance liquidchromatograph (HPLC): Waters Alliance 2695 separation module and 2487 dual wavelength detector.
Column: Agilent Poroshell C18-EC, 2.7 µm, 100 × 4.6 mm
Column temperature: 45ºC
Sample temperature: Ambient.
Mobile Phase: Methanol / water 85 / 15 v/v
Flow rate: 1 mL/min
Needle wash: Methanol / water 80 / 20 v/v
Detector wavelength: UV, 229 nm
Injection volume: 10 µL
Run time: 6 minutes
Approximate retention time: 4.6 minutes
Results method validation:
Calibration linearity (range 1-5 ug/mL): r > 0.999
Specificity: absence of peak for substance in control sample
Precisions calibration (CV 0.22% 1 ug/mL, 0.28% 5 ug/mL)
Accuracy: procedural recovery value of 101.6% (CV=1.13%, n=5) was obtained for 1 mg/mL and 101.0% (CV=0.13%, n=5) was obtained for 200 mg/mL.
Stability (15 days 4 ºC): 1 mg/mL 96% of intial; 200 mg/mL 97% of initial
Stability (1 day at 21 ºC): 1 mg/mL 105% of intial; 200 mg/mL 103.5% of initial
Homogeneity: CV < 5.6% at 1 mg/mL; CV < 1% at 200 mg/mL
LOQ: 2.2 ng/mL and 7.4 ng/mL
Preparation analyses: see below
Procedural recovery: no data
Accuracy: first: 97.8-99.7% of nominal for all concentrations; last: 101-104% of nominal for all concentrations - Details on mating procedure:
- - Impregnation procedure: cohoused
- M/F ratio per cage: 1/1
- Length of cohabitation: until detection of mating
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy - Duration of treatment / exposure:
- Day 6 to 19 after mating
- Frequency of treatment:
- daily (using a suitably graduated rubber-free syringe and a plastic catheter inserted via the mouth)
- Duration of test:
- 20 days
Doses / concentrationsopen allclose all
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Remarks:
- measured concentration 99.1-101% of nominal
- Dose / conc.:
- 330 mg/kg bw/day (nominal)
- Remarks:
- measured concentration 99.7-101% of nominal
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Remarks:
- measured concentration 97.8-104% of nominal
- No. of animals per sex per dose:
- 20 females
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Dose selection rationale:
Dose levels were selected based on the effects of a preliminary embryo-fetal study at this laboratory (Envigo study number CM44QG) which investigated dose levels of 330, 660 and 1000 mg/kg/day. At 1000 mg/kg/day, overall body weight gain and food consumption were marginally lower than that of Control. There was no conclusive effect of treatment on embryo-fetal survival, litter size or sex ratio at any dose level; however, mean fetal weights appeared slightly low at 660 or 1000 mg/kg/day when compared with Control.
Due to the minimal signs of maternal toxicity on the preliminary study, along with slight effects of fetal growth at 660 or 1000 mg/kg/day, dose levels of 100, 330 and 1000 mg/kg/day were selected for this study.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily (A detailed physical examination was performed on each animal on Days 0, 5, 12, 18 and 20 after mating)
DOSING OBSERVATIONS: Pre-dose and 1-2 hours after completion of dosing of all groups (during week 1 also at the end of the working day)
BODY WEIGHT: Yes
- Time schedule for examinations: day 0, day 3 and daily from day 6 to 20
FOOD CONSUMPTION: Yes
- Time schedule for examinations: Days 0-2, 3-5, 6-9, 10-13, 14-17 and 18-19 after mating
WATER CONSUMPTION: No
HEMATOLOGY: Yes
- Time schedule for collection of blood: at termination
- Anaesthetic used for blood collection: Yes isoflurane
- Animals fasted: no
- How many animals: all
- Parameters checked: Prothrombin time (PT), Activated partial thromboplastin time (APTT)
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: week 13
- Anaesthetic used for blood collection: Yes isoflurane
- Animals fasted: no
- How many animals: all
- Parameters checked: Alanine amino-transferase (ALT), Aspartate amino-transferase (AST), Bilirubin (Bili), Urea, Total protein (Total Prot), Albumin (ALB) by chemical assay, Zinc (Zn)
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Gross necropsy: for all animals all external features and orifices were examined visually
OTHER: residual lithium heparin samples be analyzed for Zinc on the Roche P Modular Analyzer - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Fetuses (live and dead): Yes
- Other: non-pregnant females: The number of uterine implantation sites were checked after staining with ammonium sulphide - Fetal examinations:
- - External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [half per litter]: fixed in Bouin’s fluid
- Skeletal examinations: Yes: [half per litter]: stained with Alizarin Red
- Statistics:
- For body weight, gravid uterus weight, food consumption, corpora lutea, implantations, live young, fetal, placental and litter weight data:
A parametric analysis was performed if Bartlett's test for variance homogeneity (Bartlett 1937) was not significant at the 1% level. The F1 approximate test was applied.
A non-parametric analysis was performed if Bartlett's test was still significant at the 1% level following both logarithmic and square-root transformations. The H1 approximate test, the non-parametric equivalent of the F1 test described above, was applied.
For litter size and survival indices and fetal, placental and litter weight, gravid uterine weight and clinical pathology data, if 75% of the data (across all groups) were the same value, for example c, Fisher’s exact tests (Fisher 1973) were performed.
Pre/post implantation loss and sex ratio were analyzed by generalized mixed linear model with binomial errors, a logit link function and litter as a random effect (Lipsitz 1991). Each treated group was compared to control using a Wald chi-square test. For pre implantation loss, the numerator was number of corpora lutea - number of implantations, the denominator was number of corpora lutea. For post-implantation loss, the numerator was number of implantations - number of live fetuses, the denominator was number of implantations. For sex ratio, the numerator was number of males; the denominator was number of live fetuses.
For resorptions, each treated group was compared to control by exact Wilcoxon rank sum test (Wilcoxon 1945).
Significant differences between the groups compared were expressed at the 5% (p<0.05) or 1% (p<0.01) level. - Historical control data:
- available in the report for fetal abnormalities (major and minor) and variations
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- total litter resorption in 1 female at 100 mg/kg bw appeared with discharge of blood from the vagina, piloerection of the coat and a pale skin colour across the whole body and the appearance of blood clots one day thereafter
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Body weight gains were lower than Controls for females receiving 1000 mg/kg/day from Gestation Days 6 to 20 (85%). It is noted that prior to treatment (Gestation Days 0 to 6), bodyweight gains for females were lower than Controls.
When adjusted for the weight of the gravid uterus the effect on body weight remained, but body weights on day 20 were within control ranges
see attached table - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Food consumption during Gestation Days 6-19 was similar to Control at 100 and 330 mg/kg/day, and slightly low at 1000 mg/kg/day (90%).
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The hematological examination at termination revealed, when compared to Controls, a statistically significantly low prothrombin time for females treated at 1000 mg/kg/day (90%).
see overview table - Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- The biochemical examination of the blood plasma at termination revealed, when compared to Control, slightly low alanine amino-transferase at 1000 mg/kg/day (86%) and slightly low aspartate amino-transferase at 330 or 1000 mg/kg/day (83% both). High urea concentrations (126%) were observed at 1000 mg/kg/day, along with slightly higher albumin/globulin ratio (115%) that were attributed to statistically significantly low total protein (88%).
see overview table - Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Mean gravid uterine weight was similar to Control at 100 and 330 mg/kg/day, but low at 1000 mg/kg/day (86%).
Placental weights were not affected
see attached table - Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- There were no clear effects of treatment on pre/post implantation losses.
see overview table - Total litter losses by resorption:
- effects observed, non-treatment-related
- Description (incidence and severity):
- total resoprtion in 1 female at 100 mg/kg bw
- Early or late resorptions:
- no effects observed
- Description (incidence and severity):
- There were no clear effects of treatment on early or late resorptions
see overview table - Dead fetuses:
- no effects observed
- Description (incidence and severity):
- There were no clear effects of treatment on numbers of live young
see overview table - Changes in pregnancy duration:
- not examined
- Changes in number of pregnant:
- no effects observed
- Description (incidence and severity):
- 1 female at 330 mg/kg bw was non-pregnant
- Other effects:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Corpora lutea counts were slightly low for females in treated groups, however the number of implantations for all dose groups were similar to Control
see overview table - Details on maternal toxic effects:
- At 1000 mg/kg/day, body weight gain was low, and correlated with low food intake at this dose. The lower weight gain was attributed to a lower gravid uterine weight.
The hematological examination at termination revealed low prothrombin time for females treated at 1000 mg/kg/day.
The biochemical examination of the blood plasma at termination revealed slightly lower alanine amino-transferase and total protein at the high dose level, and low aspartate amino-transferase at the intermediate and high dose level. Additionally, higher urea concentrations and albumin/globulin ratio (115%) were observed at the high dose level.
Adult females were macroscopically normal.
The number of implantations, resorptions, pre and post-implantation loss, number of live young, sex ratio of males to females and placental weights were unaffected by treatment.
Effect levels (maternal animals)
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: observed effects were minimal
Maternal abnormalities
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- When compared to Control, the litter and fetal weights of animals receiving 1000 mg/kg/day was low (75% and 80%, respectively), but were similar to Controls for females receiving 100, 330 mg/kg/day.
- Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- There were no clear effects of treatment on numbers of live young
see overview table - Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- There were no clear effects of treatment on sex ratio
see overview table - Changes in litter size and weights:
- not examined
- Changes in postnatal survival:
- not examined
- External malformations:
- no effects observed
- Skeletal malformations:
- effects observed, treatment-related
- Description (incidence and severity):
- In the treated groups there was a slight increased incidence of major abnormalities which included short/bent/thickened long bones. At 1000 mg/kg/day, there were three litters with major abnormalities (partially split sternum, bent scapula and short/thickened long bones) in 1-2 fetuses/litter, the incidence of which exceeded historical control data. One fetus at 330 mg/kg/day had multiple thoracic vertebral/rib abnormalities.
At 1000 mg/kg/day there was an increased incidence of medially thickened/kinked ribs; short supernumerary cervical rib; 14th supernumerary rib; 20 thoracolumbar vertebrae; unilateral shift of pelvic girdle and a generalised delay in ossification affecting, but not restricted to, cranial bones, sternebrae, vertebrae and digits compared to concurrent Control and outside of historical control data (HCD).
At 330 mg/kg/day there was an increased incidence of 14th supernumerary rib; unilateral shift of pelvic girdle and a slight delay in ossification of cranial bones compared to concurrent Control and outside of HCD.
A delay in ossification is a transient stages of fetal development and can be attributed to low fetal bodyweight.
see attached table and overview table - Visceral malformations:
- effects observed, treatment-related
- Description (incidence and severity):
- In the treated groups there was a slight increased incidence of major abnormalities which included a low incidence of heart and major vessel abnormalities. At 1000 mg/kg/day, there was one litter with major abnormalities (retosophageal right subclavian artery and malrotated heart), the incidence of which exceeded historical control data. At 100 and 330 mg/kg/day, the findings were seen in a single fetus.
At 1000 mg/kg/day there was an increased incidence of variation in lens shape; partially undescended lobe of thymus and shiny skin compared to concurrent Control and outside of historical control data (HCD).
At 330 mg/kg/day there was an increased incidence of partially undescended lobe of thymus compared to concurrent Control and outside of HCD.
The variation in lens shape and partially undescended lobe of thymus are transient stages of fetal development.
see attached table and overview table - Details on embryotoxic / teratogenic effects:
- Fetal and litter weights were low at 1000 mg/kg/day compared with Control.
There was an increased incidence of major abnormalities at 1000 mg/kg/day.
Visceral and skeletal abnormalities were seen at a higher incidence at 330 and 1000 mg/kg/day. The delays in ossification, variation in lens shape and partially undescended lobe of thymus were considered to represent transient stages of fetal development. Other minor skeletal abnormalities such as short supernumerary cervical ribs and 14th supernumerary ribs seen at 1000 mg/kg/day are not attributable to the low fetal weights in this group.
Effect levels (fetuses)
- Dose descriptor:
- NOAEL
- Effect level:
- 330 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- skeletal malformations
- visceral malformations
Fetal abnormalities
- Abnormalities:
- effects observed, treatment-related
- Localisation:
- skeletal: vertebra
- visceral/soft tissue: cardiovascular
- other: skeletal/appendicular
Overall developmental toxicity
- Developmental effects observed:
- yes
- Lowest effective dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Treatment related:
- yes
- Relation to maternal toxicity:
- developmental effects in the absence of maternal toxicity effects
Any other information on results incl. tables
Overview table
Dose (mg/kg bw) |
0 |
100 |
330 |
1000 |
Treatment related |
|
|
Endpoint |
|
|
|
|
|
|
|
Mortality |
0/20 |
0/20 |
0/20 |
0/20 |
|
|
|
Clinical signs |
NTRE |
|
|
||||
Body weight (gain) |
|
|
(↓ day 0-6 18%) |
↓day 7 to 20 (↓ day 0-6 14%, ↓ day 7-20 15%) |
yes |
|
|
Food consumption day 0-20 |
|
|
|
↓ day 0-6 6%, ↓ day 7-20 10% |
yes |
|
|
Pregnancy rate |
20/20 |
19/20 |
19/20 |
20/20* |
|
|
|
Litter resorption |
|
1/20 |
|
|
|
|
|
Gravid uterus weight |
|
|
|
↓ 14% (↓ 4% adj BW) |
|
|
|
Haematology |
|
|
|
PTT ↓ 10% |
|
|
|
Clinical biochemistry |
|
|
ASAT ↓ 17%
|
ALAT ↓ 16% ASAT ↓ 17% Urea ↑ 26% TP ↓ 12% Alb ↓ 6% A/G ↑ 15% |
yes |
|
|
Macroscopy |
NTRE |
|
|||||
Corpora lutea |
13.3 |
12.0 ↓ |
12.1 ↓ |
12.1 ↓ |
yes |
|
|
Implantations |
11.9 |
10.9 |
11.3 |
11.4 |
|
|
|
Early resorptions |
0.7 |
0.4 |
0.7 |
0.8 |
|
|
|
Late resorptions |
0.1 |
0.1 |
0.0 |
0.1 |
|
|
|
Pre-implementation loss (%) |
11.1 |
9.6 |
6.4 |
7.1 |
|
|
|
Post-implementation loss (%) |
6.4 |
6.1 |
6.5 |
9.2 |
|
|
|
Live young/Litter |
11.1 |
10.4 |
10.5 |
10.4 |
|
|
|
Sex ratio young (% males) |
51.6 |
40.8 ↓ |
50.7 |
48.8 |
|
|
|
Placental weight |
NTRE |
|
|||||
Litter weight |
|
|
|
↓ 25% |
yes |
|
|
Fetal weight |
|
|
|
↓ 20% |
yes |
|
|
Fetal major abnormalities Cervical/Thoracic Skeletal -Partially split sternum -Multiple thoracic vertebral/rib abn Visceral -Retroesophageal right subclavian art -Retroesophageal aortic arch -Interrupted aortic arch -Transposition of ascending aorta and pulmonary trunk -Muscular ventricular septal defect -Atrial septal defect -Malrotated heart Lumbar/Sacral/Caudal Visceral -Omphalocele Appendicular Skeletal -Bent scapula(e) -Short/thickened long bones |
|
1/19 (1/198 fetuses)#
1/19 (1/198 fetuses)#
1/19 (1/198 fetuses)# 1/19 (1/198 fetuses)#
1/19 (1/198 fetuses)
|
1/19 (1/200 fetuses)
1/19 (1/200 fetuses)
|
1/19 (1/198 fetuses)
1/19 (2/198 fetuses)#
1/19 (1/198 fetuses)#
1/19 (1/198 fetuses) 2/19 (3/198 fetuses) |
yes |
|
|
Fetal minor abnormalities + variations Skeletal -Minor skeletal abnormalities -Rib and vertebral configuration -Thoracolumbar vertebrae 20 -Pelvic girdle (caudal/cranial shift) -Delayed/Incomplete ossification/unossified Visceral |
2/20 (2/112 fetuses) Up to 9/20 (17/112 fetuses)
Up to 17/20 (43/112 fetuses) Up to 5/20 (7/110 fetuses) |
4/19 (4/99 fetuses) Up to 9/19 (23/99 fetuses)
Up to 14/19 (31/99 fetuses) Up to 15/19 (24/98 fetuses) |
3/19 (3/102 fetuses) Up to 17/19 (39/102 fetuses)
4/19 (4/102 fetuses)
Up to 17/19 (47/102 fetuses) Up to 9/19 (12/98 fetuses) |
11/19 (21/100 fetuses) Up to 17/19 (54/100 fetuses) 7/19 (12/100 fetuses) 4/19 (4/100 fetuses)
Up to 19/19 (98/100 fetuses) Up to 12/19 (21/98 fetuses) |
Yes |
|
|
NTRE= no treatment related effects
↑/↓= significantly increased/decreased
% compared to controls
*one female was not dosed during two days and was excluded from the evaluations
#effects reported in the same fetus
Applicant's summary and conclusion
- Conclusions:
- Based on results of this study, the substance was well tolerated and the maternal no observed adverse effect level (NOAEL) was considered to be 1000 mg/kg/day. Due to the occurrence of major fetal abnormalities at 1000 mg/kg/day the fetal NOAEL was considered to be 330 mg/kg/day
- Executive summary:
Three groups of 20 femal rats received the substance at doses of 100, 330 and 1000 mg/kg/day by oral gavage administration, from Day 6 to 19 after mating. A similarly constituted Control group received the vehicle,1% w/v methylcellulose at the same volume dose as treated groups and for the same duration. Animals were killed on Day 20 after mating for reproductive assessment and fetal examination.
During the study clinical observations, body weight, food consumption hematology (peripheral blood) and blood chemistry investigations were undertaken. Adult females were examined macroscopically at necropsy on Day 20 after mating and the gravid uterus weight recorded. All fetuses were examined macroscopically at necropsy and subsequently by detailed internal visceral examination or skeletal examination.
At 1000 mg/kg/day, body weight gain was low, and correlated with low food intake at this dose. The lower weight gain was attributed to a lower gravid uterine weight.
The hematological examination at termination revealed low prothrombin time for females treated at 1000 mg/kg/day.
The biochemical examination of the blood plasma at termination revealed slightly lower alanine amino-transferase and total protein at the high dose level, and low aspartate amino-transferase at the intermediate and high dose level. Additionally, higher urea concentrations and albumin/globulin ratio (115%) were observed at the high dose level.
Adult females were macroscopically normal.
The number of implantations, resorptions, pre and post-implantation loss, number of live young, sex ratio of males to females and placental weights were unaffected by treatment.
Fetal and litter weights were low at 1000 mg/kg/day compared with Control.
There was an increased incidence of major abnormalities at 1000 mg/kg/day.
Visceral and skeletal abnormalities were seen at a higher incidence at 330 and 1000 mg/kg/day. The delays in ossification, variation in lens shape and partially undescended lobe of thymus were considered to represent transient stages of fetal development. Other minor skeletal abnormalities such as short supernumerary cervical ribs and 14th supernumerary ribs seen at 1000 mg/kg/day are not attributable to the low fetal weights in this group.
Based on results of this study, the substance was well tolerated and the maternal no observed adverse effect level (NOAEL) was considered to be 1000 mg/kg/day. Due to the occurrence of major fetal abnormalities at 1000 mg/kg/day, the fetal NOAEL was considered to be 330 mg/kg/day.
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