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EC number: 207-330-6 | CAS number: 462-95-3
- 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:
- From 14 NOVEMBER 2018 to 22 FEBRUARY 2019
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 020
- Report date:
- 2020
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- 03 September 2018
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- Diethoxymethane
- EC Number:
- 207-330-6
- EC Name:
- Diethoxymethane
- Cas Number:
- 462-95-3
- Molecular formula:
- C5H12O2
- IUPAC Name:
- diethoxymethane
- Test material form:
- liquid
- Details on test material:
- Clear liquid
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source and lot/batch number of test material: Lambiotte & Cie - 1808061400R
- Expiration date of the lot/batch: 06 August 2020
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River (UK) Ltd
- Age at study initiation: Approximately 71 days old
- Weight at study initiation: 228 to 290 g
- Housing: Acclimatization: up to four animals per cage; During pairing: one (stock) male and one female per cage; Gestation: one female per cage
- Diet: SDS VRF1 Certified pelleted diet. Non-restricted
- Water: Potable water from the public supply via polycarbonate bottles with sipper tubes. Bottles were changed at appropriate intervals. Non-restricted
- Acclimation period: Five days before commencement of pairing
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 40-70%
- Air changes: Filtered fresh air which was passed to atmosphere and not recirculated
- Photoperiod: 12 hours light: 12 hours dark
IN-LIFE DATES: From: 14 November 2018 To:10 to 15 December 2018
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: Starting with the lowest concentration, the required amount of test item was weighed into a suitable container and immediately transferred to a measuring cylinder. Vehicle was added to make up to about 20% of the final volume. The weighing container was rinsed out and formulation made up to the required volume with vehicle.
The formulation was then magnetically stirred in a sealed container of the appropriate size with no head space.
A series of formulations at the required concentrations were prepared by dilution of individual weighings of the test item.
Frequency of preparation: Weekly.
Storage of formulation: Refrigerated (2 to 8 ºC) for up to 10 days.
VEHICLE
- Concentration in vehicle: 0, 20, 66 and 200 mg/mL
- Amount of vehicle: 5 mL/kg - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The analytical method involved extraction and dilution in acetone followed by gas chromatographic analysis with flame ionization detection. Sample concentrations were determined with reference to external standards prepared in the concentration range 10 μg/mL to 100 μg/mL.
The mean concentrations were within +10/-15% of the nominal concentration, confirming accurate formulation. The percentage difference from mean values remained within 1%, confirming precise analysis, with the exception of the last formulation occasion of Group 4. Initial results from the last sample occasion of Group 4 were low; however, extracted samples were reanalyzed, in accordance with standard operating procedures, confirming the mean concentrations were within acceptance criteria. As a result, the percentage difference for this group was expectedly high (±10.49%). - Details on mating procedure:
- - Impregnation procedure: cohoused
- M/F ratio per cage: 1:1 with identified stock males
- Daily checks for evidence of mating: Ejected copulation plugs in cage tray and vaginal smears were checked for the presence of sperm.
- Day 0 of gestation: When positive evidence of mating was detected.
A colony of stud males was maintained specifically for the purpose of mating; these animals were not part of the study and were maintained as stock animals. - Duration of treatment / exposure:
- Females: Day 6 to 19 after mating
- Frequency of treatment:
- Once daily at approximately the same time each day
- Duration of test:
- 20 days
Doses / concentrationsopen allclose all
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Dose / conc.:
- 330 mg/kg bw/day (nominal)
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- Control - corn oil
- No. of animals per sex per dose:
- 20
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Dose selection rationale: Dose levels have been selected, in conjunction with the Sponsor, based on the effects seen in a preliminary embryo-fetal study conducted at this laboratory which investigated dose levels of 330, 660 and 1000 mg/kg/day. Initial treatment from Gestation day 6 to 7 resulted in overall group mean body weight stasis at 330 or 1000 mg/kg/day; however overall body weight gains over the whole treatment period were unaffected. There was no conclusive effect of treatment on embryo-fetal development, survival, litter size or sex ratio at any dose level.
Dose levels of 100, 330 and 1000 mg/kg/day were therefore considered appropriate for this study.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
CLINICAL OBSERVATIONS: Animals were inspected visually at least twice daily for evidence of ill-health or reaction to treatment. Cages were inspected daily for evidence of animal ill-health amongst the occupant(s). Any deviation from normal was recorded at the time in respect of nature and severity, date and time of onset, duration and progress of the observed condition, as appropriate.
During the acclimatization period, observations of the animals and their cages were recorded at least once per day.
A detailed physical examination was performed on each animal on Days 0, 5, 12, 18 and 20 after mating to monitor general health.
BODY WEIGHT: The weight of each adult was recorded on Days 0, 3, 6-20 after mating.
FOOD CONSUMPTION: The weight of food supplied to each adult, that remaining and an estimate of any spilled was recorded for the periods Days 0-2, 3-5, 6-9, 10-13, 14-17 and 18-19 inclusive after mating.
SIGNS ASSOCIATED WITH DOSING: Detailed observations were recorded daily during the treatment period at the following times in relation to dose administration:
Pre-dose observation.
Immediately after completion of dosing each Group.
One to two hours after completion of dosing.
As late as possible in the working day.
POST-MORTEM EXAMINATIONS: All adult animals were subject to a detailed necropsy. After a review of the history of each animal, a full macroscopic examination of the tissues was performed. All external features and orifices were examined visually. Any abnormality in the appearance or size of any organ and tissue (external and cut surface) was recorded and the required tissue samples preserved in appropriate fixative. - 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 - Fetal examinations:
- - External examinations: Yes
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
- Head examinations: Yes
- Fetal weight: Yes
- Ano-genital distance: Yes - Statistics:
- A parametric analysis was performed if Bartlett's test for variance homogeneity was not significant at the 1% level. If the F1 approximate test was significant, suggesting that the dose response was not monotone, Dunnett's test was performed instead.
A non-parametric analysis was performed if Bartlett's test was still significant at the 1% level following both logarithmic and square-root transformations. For pre treatment data, Kruskal-Wallis’ test was used to test for any group differences. Where this was significant (p<0.05) inter group comparisons using Wilcoxon rank sum tests were made.
If the H1 approximate test was significant, suggesting that the dose-response was not monotone, Steel's test was performed instead.
For live birth and viability indices dichotomized to 1 when 100% and 0 otherwise, if the Cochran Armitage test was significant at the 5% level, then the direction of the trend was established and one-tailed step-down testing in this direction was performed. If the Cochran-Armitage test was not significant at the 5% level, then a Chi-square test was applied. If the Chi-square test was significant at the 5% level, the treatment groups were compared using pairwise comparisons of each dose group against the Control using Fisher’s exact tests; otherwise, no further comparisons were made.
For organ weight data, analysis of covariance was performed using terminal body weight as covariate, unless non-parametric methods were applied. - Indices:
- Reproductive assessment:
The following were recorded for all animals:
For each ovary/uterine horn - Number of:
Corpora lutea.
Implantation sites.
Resorption sites (classified as early or late).
Fetuses (live and dead). - Historical control data:
- Historical control data on :
- Fetal examinations - Major abnormalities (Table 16)
- Fetal examinations - Skeletal (Table 18)
- Fetal examinations - Visceral (Table 20)
- Thyroid hormone data (Table 22)
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- At routine physical examination, there was an increased incidence of hair loss of the forelimbs in females treated with Ethylal, although it is unclear if this is treatment related since this finding occurs commonly.
One female (2F 28) was seen with two swollen areas of the upper ventral surface on Day 16, one of which apparently increased in size to 20 x 20 mm.
Following initial treatment (gestation day 6), signs associated with dosing Ethylal at 1000 mg/kg/day included unsteady gait in 11 animals, decreased activity in 5 animals, flattened posture, or gait, in 4 animals and partially closed eye lids in 3 animals.
The type of observation seen was associated with specific signs (i.e. unsteady gait at the start of treatment and chin rubbing towards the end) and although treatment related, the signs were either recoverable or transient and, therefore, considered non-adverse. Signs associated with dosing in Group 3 were confined to salivation which is not viewed as adverse.
Tables 1 and 2 - Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There was no clear difference in the overall (gestation day 6 to 20) body weight change for females treated with Ethylal at any dose level.
Body weight loss/stasis was seen in females receiving 330 or 1000 mg/kg/day following initial treatment gestation day 6 to 7, however the body weight performance improved and daily gains were generally similar to Control thereafter.
It is noted that body weight gains from gestation day 0 to 6 (prior to treatment) were statistically significantly low in females allocated to the 1000 mg/kg/day group and consequently not due to treatment.
Body weight gains (gestation days 6 to 20), adjusted for gravid uterine weights were slightly low at 1000 mg/kg/day when compared to Control and, also, achieved statistical significance. However
the overall performance was unaffected by treatment.
Tables 3 and 4 - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Food consumption of females treated at 1000 mg/kg/day was statistically significantly low prior to the start of treatment and remained low throughout treatment, although statistical significance was not attained on the last recording occasion.
Table 5 - Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- Thyroid and parathyroid weights were unaffected by treatment.
There was no effect of treatment on gravid uterine weight
Table 6 - Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- Table 7
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The microscopic examination of the thyroids revealed no test item-related lesions.
The incidence and distribution of all findings were considered to be unrelated to treatment. Such findings included the follicular cysts in the thyroid tissue, since there was a low incidence and the distribution of cyst findings was unrelated to treatment.
Table 8 - Histopathological findings: neoplastic:
- not examined
- Other effects:
- effects observed, treatment-related
- Description (incidence and severity):
- Thyroid hormone analysis:
The group mean values of T3 and T4 concentrations in serum for females receiving 330 or 1000 mg/kg/day were slightly low, when compared to Control, with the difference attaining statistical significance.
The group mean values of serum TSH concentrations in females receiving 1000 mg/kg/day (Group 4) was slightly higher, when compared to Control, with the difference attaining statistical significance. - Details on results:
- These minor variations in the circulating levels of T3, T4 and TSH (that were within the normal historical control range) were not associated with changes in ano-genital distances and no macroscopic or microscopic changes to the thyroid gland were observed. In the absence of any histopathological correlate and with no evidence of disturbance to the growth or development of fetuses, the small differences in the circulating levels of thyroid hormones in the females receiving 330 or 1000 mg/kg/day, although statistically significant, were considered nonadverse
Tables 9, 10, 11 and 22
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- Tables 12 and 13
- Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- Tables 12 and 13
- Early or late resorptions:
- no effects observed
- Description (incidence and severity):
- Tables 12 and 13
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- Tables 12 and 13
- Changes in pregnancy duration:
- no effects observed
- Changes in number of pregnant:
- no effects observed
- Other effects:
- no effects observed
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: absence of effects
- Remarks on result:
- other: absence of effects
Maternal abnormalities
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- Table 14
- Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- Tables 12 and 13
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- Table 13
- Changes in litter size and weights:
- no effects observed
- Description (incidence and severity):
- Table 14
- External malformations:
- no effects observed
- Skeletal malformations:
- no effects observed
- Description (incidence and severity):
- Tables 17 and 18
- Visceral malformations:
- no effects observed
- Description (incidence and severity):
- Tables 19 and 20
- Other effects:
- no effects observed
- Description (incidence and severity):
- There was no effect of treatment on ano-genital distances.
Table 21
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: absence of effects
- Remarks on result:
- other: absence of effects
Fetal abnormalities
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Developmental effects observed:
- no
Any other information on results incl. tables
|
Control |
Ethylal |
||
Dose Group |
1 |
2 |
3 |
4 |
Dose (mg/kg/day) |
0 |
100 |
330 |
1000 |
Table 1: Signs associated with dosing – group distribution of observations after mating
|
|
|
Number of animals affected |
|||
Category |
Observation |
Group/Sex: Initial no.: |
1F 20 |
2F 20 |
3F 20 |
4F 20 |
Abnormal gait |
Flattened |
|
0 |
0 |
0 |
1 |
|
Unsteady |
|
0 |
0 |
0 |
13 |
Behavior |
Chin rubbing |
|
0 |
0 |
0 |
3 |
|
Decreased activity |
|
0 |
0 |
0 |
8 |
|
Salivation |
|
0 |
0 |
4 |
19 |
Eyelids |
Partially closed, Bilateral |
|
0 |
0 |
0 |
3 |
Posture |
Flattened |
|
0 |
0 |
0 |
5 |
Table 2: Clinical signs - group distribution of observations after mating
|
|
|
Number of animals affected |
|||
Category |
Observation |
Group/Sex: Initial no.: |
1F 20 |
2F 20 |
3F 20 |
4F 20 |
Build (Deformity) |
Swollen area, Upper ventral surface |
|
0 |
1 |
0 |
0 |
Coat |
Hair loss, Forelimbs |
|
0 |
3 |
5 |
3 |
Skin |
Encrustation, Ear - left |
|
1 |
0 |
0 |
0 |
|
Encrustation, Forelimb - left |
|
0 |
0 |
1 |
0 |
Staining |
Abnormal color, Red, Forelimb - left |
|
0 |
0 |
0 |
1 |
Table 3: Body weight and body weight change - group mean values (g) during gestation
Group /Sex |
|
Day 0 |
3 |
6 |
7 |
8 |
9 |
10 |
11 |
12 |
13 |
14 |
15 |
16 |
Statistics test |
Av |
Av |
Av |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
|
1F |
Mean |
251 |
271 |
283 |
285 |
291 |
295 |
301 |
307 |
314 |
320 |
327 |
335 |
348 |
|
SD |
12.2 |
13.4 |
12.3 |
14.3 |
13.4 |
13.7 |
12.9 |
13.4 |
14.1 |
13.7 |
13.6 |
15.5 |
15.6 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
2F |
Mean |
252 |
268 |
279 |
282 |
285 |
290 |
296 |
303 |
310 |
316 |
322 |
330 |
342 |
|
SD |
13.5 |
13.6 |
14.2 |
15.6 |
14.9 |
15.3 |
16.0 |
17.5 |
15.5 |
17.1 |
18.5 |
19.5 |
19.6 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
3F |
Mean |
250 |
268 |
280 |
280 |
285 |
290 |
297 |
303 |
308 |
316 |
323 |
332 |
344 |
|
SD |
10.0 |
10.9 |
12.4 |
13.5 |
12.7 |
12.2 |
12.7 |
14.7 |
13.5 |
15.1 |
16.1 |
15.5 |
16.4 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
4F |
Mean |
253 |
267 |
278 |
277 |
281 |
285* |
291 |
297 |
304* |
309* |
315* |
324 |
336 |
|
SD |
15.2 |
14.3 |
17.4 |
18.1 |
18.3 |
18.2 |
19.5 |
19.4 |
17.6 |
19.1 |
19.3 |
19.9 |
22.4 |
|
N |
19 |
19 |
19 |
19 |
19 |
19 |
19 |
19 |
19 |
19 |
19 |
19 |
19 |
Table 3 (cont): Body weight and body weight change - group mean values (g) during gestation
Group /Sex |
|
Day 17 |
18 |
19 |
20 |
Change 0-6 |
Change 6-20 |
Statistics test |
Wi |
Wi |
Wi |
Wi |
Av |
Wi |
|
1F |
Mean |
362 |
379 |
395 |
413 |
32 |
130 |
|
SD |
15.5 |
17.8 |
18.4 |
20.6 |
6.9 |
10.9 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
2F |
Mean |
356 |
373 |
388 |
405 |
27* |
125 |
|
SD |
21.0 |
22.1 |
22.6 |
26.2 |
7.3 |
16.2 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
3F |
Mean |
359 |
375 |
389 |
404 |
30 |
124 |
|
SD |
18.7 |
21.7 |
24.0 |
26.5 |
6.0 |
18.3 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
4F |
Mean |
351 |
366 |
381 |
398 |
26** |
120 |
|
SD |
23.6 |
24.3 |
27.9 |
29.8 |
5.3 |
17.9 |
|
N |
19 |
19 |
19 |
19 |
19 |
19 |
Table 4: Gravid uterine weight, adjusted body weight and adjusted body weight change - group mean values (g) on Day 20 of gestation
Group /Sex |
|
Body weight Day 6 |
Terminal body weight Day 20 |
Body weight change 6-20 |
Gravid uterine weight |
Adjusted body weight Day 20 |
Adjusted body weight change 6-20 |
Statistics test |
Av |
Wi |
Wi |
Sh |
Wi |
Wi |
|
1F |
Mean |
283 |
412 |
130 |
92.9 |
319 |
37 |
|
SD |
12.3 |
20.2 |
10.8 |
7.31 |
17.7 |
8.9 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
2F |
Mean |
279 |
405 |
125 |
91.2 |
313 |
34 |
|
SD |
14.2 |
26.0 |
16.3 |
11.99 |
21.2 |
10.0 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
3F |
Mean |
280 |
405 |
125 |
87.7 |
317 |
37 |
|
SD |
12.4 |
26.3 |
18.2 |
16.68 |
15.4 |
9.3 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
4F |
Mean |
278 |
398 |
120 |
89.5 |
308 |
30* |
|
SD |
17.4 |
29.7 |
18.0 |
13.41 |
20.0 |
8.7 |
|
N |
19 |
19 |
19 |
19 |
19 |
19 |
Table 5: Food consumption - group mean values (g/animal/day) during gestation
Group /Sex |
|
Day 0-3 |
3-6 |
6-10 |
10-14 |
14-18 |
18-20 |
Statistics test |
Av |
Av |
Wi |
Wi |
Wi |
Wi |
|
1F |
Mean |
21 |
23 |
20 |
22 |
25 |
24 |
|
SD |
1.7 |
1.7 |
1.7 |
2.0 |
2.2 |
2.3 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
2F |
Mean |
20* |
22 |
19 |
21 |
23 |
23 |
|
SD |
1.9 |
1.8 |
1.7 |
1.9 |
2.2 |
2.2 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
3F |
Mean |
21 |
23 |
20 |
22 |
25 |
23 |
|
SD |
1.9 |
1.9 |
1.7 |
1.4 |
2.0 |
2.2 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
4F |
Mean |
19** |
22* |
18** |
20** |
23** |
22 |
|
SD |
1.4 |
1.9 |
1.7 |
1.7 |
2.5 |
3.7 |
|
N |
19 |
19 |
19 |
19 |
19 |
19 |
Table 6: Organ weights - group mean absolute and adjusted values (g) on Day 20 of gestation
Group /Sex |
|
Terminal Body weight |
Thyroids and Parathyroids |
Statistics test |
Wi |
|
|
1F |
Mean |
412 |
0.012 |
|
SD |
20 |
0.002 |
|
N |
20 |
20 |
2F |
Mean |
405 |
0.012 |
|
SD |
26 |
0.002 |
|
N |
20 |
20 |
3F |
Mean |
405 |
0.013 |
|
SD |
26 |
0.003 |
|
N |
20 |
20 |
4F |
Mean |
398 |
0.012 |
|
SD |
30 |
0.003 |
|
N |
19 |
19 |
|
|
Thyroids and Parathyroids |
Statistics test |
|
Wi |
1F |
Adjusted Mean |
0.012 |
2F |
Adjusted Mean |
0.011 |
3F |
Adjusted Mean |
0.013 |
4F |
Adjusted Mean |
0.012 |
Table 7: Macropathology – group distribution of findings on Day 20 of gestation
|
|
Number of animals affected |
|||
Tissue/Organ and Findings |
Group/Sex No. of animals |
1F 20 |
2F 20 |
3F 20 |
4F 19 |
Liver Mass(es) Pale area(s) |
|
1 0 |
0 1 |
0 0 |
0 0 |
Palpable Mass Found at necropsy |
|
0 |
1 |
0 |
0 |
Placenta Enlarged |
|
1 |
0 |
0 |
0 |
Table 8: Histopathology – group distribution of findings on Day 20 of gestation
|
|
Number of animals affected |
|||
Tissue/Organ and Findings |
Group/Sex No. of animals |
1F 20 |
2F 20 |
3F 20 |
4F 19 |
Thyroids Cyst(s), Ultimobranchial, Prominent
Cyst(s), Follicular |
No. examined Total
Total |
20 4
0 |
20 5
0 |
19 3
0 |
19 5
2 |
Table 9: Group mean values for T3
Group |
Treatment |
mg/kg/day |
|
Value |
Statistical test |
Wi |
|||
1 |
Control |
0 |
Mean (pg/mL) |
448 |
|
|
|
SD |
111 |
|
|
|
N |
20 |
2 |
Ethylal |
100 |
Mean (pg/mL) |
456 |
|
|
|
SD |
97 |
|
|
|
N |
19 |
3 |
Ethylal |
330 |
Mean (pg/mL) |
378* |
|
|
|
SD |
96 |
|
|
|
N |
19 |
4 |
Ethylal |
1000 |
Mean (pg/mL) |
363* |
|
|
|
SD |
107 |
|
|
|
N |
19 |
Excluding non-pregnant animals.
Table 10: Group mean values for T4
Group |
Treatment |
mg/kg/day |
|
Value |
Statistical test |
Wi |
|||
1 |
Control |
0 |
Mean (pg/mL) |
15545 |
|
|
|
SD |
3122 |
|
|
|
N |
20 |
2 |
Ethylal |
100 |
Mean (pg/mL) |
17058 |
|
|
|
SD |
3658 |
|
|
|
N |
19 |
3 |
Ethylal |
330 |
Mean (pg/mL) |
19221** |
|
|
|
SD |
4295 |
|
|
|
N |
19 |
4 |
Ethylal |
1000 |
Mean (pg/mL) |
19879** |
|
|
|
SD |
3982 |
|
|
|
N |
19 |
Excluding non-pregnant animals.
Table 11: Group mean values for TSH
Group |
Treatment |
mg/kg/day |
|
Value |
Statistical test |
lWi |
|||
1 |
Control |
0 |
Mean (pg/mL) |
1342 |
|
|
|
SD |
479 |
|
|
|
N |
20 |
2 |
Ethylal |
100 |
Mean (pg/mL) |
1512 |
|
|
|
SD |
602 |
|
|
|
N |
20 |
3 |
Ethylal |
330 |
Mean (pg/mL) |
1294 |
|
|
|
SD |
432 |
|
|
|
N |
20 |
4 |
Ethylal |
1000 |
Mean (pg/mL) |
1945* |
|
|
|
SD |
1087 |
|
|
|
N |
19 |
Excluding non-pregnant animals.
Table 12: Summary of litter data
Group |
No. of pregnant females |
No. of females with live young on Day 20 |
Pre-implantation loss (a) |
Post-implantation (b) |
Percent of live offspring to implantations (c) |
1 |
20 |
20 |
46 |
15 |
95.4 |
2 |
20 |
20 |
33 |
11 |
96.6 |
3 |
20 |
20 |
47 |
23 |
92.2 |
4 |
20 |
19 |
31 |
21 |
95.5 |
a – Total pre-implantation loss considered to be, total number of corpora lutea – total number of implantations. Where implantations exceed corpora lutea, number of implantations will be considered to be equal to corpora lutea.
b – Total post-implantation loss is considered to be, total number of implantations – total number of live young.
c - Percentage of live young is considered to be = (100 – ‘post-implantation loss’)
Table 13: Litter data - group mean values on Day 20 of gestation
Group /Sex |
|
Corpora lutea |
Implantations |
Resorptions |
Implantation loss (%) |
Live young |
Sex ratio (%M) |
|||||
Early |
Late |
Total |
Pre- |
Post- |
Male |
Female |
Total |
|||||
Statistics test |
Wi |
Sh |
|
|
|
Wi |
Wi |
|
|
Sh |
Wi |
|
1F |
Mean |
18.7 |
16.5 |
0.8 |
0.0 |
0.8 |
11.0 |
4.6 |
8.1 |
7.6 |
15.7 |
51.8 |
|
SD |
2.87 |
1.00 |
0.85 |
0.00 |
0.85 |
9.99 |
5.23 |
1.92 |
2.09 |
1.42 |
12.56 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
2F |
Mean |
17.4 |
15.8 |
0.5 |
0.1 |
0.6 |
9.4 |
3.4 |
7.1 |
8.2 |
15.3 |
46.4 |
|
SD |
1.53 |
2.17 |
0.83 |
0.22 |
0.83 |
11.26 |
5.25 |
2.47 |
2.28 |
2.17 |
13.47 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
3F |
Mean |
18.2 |
15.9 |
1.2 |
0.0 |
1.2 |
12.0 |
7.8 |
7.3 |
7.4 |
14.7 |
49.1 |
|
SD |
2.84 |
2.68 |
1.27 |
0.00 |
1.27 |
13.97 |
8.92 |
3.06 |
2.58 |
3.26 |
16.20 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
4F |
Mean |
17.1 |
16.1 |
0.6 |
0.1 |
0.7 |
7.4 |
4.5 |
7.9 |
7.4 |
15.4 |
50.2 |
|
SD |
2.61 |
1.96 |
1.02 |
0.32 |
1.06 |
7.14 |
7.25 |
3.21 |
1.80 |
2.43 |
16.07 |
|
N |
19 |
19 |
19 |
19 |
19 |
19 |
19 |
19 |
19 |
19 |
19 |
Table 14: Placental, litter and fetal weights – group mean values (g) on Day 20 of gestation
Group /Sex |
|
Placental weight |
Total litter weight |
Male fetal weight |
Female fetal weight |
Overall fetal weight |
Statistics test |
Wi |
Wi |
Wi |
Wi |
Wi |
|
1F |
Mean |
0.53 |
58.66 |
3.86 |
3.63 |
3.74 |
|
SD |
0.085 |
5.922 |
0.221 |
0.204 |
0.212 |
|
N |
20 |
20 |
20 |
20 |
20 |
2F |
Mean |
0.54 |
57.32 |
3.88 |
3.67 |
3.77 |
|
SD |
0.065 |
8.618 |
0.273 |
0.302 |
0.285 |
|
N |
20 |
20 |
20 |
20 |
20 |
3F |
Mean |
0.54 |
55.37 |
3.86 |
3.67 |
3.78 |
|
SD |
0.060 |
12.055 |
0.281 |
0.223 |
0.220 |
|
N |
20 |
20 |
20 |
20 |
20 |
4F |
Mean |
0.52 |
56.40 |
3.78 |
3.58 |
3.67 |
|
SD |
0.067 |
8.924 |
0.212 |
0.207 |
0.196 |
|
N |
19 |
19 |
19 |
19 |
19 |
Table 15: Fetal examinations - major abnormality findings - group incidences
|
|
Fetuses |
Litters |
||||||
Group |
|
1 |
2 |
3 |
4 |
1 |
2 |
3 |
4 |
Number Examined |
|
314 |
305 |
294 |
292 |
20 |
20 |
20 |
19 |
Total Number Affected |
|
1 |
1 |
0 |
0 |
1 |
1 |
0 |
0 |
Cervical/Thoracic |
|
|
|
|
|
|
|
|
|
Visceral |
Retroesophageal right subclavian artery Dorsally displaced pulmonary trunk Muscular ventricular septal defect Malrotated heart |
0 0 0 0 |
1 1 1 1 |
0 0 0 0 |
0 0 0 0 |
0 0 0 0 |
1 1 1 1 |
0 0 0 0 |
0 0 0 0 |
Appendicular |
|
|
|
|
|
|
|
|
|
Skeletal |
Thickened/misshapen long bones Polydactyly forepaw(s) |
1 1 |
0 0 |
0 0 |
0 0 |
1 1 |
0 0 |
0 0 |
0 0 |
Note: individual fetuses/litters may occur in more than one category
Table 16: Fetal examinations – Major Historical Control Data
Species/strain/source: Rat/ Sprague Dawley/ Charles River UK
Necropsy date range: May 2018– February 2019
Number of studies: 8
Study types: Main
|
|
TR83VY |
HCD Range |
||||||||
|
|
Fetuses |
Litters |
||||||||
Group |
|
1 |
2 |
3 |
4 |
1 |
2 |
3 |
4 |
||
Number Examined |
|
314 |
305 |
294 |
292 |
20 |
20 |
20 |
19 |
2087 |
143 |
Cervical/Thoracic Visceral |
Retroesophageal right subclavian artery Dorsally displaced pulmonary trunk Muscular ventricular septal defect Malrotated heart |
0 0 0 0 |
1 1 1 1 |
0 0 0 0 |
0 0 0 0 |
0 0 0 0 |
1 1 1 1 |
0 0 0 0 |
0 0 0 0 |
0-1 0-0 0-0 0-0 |
0-1 0-0 0-0 0-0 |
Table 17: Fetal examinations – minor skeletal abnormality and variants findings – group incidences
|
|
Fetuses |
Litters |
||||||
Group |
|
1 |
2 |
3 |
4 |
1 |
2 |
3 |
4 |
Number Examined |
|
158 |
153 |
146 |
146 |
20 |
20 |
20 |
19 |
Minor skeletal abnormalities |
|
|
|
|
|
|
|
|
|
Cranial |
sutural bone(s) interparietal fissure(s) |
0 1 |
1 1 |
1 0 |
0 0 |
0 1 |
1 1 |
1 0 |
0 0 |
Vertebral element abnormality |
thoracic |
0 |
0 |
1 |
1 |
0 |
0 |
1 |
1 |
Ribs |
medially thickened/kinked |
1 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
Sternebrae |
misaligned hemicentres |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
Costal cartilage |
misaligned |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
Appendicular |
misshapen cranial margin scapula(e) |
0 |
0 |
1 |
3 |
0 |
0 |
1 |
1 |
Total affected by one or more of the above |
|
2 |
2 |
3 |
5 |
2 |
2 |
3 |
3 |
Rib and vertebral configuration |
|
|
|
|
|
|
|
|
|
Cervical rib |
short supernumerary |
2 |
1 |
0 |
0 |
1 |
1 |
0 |
0 |
13th rib |
short without costal cartilage |
1 |
2 |
0 |
1 |
1 |
1 |
0 |
1 |
Number of 14th ribs |
short supernumerary full supernumerary total |
5 0 5 |
5 0 5 |
6 0 6 |
11 2 13 |
5 0 5 |
3 0 3 |
4 0 4 |
5 1 5 |
Thoracolumbar vertebrae |
18 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0 |
Pelvic girdle |
unilateral cranial shift |
1 |
0 |
1 |
0 |
1 |
0 |
1 |
0 |
Note: individual fetuses/litters may occur in more than one category
Table 17 (cont): Fetal examinations – minor skeletal abnormality and variants findings – group incidences
|
|
Fetuses |
Litters |
||||||
Group |
|
1 |
2 |
3 |
4 |
1 |
2 |
3 |
4 |
Number Examined |
|
158 |
153 |
146 |
146 |
20 |
20 |
20 |
19 |
Delayed/Incomplete ossification/unossified |
|
|
|
|
|
|
|
|
|
Cranial |
large nasofrontal suture cranial centres presphenoid hyoid |
0 8 1 26 |
0 12 0 16 |
2 9 0 31 |
0 1 0 6 |
0 4 1 11 |
0 7 0 7 |
2 4 0 15 |
0 1 0 5 |
Sternebrae |
5th and/or 6th other total |
98 10 99 |
76 3 78 |
60 5 61 |
70 7 73 |
18 9 18 |
18 1 18 |
19 3 19 |
18 3 18 |
Vertebrae |
cervical thoracic sacrocaudal caudal |
3 8 13 1 |
3 10 8 0 |
4 10 7 1 |
1 9 4 0 |
3 6 6 1 |
1 6 6 0 |
2 7 6 1 |
1 6 3 0 |
Ribs |
any |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0 |
Appendicular |
pelvic bones metacarpals metatarsals |
11 1 1 |
9 0 0 |
7 2 1 |
0 0 0 |
5 1 1 |
4 0 0 |
6 2 1 |
0 0 0 |
Increased ossification |
|
|
|
|
|
|
|
|
|
Cervical vertebral centra |
all ossified |
0 |
0 |
1 |
1 |
0 |
0 |
1 |
1 |
Note: individual fetuses/litters may occur in more than one category
Table 18: Fetal examinations - Skeletal Historical Control Data
Species/strain/source: Rat/ Sprague Dawley/ Charles River UK
Necropsy date range: May 2018– February 2019
Number of studies: 8
Study types: Main
|
|
TR83VY |
HCD Range |
||||||||
|
|
Fetuses |
Litters |
||||||||
Group |
|
1 |
2 |
3 |
4 |
1 |
2 |
3 |
4 |
||
Number Examined |
|
158 |
153 |
146 |
146 |
20 |
20 |
20 |
19 |
1097 |
143 |
Minor skeletal abnormalities |
|
|
|
|
|
|
|
|
|
|
|
Cranial Vertebral element abnormality Sternebrae Costal cartilage Appendicular |
sutural bone(s) thoracic misaligned hemicentres misaligned misshapen cranial margin scapula(e) |
0 0 0 0 0 |
1 0 0 0 0 |
1 1 0 0 1 |
0 1 1 1 3 |
0 0 0 0 0 |
1 0 0 0 0 |
1 1 0 0 1 |
0 1 1 1 1 |
0-2 0-3 0-2 0-2 0-1 |
0-1 0-2 0-2 0-2 0-1 |
Rib and vertebral configuration Number of 14th ribs Thoracolumbar vertebrae |
full supernumerary 18 |
0 0 |
0 0 |
0 1 |
2 0 |
0 0 |
0 0 |
0 1 |
1 0 |
0-1 0-2 |
0-1 0-1 |
Delayed/Incomplete ossification/unossified Cranial Ribs Increased ossification Cervical vertebral centra |
large nasofrontal suture any
all ossified |
0 0
0 |
0 0
0 |
2 1
1 |
0 0
1 |
0 0
0 |
0 0
0 |
2 1
1 |
0 0
1 |
0-2 0-1
0-1 |
0-2 0-1
0-1 |
Table 19: Fetal examinations - minor visceral abnormality and necropsy findings - group incidences
|
|
Fetuses |
Litters |
||||||
Group |
|
1 |
2 |
3 |
4 |
1 |
2 |
3 |
4 |
Number Examined |
|
156 |
152 |
148 |
146 |
20 |
20 |
20 |
19 |
Total Number Affected |
|
25 |
23 |
21 |
11 |
15 |
16 |
13 |
9 |
Visceral abnormalities |
|
|
|
|
|
|
|
|
|
Thymus |
partially undescended lobe thymic remnant |
3 1 |
2 0 |
4 0 |
1 0 |
3 1 |
1 0 |
4 0 |
1 0 |
Lungs |
absent accessory lobe |
0 |
1 |
0 |
0 |
0 |
1 |
0 |
0 |
Diaphragm |
thinning with liver protrusion |
1 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
Liver |
fissured posterior caudate lobe folded posterior caudate lobe |
1 0 |
0 0 |
0 1 |
1 0 |
1 0 |
0 0 |
0 1 |
1 0 |
Spleen |
small |
0 |
1 |
0 |
0 |
0 |
1 |
0 |
0 |
Testis(es) |
malpositioned |
1 |
1 |
1 |
0 |
1 |
1 |
1 |
0 |
Umbilical artery |
left |
2 |
2 |
1 |
0 |
2 |
2 |
1 |
0 |
Haemorrhages |
|
|
|
|
|
|
|
|
|
Head |
brain vitreous humour eye |
1 2 |
2 0 |
2 0 |
2 0 |
1 2 |
2 0 |
2 0 |
2 0 |
Neck/Thorax |
dorsal fat pad thoracic cavity |
1 0 |
1 0 |
0 1 |
1 0 |
1 0 |
1 0 |
0 1 |
1 0 |
Abdomen |
abdominal cavity liver lobes |
10 2 |
9 3 |
10 1 |
5 2 |
7 2 |
6 3 |
8 1 |
4 2 |
General |
subcutaneous |
1 |
1 |
1 |
0 |
1 |
1 |
1 |
0 |
Necropsy observations (external) |
|
|
|
|
|
|
|
|
|
Skin |
shiny subcutaneous edema |
0 0 |
2 1 |
2 0 |
0 0 |
0 0 |
2 1 |
2 0 |
0 0 |
Note: individual fetuses/litters may occur in more than one category
Table 20: Fetal examinations – Visceral Historical Control Data
Species/strain/source: Rat/ Sprague Dawley/ Charles River UK
Necropsy date range: May 2018– February 2019
Number of studies: 8
Study types: Main
|
|
Fetuses |
Litters |
HCD Range |
|||||||
Group |
|
1 |
2 |
3 |
4 |
1 |
2 |
3 |
4 |
||
Number Examined |
|
156 |
152 |
148 |
146 |
20 |
20 |
20 |
19 |
||
Total Number Affected |
|
25 |
23 |
21 |
11 |
15 |
16 |
13 |
9 |
1091 |
19 |
Visceral abnormalities Lungs
Spleen |
absent accessory lobe folded posterior caudate lobe small |
0 0 0 |
1 0 1 |
0 1 0 |
0 0 0 |
0 0 0 |
1 0 1 |
0 1 0 |
0 0 0 |
0-0 0-3 0-0 |
0-0 0-3 0-0 |
Haemorrhages |
thoracic cavity |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0 |
0-1 |
0-1 |
Necropsy observations (external) Skin |
shiny subcutaneous edema |
0 0 |
2 1 |
2 0 |
0 0 |
0 0 |
2 1 |
2 0 |
0 0 |
0-1 0-1 |
0-1 0-1 |
Table 21: Ano-genital distance - group mean absolute and adjusted values for fetuses
Group /Sex |
|
Fetal weight (g) |
Ano-genital distance (mm) |
Statistics test |
Wi |
|
|
1M |
Mean |
3.9 |
4.1 |
|
SD |
0.22 |
0.19 |
|
N |
20 |
20 |
2M |
Mean |
3.9 |
4.0 |
|
SD |
0.28 |
0.21 |
|
N |
20 |
20 |
3M |
Mean |
3.9 |
4.1 |
|
SD |
0.28 |
0.20 |
|
N |
20 |
20 |
4M |
Mean |
3.8 |
4.1 |
|
SD |
0.21 |
0.14 |
|
N |
19 |
19 |
|
Ano-genital distance (mm) |
|
Statistics test |
Wi |
|
1M |
Adjusted Mean |
4.1 |
2M |
Adjusted Mean |
4.0 |
3M |
Adjusted Mean |
4.1 |
4M |
Adjusted Mean |
4.1 |
Table 21 (cont): Ano-genital distance - group mean absolute and adjusted values for fetuses
Group /Sex |
|
Fetal weight (g) |
Ano-genital distance (mm) |
Statistics test |
Wi |
|
|
1F |
Mean |
3.6 |
2.5 |
|
SD |
0.20 |
0.13 |
|
N |
20 |
20 |
2F |
Mean |
3.7 |
2.5 |
|
SD |
0.26 |
0.18 |
|
N |
20 |
20 |
3F |
Mean |
3.7 |
2.5 |
|
SD |
0.23 |
0.20 |
|
N |
20 |
20 |
4F |
Mean |
3.6 |
2.6 |
|
SD |
0.21 |
0.21 |
|
N |
19 |
19 |
|
Ano-genital distance (mm) |
|
Statistics test |
Wi |
|
1F |
Adjusted Mean |
2.5 |
2F |
Adjusted Mean |
2.5 |
3F |
Adjusted Mean |
2.5 |
4F |
Adjusted Mean |
2.6 |
Table 22: Thyroid hormone data
Species/strain/source: Rat/ Sprague Dawley/ Charles River UK
Necropsy date range: Sept 2019– December 2019
Number of studies: 4
Study types: Main
|
T3 (pg/mL) |
T4 (pg/mL) |
TSH (pg/mL) |
N |
80 |
80 |
80 |
1% |
287 |
8204 |
303 |
5% |
326 |
9916 |
419 |
50% |
473 |
16950 |
1030 |
95% |
625 |
26275 |
2476 |
99% |
701 |
50765 |
2974 |
Mean |
483 |
18730 |
1250 |
SD |
97.8 |
13191.3 |
702.3 |
Applicant's summary and conclusion
- Conclusions:
- Based on the results of this study, the maternal and embryo-fetal No-Observed-Adverse-Effect-Level (NOAEL) was 1000 mg/kg/day.
- Executive summary:
Introduction
The purpose of this study was to assess the influence of Ethylal (an industrial chemical) on embryo-fetal survival and development when administered during the organogenesis and fetal growth phases of pregnancy in the Sprague Dawley rat.
Four groups of 20 females received Ethylal at doses of 100, 330 or 1000 mg/kg/day by oral gavage administration, from Day 6 to 19 after mating. A similarly constituted Control group received the vehicle, corn oil at the same volume dose as treated groups. Animals were killed on Day 20 after mating for reproductive assessment and fetal examination.
Clinical observations, body weight and food consumption were recorded. Adult females were examined; macroscopic and microscopic pathology investigation were undertaken on Day 20 after mating and the gravid uterus weight and thyroid weight were recorded. Ano‑genital distance were measured for all fetuses and were examined macroscopically at necropsy and subsequently by detailed internal visceral examination or skeletal examination.
Results
Following initial treatment (gestation day 6), signs associated with dosing Ethylal at 1000 mg/kg/day included unsteady gait in 11 animals, decreased activity in 5 animals, flattened posture, or gait, in 4 animals and partially closed eye lids in 3 animals. At 1000 mg/kg/day, chin rubbing was seen towards the end of treatment and at 330 mg/kg/day, or above, salivation was seen throughout the treatment period.
There was no clear difference in the overall (gestation day 6 to 20) body weight change for females treated with Ethylal at any dose level. Although body weight loss/stasis was seen in females receiving 330 or 1000 mg/kg/day following initial treatment gestation Day 6 to 7.
There was no effect of treatment on gravid uterine weight.
Food consumption of females treated at 1000 mg/kg/day was statistically significantly low prior to the start of treatment and remained low throughout treatment, although statistical significance was not attained on the last recording occasion.
There was no effect of treatment on the macroscopic appearance of organs in the adults or the external appearance of fetuses at necropsy.
The microscopic examination of the thyroid and parathyroid revealed no test item-related lesions.
There were no clear effects of treatment on early or late resorptions, numbers of live young, sex ratio or pre/post implantation losses.
There were no effects of treatment on placental, litter or fetal weights.
There was no effect of treatment on ano-genital distances. There was a slight dose related decrease in levels of T3 at 330 or 1000 mg/kg/day, a slight increase in T4 levels at 330 or 1000 mg/kg/day and a slight increase in TSH levels at 1000 mg/kg/day.
The incidence of major and minor abnormalities and skeletal variants in fetuses show no relationship to treatment.
Conclusion
Based on the results of this study, the maternal and the embryo-fetal No-Observed-Adverse-Effect-Level (NOAEL) was 1000 mg/kg/day.
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