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EC number: 202-860-4 | CAS number: 100-52-7
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2021-AUG-19 to 2022-MAR-09
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 022
- Report date:
- 2022
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Benzaldehyde
- EC Number:
- 202-860-4
- EC Name:
- Benzaldehyde
- Cas Number:
- 100-52-7
- Molecular formula:
- C7H6O
- IUPAC Name:
- benzaldehyde
- Test material form:
- liquid
- Details on test material:
- Test material: Benzaldehyde
CAS No. 100-52-7
EC No. 202-860-4
Batch No. #2101-4
Expiration date: 04 January 2023
Purity: > 99.5% w/w
Storage: Stored in darkness at ambient temperature (approximately 21°C). All samples were stored under nitrogen.
Constituent 1
- Specific details on test material used for the study:
- Test material: Benzaldehyde
CAS No. 100-52-7
EC No. 202-860-4
Batch No. #2101-4
Expiration date: 04 January 2023
Purity: > 99.5% w/w
Storage: Stored in darkness at ambient temperature (approximately 21°C). All samples were stored under nitrogen.
Test animals
- Species:
- rat
- Strain:
- Wistar
- Remarks:
- RccHan®:WIST.(Han Wistar)
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Envigo RMS Limited
- Age at study initiation: 11 to 12 weeks old at arrival
- Weight at study initiation: 181 to 235 grams
- Fasting period before study: Not specified
- Housing: Individually in solid (polycarbonate) bottom cages during the acclimatization and gestation periods
- Diet (e.g. ad libitum): SDS VRF1 Certified, pelleted diet ad libitum
- Water (e.g. ad libitum): Potable water from the public supply via polycarbonate bottles with sipper tubes ad libitum
- Acclimation period: 4 days (from arrival on Day 2 after mating to commencement of treatment on Day 6 after mating)
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 40-70%
- Air changes (per hr): Filtered fresh air was passed to atmosphere and not recirculated
- Photoperiod (hrs dark / hrs light): 12 hrs dark / 12 hrs light
IN-LIFE DATES: From: 2021-AUG-26 to 29 To:2021-SEP-14 to 21
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: 0.5% methylcellulose with 0.5% Tween-80 in purified water
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
Formulations were prepared weekly and in advance of the first day of dosing under yellow light. The required amount of test material was weighed into a suitable sized beaker to hold the whole formulation. Vehicle was added to achieve the required weight and the formulation was mixed using a high shear homogenizer until fully homogenous. Formulations were magnetically stirred for a minimum of 20 minutes then transferred to their final containers via syringe while being magnetically stirred. A series of formulations at the required concentrations were prepared by dilution of individual weighing’s of the test material and stored refrigerated at 2 to 8°C.
VEHICLE
- Justification for use and choice of vehicle (if other than water): 0.5% methylcellulose with 0.5% Tween-80 in purified water (Justification not specified)
- Concentration in vehicle: 0, 10, 30, or 60 mg/mL for the 0, 100, 300, and 600 mg/kg/day dose groups, respectively.
- Amount of vehicle (if gavage): 10 mL/kg
- Lot/batch no. (if required): Not specified - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Stability and homogeneity
The homogeneity and stability of formulations during storage were determined as part of Labcorp Study No. 8462384. Formulations in the range 1 to 250 mg/mL were determined to be stable for: One day at ambient temperature (15 to 25°C); 15 days when stored refrigerated (2 to 8°C).
Achieved concentration
Samples of each formulation prepared for administration in the first and last week of treatment were analyzed for achieved concentration of the test material. - Details on mating procedure:
- - Impregnation procedure: 88 female rats purchased timed pregnant (arrived at CRO on Day 2 post mating)
Natural mating with Han Wistar of established fertility at the supplier’s facility. Males and females were not related and positive evidence of mating was designated as Day 0. - Duration of treatment / exposure:
- Day 6 to Day 20 (inclusive) after mating.
- Frequency of treatment:
- Once daily
- Duration of test:
- Day 6 to Day 20 (inclusive) after mating.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- Group 1 (Control)
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Remarks:
- Group 2
- Dose / conc.:
- 300 mg/kg bw/day (nominal)
- Remarks:
- Group 3
- Dose / conc.:
- 600 mg/kg bw/day (nominal)
- Remarks:
- Group 4
- No. of animals per sex per dose:
- 22 females/dose
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:
The doses selected in this study (0, 100, 300 and 600 mg/kg/day) were were based on the results of the preliminary study (Labcorp Study Number 8462299). In that study doses of 0, 100, 300 and 600 mg/kg/day were investigated. There were no premature deaths and no treatment-related clinical signs. At 600 mg/kg/day, transient signs of decreased activity (in one female on Day 16 after mating and in two females on Day 17 of gestation), irregular breathing (in one female on Day 17 of gestation) and salivation (in one female on Day 18 of gestation) were observed post-dosing. Overall mean maternal body weight gain was slightly reduced at the 300 and 600 mg/kg/day dose levels, as was mean maternal body weight adjusted for the contribution of the gravid uterine weight at 600 mg/kg/day. Mean gravid uterine weight was slightly low at 600 mg/kg/day. Food intake was slightly low during Days 18-21 of gestation for females at 600 mg/kg/day.
One female that received 600 mg/kg/day was found not to be pregnant at macroscopic examination and one female that received 300 mg/kg/day had a total litter resorption. Post-implantation loss was higher than Control in all groups of treated females, however, no dose response was apparent. There was no clear effect of treatment on the number of implantations, resorptions (early, late and total), pre-implantation loss, or the number of live young or sex ratio at any dose level investigated. Mean placental weights were lower than Control for all groups of treated females, with a dose response apparent. Mean total litter weight was lower than Control at 600 mg/kg/day. Male, female, and overall fetal weights were statistically significantly lower than Control at 600 mg/kg/day. There were no findings at macroscopic examination of the adult females and no treatment related findings at external examination of the fetuses at any dose level investigated.
The high-dose level should produce some maternal and/or developmental toxic effects, but not death nor obvious suffering. The mid-dose level is expected to produce minimal to moderate toxic effects. The low-dose level should produce no observable indications of toxicity. Therefore, doses of 0, 100, 300 and 600 mg/kg/day were investigated in the current OECD 414 study in the rat.
- Rationale for animal assignment (if not random): Randomly to each group on the day of arrival
- Fasting period before blood sampling for (rat) dam thyroid hormones: No overnight deprivation of food
- Time of day for (rat) dam blood sampling: At termination
- Other:
Route of administration: The oral gavage route of administration was chosen to simulate the conditions of possible human exposure.
Animal Model: The rat was chosen as the test species because of the requirement for a rodent species by regulatory agencies. The Han Wistar (RccHan®:WIST) strain was used because of the historical control data available at the CRO.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Cages were inspected daily for evidence of animal ill-health and a viability check was performed near the start and end of each working day.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: 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. During the acclimatization period, observations of the animals and their cages were recorded at least once per day.
BODY WEIGHT: Yes
- Time schedule for examinations:The weight of each adult was recorded on the day after arrival (Day 3 after mating) and on Days 6, 9, 12, 15, 18, and 21 after mating.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes / No / No data
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes; The weight of food supplied to each adult, that remaining and an estimate of any spilled was recorded for the periods Days 3-6, 6-9, 9-12, 12-15, 15-18 and 18-21 after mating inclusive
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 21
Animals surviving until the end of the scheduled study period were killed by carbon dioxide asphyxiation on Day 21 after mating
- Organs examined: Gravid uterine weight (including cervix and ovaries); Thyroid - 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
- Other: Fetuses (live and dead) - Blood sampling:
- Blood samples (1.0 mL) were collected under Isoflurane anesthesia from the sublingual vein of all adult females (excluding premature deaths) at termination. Samples were kept at ambient temperature (15 to 25°C) for a minimum of 30 minutes prior to centrifugation (At 2000g for ten minutes at 4°C). Two aliquots (Aliquot 1: 0.2 mL serum for T3/T4 and Aliquot 2: residual serum for TSH) were taken per animal.
- Fetal examinations:
- - External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [half per litter]
- Skeletal examinations: Yes: [half per litter]
- Head examinations: Yes: [half per litter]
- Anogenital distance of all live rodent pups: Yes - Statistics:
- For information on statistics please see 'Any other information on materials and methods incl. tables'.
- Indices:
- Reproductive Assessment
Prenatal losses were separated into pre- and post-implantation phases. Pre-implantation loss was considered to reflect losses due to non-fertilization of ova and failure to implant. It was calculated from the formula:
Pre-implantation loss (%) = ((Number of corpora lutea - Number of implantations) / Number of corpora lutea) x 100
Where the number of implantations exceeded the number of corpora lutea observed, pre implantation loss was assumed to be zero (i.e. no pre-implantation loss was considered to have occurred).
Post-implantation loss was calculated from the formula:
Post-implantation loss (%) = ((Number of implantations - Number of live fetuses) / Number of implantations) x 100 - Historical control data:
- July 2015 - Present Historical Control Data (HCD) presented in Tables 10, 11, 12, and 13 in 'Any other information on results incl. tables'.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No treatment-related signs of clinical toxicity were observed at routine examination or following dose administration.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- One female (4F 71) in the 600 mg/kg/day dose group was euthanized (for welfare reasons) on Day 11 of gestation, due to general poor clinical condition with clinical signs of decreased activity, piloerection, hunched posture and abnormal (swaying) gait. This female was also abnormally cold to touch and had a distended abdomen. Macroscopic examination revealed abnormal, pale contents in the stomach and a distended stomach. The female was found to be pregnant with 12 live fetuses. Since no other premature deaths occurred on study and no similar signs were observed among the remaining females, this premature death was not considered to be treatment-related.
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There was no clear effect of treatment on body weight gain at any dose level investigated. No adverse effect of treatment on mean body weight gain adjusted for the contribution of the gravid uterine weight was observed at any dose level investigated. Mean adjusted body weight on Day 21 of gestation and mean adjusted body weight gain at 300 or 600 mg/kg/day were statistically significantly higher than Control. There was no clear effect of treatment on gravid uterine weight at 100 or 300 mg/kg/day. At 600 mg/kg/day, mean gravid uterine weight was slightly, but not statistically significantly, lower than Control.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- Food consumption remained unaffected through the study period.
- 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
- Endocrine findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Mean serum T3 or T4 concentration of maternal females in the 100 or 300 mg/kg/day remained unaffected post-treatment. Statistically significantly low mean serum T3 and T4 concentrations were observed at 600 mg/kg/day when compared to control animals (reduction of 24% and 26%, respectively). These differences were not considered to be adverse in the absence of any microscopic changes of the thyroid and with no effect of treatment on TSH concentration.
Mean serum TSH concentrations of animals in all treatment groups appeared unaffected by treatment with the test material. The mean serum TSH concentration in the 300 mg/Kg/day dose group was observed to be statistically significantly higher than control. However, one animal (3F 62) had a much higher TSH concentration than the other animals within the group, and therefore, the observed increased mean was more likely due to biological variation than exposure to the test material. No such effects were observed in animals in the 100 and 600 mg/kg/day dose groups. - 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 weights were unaffected by treatment.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- Gross necropsy did not reveal any remarkable treatment-related findings.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- There were no treatment-related microscopic findings in the thyroids
- 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):
- No treatment-related effects observed.
- Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- No treatment-related effects observed.
- Early or late resorptions:
- no effects observed
- Description (incidence and severity):
- No treatment-related effects observed.
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- No treatment-related effects observed.
- Changes in pregnancy duration:
- no effects observed
- Description (incidence and severity):
- No treatment-related effects observed.
- Changes in number of pregnant:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Three rats in the control group, two in the 100 mg/kg/day dose group, one in the 300 mg/kg/day dose group, and one female in the 600 mg/kg/day dose group were found to be not pregnant at macroscopic examination.
- Other effects:
- no effects observed
- Description (incidence and severity):
- Mean placental weights were unaffected by treatment
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 600 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: Systemic Toxicity
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- There was no effect of treatment on fetal weights at 100 or 300 mg/kg/day. However, male, female and overall fetal weights were statistically significantly low at 600 mg/kg/day when compared to Controls (overall fetal weight was 16% lower than Controls).
- Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- Number of live young was unaffected by treatment.
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- Sex ratio was unaffected by treatment.
- Changes in litter size and weights:
- effects observed, treatment-related
- Description (incidence and severity):
- Mean total litter weights were observed to be slightly, but not statistically significantly lower than Control at 600 mg/kg/day.
- Anogenital distance of all rodent fetuses:
- no effects observed
- Description (incidence and severity):
- Fetal ano-genital distance was unaffected by treatment.
- Changes in postnatal survival:
- no effects observed
- External malformations:
- effects observed, treatment-related
- Description (incidence and severity):
- 8 fetuses in 4 litters in the 600 mg/kg/day dose group were observed to have major eye abnormalities; anophthalmia and microphthalmia exceeding the Historical Control Data (HCD) range. These findings were considered to be adverse treatment-related effects.
At 100 and 600 mg/kg/day, there were 5 fetuses with apparent malrotation of the hindlimb(s) noted at necropsy external examination. At subsequent skeletal examination, although the limbs still appeared slightly malrotated, both the bones and cartilage of the hindlimbs were normal. This finding was therefore considered to be incidental and not treatment-related. - Skeletal malformations:
- effects observed, treatment-related
- Description (incidence and severity):
- 8 fetuses in 4 litters in the 600 mg/kg/day dose group were observed to have small orbital socket(s) at skeletal examination, all exceeding the Historical Control Data (HCD) range. These findings were considered to be adverse treatment-related effects.
Additionally, at 600 mg/kg/day, there was an increase in the incidence of minor skeletal abnormalities/variants compared to concurrent control which exceeded the HCD range; medially thickened/kinked ribs (the incidence was also increased to a lesser extent at 100 or 300 mg/kg/day), short supernumerary cervical ribs, supernumerary 14th rib(s), 20 thoracolumbar vertebrae, incompletely ossified cranial centres, sternebrae and cervical vertebrae. These findings, although treatment-related, were not considered adverse.
At 100 and 600 mg/kg/day, there were 5 fetuses with apparent malrotation of the hindlimb(s) noted at necropsy external examination. At subsequent skeletal examination, although the limbs still appeared slightly malrotated, both the bones and cartilage of the hindlimbs were normal. This finding was therefore considered to be incidental and not treatment-related. - Visceral malformations:
- effects observed, treatment-related
- Description (incidence and severity):
- 8 fetuses in 4 litters in the 600 mg/kg/day dose group were observed to have major eye abnormalities; anophthalmia and microphthalmia with absent optic nerve at fixed visceral examination, all exceeding the Historical Control Data (HCD) range. These findings were considered to be adverse treatment-related effects.
- Other effects:
- not examined
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 300 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- fetal/pup body weight changes
- external malformations
- skeletal malformations
- visceral malformations
Fetal abnormalities
- Key result
- Abnormalities:
- effects observed, treatment-related
- Localisation:
- external: eye
- skeletal: skull
- visceral/soft tissue: eye
- Description (incidence and severity):
- 8 fetuses in 4 litters in the 600 mg/kg/day dose group were observed to have major eye abnormalities; anophthalmia and microphthalmia with absent optic nerve at fixed visceral examination. Small orbital socket(s) were also observed in these animals at skeletal examination, all exceeding the Historical Control Data (HCD) range.
Overall developmental toxicity
- Key result
- Developmental effects observed:
- yes
- Lowest effective dose / conc.:
- 600 mg/kg bw/day (nominal)
- Treatment related:
- yes
- Relation to maternal toxicity:
- developmental effects in the absence of maternal toxicity effects
- Dose response relationship:
- yes
- Relevant for humans:
- not specified
Any other information on results incl. tables
The mean concentrations of all test material formulations analyzed were within ± 20% of nominal concentrations.
Table 2. Results of Formulation Analysis |
|||
Sample ID |
Nominal Concentration (mg/mL) |
Concentration Found (mg/mL) |
Expressed as % of Nominal |
2021-AUGUST-28 |
|||
F8046 |
0 |
ND |
- |
F8047 |
10 |
9.24 |
92 |
F8048 |
30 |
28.2 |
94 |
F8049 |
60 |
58.4 |
97 |
2021-SEPTEMBER-02 |
|||
F8074 |
0 |
ND |
- |
F8073 |
10 |
8.32 |
83 |
F8072 |
30 |
26.7 |
89 |
F8071 |
60 |
55.9 |
93 |
Results are a mean of duplicate analysis
Table 3. Body weight and body weight change - group mean values (g) during gestation |
|||||||||||||||
Dose Group (mg/kg/day) |
|
Day |
|
Change |
|||||||||||
3 |
6 |
9 |
12 |
15 |
18 |
21 |
6-9 |
9-12 |
6-12 |
12-15 |
15-18 |
18-21 |
6-21 |
||
Statistics test |
|
Av |
Av |
Wi |
Wi |
Wi |
Wi |
Wi |
Sh |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Group 1 (Control – 0 mg/kg/day) |
Mean |
203 |
211 |
218 |
230 |
243 |
268 |
294 |
7 |
12 |
19 |
12 |
25 |
26 |
82 |
SD |
11.2 |
10.4 |
11.6 |
13.4 |
14.8 |
17.7 |
22.0 |
2.9 |
4.2 |
4.8 |
4.5 |
5.9 |
6.5 |
15.0 |
|
N |
19 |
19 |
19 |
19 |
19 |
19 |
19 |
19 |
19 |
19 |
19 |
19 |
19 |
19 |
|
|
|||||||||||||||
Group 2 (Control – 100 mg/kg/day) |
Mean |
201 |
210 |
217 |
229 |
241 |
266 |
294 |
7 |
12 |
19 |
12 |
25 |
28 |
84 |
SD |
9.5 |
9.4 |
9.9 |
12.8 |
15.1 |
18.0 |
22.4 |
2.6 |
4.2 |
4.7 |
6.1 |
7.6 |
7.3 |
18.2 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
|
|
|||||||||||||||
Group 3 (Control – 300 mg/kg/day) |
Mean |
208 |
217 |
226 |
238 |
249 |
275 |
303 |
9 |
12 |
21 |
11 |
26 |
27 |
86 |
SD |
17.8 |
15.8 |
17.2 |
17.9 |
17.7 |
18.8 |
22.9 |
3.4 |
3.7 |
4.9 |
4.1 |
3.8 |
6.2 |
11.9 |
|
N |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
|
|
|||||||||||||||
Group 4 (Control – 600 mg/kg/day) |
Mean |
205 |
214 |
221 |
234 |
246 |
269 |
296 |
7 |
12 |
19 |
12 |
23 |
27 |
82 |
SD |
13.1 |
13.1 |
16.2 |
16.5 |
16.9 |
21.5 |
29.2 |
5.6 |
4.6 |
5.0 |
3.4 |
6.9 |
9.9 |
20.1 |
|
N |
21 |
21 |
21 |
20 |
20 |
20 |
20 |
21 |
20 |
20 |
20 |
20 |
20 |
20 |
|
Av Pre-treatment comparison of all groups using Analysis of variance followed by pairwise t-tests.
Sh Treated groups compared with Control using Shirley’s test
Wi Treated groups compared with Control using Williams’ test
Table 4. Gravid Uterine Weight, Adjusted Body Weight and Adjusted Body Weight Change - Group Mean Values (g) on Day 21 of Gestation |
|||||||
Dose Group (mg/kg/day) |
|
Body Weight Day 6 |
Terminal Body Weight Day 21 |
Body Weight Change Day 6-21 |
Gravid Uterine Weight |
Adjusted Body Weight Day 21 |
Adjusted Body Weight Change Day 6-21 |
Statistics test |
|
Av |
Wi |
Wi |
Wi |
Wi |
Wi |
Group 1 (Control – 0 mg/kg/day) |
Mean |
211 |
293 |
82 |
67.3 |
226 |
15 |
SD |
10 |
22.0 |
15.0 |
17.22 |
16.9 |
10.5 |
|
N |
19 |
19 |
19 |
19 |
19 |
19 |
|
|
|||||||
Group 2 (Control – 100 mg/kg/day) |
Mean |
210 |
294 |
83 |
63.5 |
230 |
20 |
SD |
9.4 |
22.4 |
18.3 |
18.86 |
9.3 |
6.6 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
|
|
|||||||
Group 3 (Control – 300 mg/kg/day) |
Mean |
217 |
303 |
86 |
64.7 |
238* |
21* |
SD |
15.8 |
23.2 |
12.1 |
15.39 |
16.8 |
8.2 |
|
N |
21 |
21 |
21 |
21 |
21 |
21 |
|
|
|||||||
Group 4 (Control – 600 mg/kg/day) |
Mean |
214 |
296 |
81 |
57.7 |
238* |
24** |
SD |
13.4 |
29.3 |
20.2 |
21.28 |
16.7 |
10.1 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
|
Av Pre-treatment comparison of all groups using Analysis of variance followed by pairwise t-tests.
Wi Treated groups compared with Control using Williams’ test
* p<0.05
** p<0.01
Table 5. Litter Data – Group Mean Values on Day 21 of Gestation |
||||||||||||
Dose Group (mg/kg/day) |
|
Corpora lutea |
Implantations |
Resorptions |
Implantation loss (%) |
Live young |
Sex ratio (%M) |
|||||
Early |
Late |
Total |
Pre- |
Post- |
Male |
Female |
Total |
|||||
Statistics test |
Wi |
Wi |
|
|
|
Wi |
Wi |
|
|
Wi |
Wi |
|
|
||||||||||||
Group 1 (Control – 0 mg/kg/day) |
Mean |
11.6 |
10.4 |
0.7 |
0.1 |
0.7 |
11.4 |
9.0 |
5.3 |
4.4 |
9.6 |
56.4 |
SD |
1.61 |
2.75 |
0.82 |
0.23 |
0.81 |
19.28 |
12.89 |
2.47 |
2.06 |
2.87 |
22.17 |
|
N |
19 |
19 |
19 |
19 |
19 |
19 |
19 |
19 |
19 |
19 |
19 |
|
|
||||||||||||
Group 2 (Control – 100 mg/kg/day) |
Mean |
12.2 |
9.7 |
0.7 |
0.1 |
0.7 |
18.1 |
6.5 |
4.4 |
4.7 |
9.0 |
46.4 |
SD |
2.53 |
3.16 |
0.93 |
0.22 |
0.98 |
24.13 |
8.62 |
2.16 |
2.21 |
2.97 |
18.06 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
|
|
||||||||||||
Group 3 (Control – 300 mg/kg/day) |
Mean |
12.0 |
10.0 |
0.5 |
0.0 |
0.5 |
15.4 |
4.8 |
5.0 |
4.5 |
9.5 |
53.5 |
SD |
2.06 |
2.46 |
1.12 |
0.00 |
1.12 |
19.19 |
10.28 |
2.09 |
2.04 |
2.50 |
17.88 |
|
N |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
|
|
||||||||||||
Group 4 (Control – 600 mg/kg/day) |
Mean |
12.0 |
9.9 |
0.7 |
0.0 |
0.7 |
18.9 |
9.0 |
4.5 |
4.8 |
9.3 |
46.5 |
SD |
1.45 |
3.39 |
0.81 |
0.00 |
0.81 |
23.72 |
16.70 |
2.06 |
2.35 |
3.63 |
16.84 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
|
Wi Treated groups compared with Control using Williams’ test
Table 6. Placental, Litter and Fetal Weights - Group Mean Values (g) on Day 21 of Gestation |
||||||||
Dose Group (mg/kg/day) |
|
Placental weight |
Total litter weight |
Male fetal weight |
Female fetal litter |
Overall fetal weight |
Fetal weight (g) |
Ano-genital distance (mm) |
|
||||||||
Statistics test |
|
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
|
Group 1 (Control – 0 mg/kg/day) |
Mean |
0.50 |
49.73 |
5.31 |
5.04 |
5.20 |
5.3 |
3.6 |
SD |
0.185 |
14.541 |
0.232 |
0.231 |
0.225 |
0.23 |
0.16 |
|
N |
19 |
19 |
19 |
18 |
19 |
19 |
19 |
|
|
||||||||
Group 2 (Control – 100 mg/kg/day) |
Mean |
0.48 |
47.20 |
5.39 |
5.17 |
5.25 |
5.4 |
3.8 |
SD |
0.101 |
15.063 |
0.347 |
0.270 |
0.306 |
0.35 |
0.19 |
|
N |
20 |
20 |
19 |
20 |
20 |
19 |
19 |
|
|
||||||||
Group 3 (Control – 300 mg/kg/day) |
Mean |
0.46 |
48.15 |
5.21 |
4.97 |
5.09 |
5.2 |
3.6 |
SD |
0.063 |
12.231 |
0.408 |
0.375 |
0.383 |
0.41 |
0.23 |
|
N |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
|
|
||||||||
Group 4 (Control – 600 mg/kg/day) |
Mean |
0.50 |
40.25 |
4.49** |
4.27** |
4.36** |
4.5** |
3.6 |
SD |
0.099 |
15.818 |
0.448 |
0.416 |
0.419 |
0.45 |
0.19 |
|
N |
20 |
20 |
19 |
20 |
20 |
19 |
19 |
|
** p<0.01
Wi Treated groups compared with Control using Williams’ test
Table 7. Fetal Examinations - Major Abnormality Findings - Group Incidences |
|||||||||
Group |
|
Fetuses |
Litters |
||||||
|
Group 1 (Control – 0 mg/kg/day) |
Group 2 (Control – 100 mg/kg/day) |
Group 3 (Control – 300 mg/kg/day) |
Group 4 (Control – 600 mg/kg/day) |
Group 1 (Control – 0 mg/kg/day) |
Group 2 (Control – 100 mg/kg/day) |
Group 3 (Control – 300 mg/kg/day) |
Group 4 (Control – 600 mg/kg/day) |
|
Number Examined |
|
183 |
180 |
200 |
185 |
19 |
20 |
21 |
20 |
Total Number Affected |
|
1 |
3 |
0 |
13 |
1 |
2 |
0 |
7 |
Head Skeletal
|
Microphthalmia/absent optic nerve |
|
0 |
|
|
|
|
|
|
Cervical/Thoracic |
|
1 |
|
|
|
|
|
|
|
Appendicular |
Bent scapula(e) |
|
1 |
|
|
|
|
|
|
Table 8. Fetal examinations - minor skeletal abnormality and variants findings - group incidences |
|||||||||
|
|
Fetuses |
Litters |
||||||
Group |
|
Group 1 (Control – 0 mg/kg/day) |
Group 2 (Control – 100 mg/kg/day) |
Group 3 (Control – 300 mg/kg/day) |
Group 4 (Control - 600 mg/kg/day) |
Group 1 (Control – 0 mg/kg/day) |
Group 2 (Control – 100 mg/kg/day) |
Group 3 (Control – 300 mg/kg/day) |
Group 4 (Control – 600 mg/kg/day) |
Number Examined |
|
89 |
87 |
95 |
86 |
19 |
20 |
21 |
19 |
Minor skeletal abnormalities Vertebral element abnormality |
|
|
|
|
|
|
|
|
|
Ribs |
Medially thickened/kinked absent |
0 |
3 |
6 |
22 |
0 |
2 |
5 |
8 |
Sternebrae |
Biparte ossified Misaligned ossification sites Misaligned hemicentres Supernumerary site Misshapen |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
Costal cartilage |
2ndnot connected to sternum Partially fused Misaligned Branched 7thnot connected to sternum |
1 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
Appendicular
|
Misshapen cranial margin scapula(e) |
0 2 |
1 5 |
0 8 |
0 27 |
0 2 |
1 4 |
0 5 |
0 10 |
Rib and vertebral configuration |
Short supernumerary short |
4 0 |
0 0 21 0 21 |
4 0 21 0 21 |
12 1 36 5 37 |
4 0 7 1 7 |
0 0 12 0 12 |
2 0 13 0 13 |
9 1 13 3 13 |
Thoracolumbar vertebrae |
20 |
1 0 0 |
0 0 3 |
0 0 1 |
5 1 2 |
1 0 0 |
0 0 2 |
0 0 1 |
4 1 2 |
Delayed/ Incomplete ossification/unossified |
|
8 2 10 |
13 1 14 |
13 0 13 |
|
|
|
|
19 8 19 |
Vertebrae |
Cervical |
0 1 |
0 0 |
1 0 |
22 |
0 |
0 |
1 |
12 |
Increased ossification Cranial |
|
0 |
1 |
0 |
0 |
0 |
1 |
0 |
0 |
Table 9. Fetal Examinations - Minor Visceral Abnormality and Necropsy Findings - Group Incidences |
|||||||||
|
|
Fetuses |
Litters |
||||||
Group |
|
Group 1 (Control – 0 mg/kg/day) |
Group 2 (Control – 100 mg/kg/day) |
Group 3 (Control – 300 mg/kg/day) |
Group 4 (Control – 600 mg/kg/day) |
Group 1 (Control – 0 mg/kg/day) |
Group 2 (Control – 100 mg/kg/day) |
Group 3 (Control – 300 mg/kg/day) |
Group 4 (Control – 600 mg/kg/day) |
Number Examined |
|
94 |
93 |
105 |
99 |
18 |
19 |
21 |
20 |
Number of Heads Examined at Detailed Visceral Examination |
|
|
93 |
|
|
|
|
|
|
Head abnormalities (fixed visceral) |
folded retina |
1
1
1 |
0
2
0 |
1
0
0 |
0
1
0 |
1 1
1 |
0 2 0 |
1 0 0 |
0 1
0 |
Brain
|
Subdural haemorrhage |
3 6 |
3 |
2 |
1 |
3 |
3
5 |
2 3 |
1
2 |
Necropsy observations (fresh visceral) Thymus
Abdominal cavity Kidney(s) Ureter(s) Umbilical Total affected by one or more of the above |
partially undescended lobe blood in haemorrhage dilated left |
0
0 0 1 10
|
1
1 1 0 5
7 |
0
0
6 |
0
2 0 0 10
12 |
0
0 0 1 7
|
1
1 1 0 3
4 |
0
0 0 0 6
6 |
0
1 0 0 7
7 |
Necropsy observations (external)
|
tail tip kinked |
1 0 1 |
0 0
0 |
0 0 |
1 2 |
1 1 |
0 0 |
0 0 |
1 2 |
Table 10. Fetal Examinations - Major Historical Control Data |
|||||||||||
Group |
|
8461367 |
HCD Range |
||||||||
Fetuses |
Litters |
Fetuses |
Litters |
||||||||
Group 1 (Control – 0 mg/kg/day) |
Group 2 (Control – 100 mg/kg/day) |
Group 3 (Control – 300 mg/kg/day) |
Group 4 (Control – 600 mg/kg/day) |
Group 1 (Control – 0 mg/kg/day) |
Group 2 (Control – 100 mg/kg/day) |
Group 3 (Control – 300 mg/kg/day) |
Group 4 (Control – 600 mg/kg/day) |
|
|
||
Number Examined |
|
183 |
180 |
200 |
185 |
19 |
20 |
21 |
20 |
1213 |
119 |
Head |
|
0 |
1 |
0 |
0 |
|
|
|
|
0-1 |
0-1 |
Visceral |
Anophthalamia/absent optic nerve Microphthalmia/absent optic nerve |
0
0 |
0
0
|
0
0 |
3
4 |
0 0 |
0
0 |
0 0 |
2 4 |
0-0
0-0 |
0-0
0-0 |
Cervical/Thoracic |
|
|
|
|
|
|
|
|
|
|
0-0 |
Appendicular |
Bent scapula(e)
|
|
|
0 |
|
|
|
0 0 |
0 1 |
0-0 |
0-0 |
External |
Hyperflexion hindlimb(s) Malrotated hindlimb(s)
|
0
0 |
1
3 |
0
0 |
0
2 |
0
0 |
1
2 |
0
0 |
0
2 |
0-0
0-1 |
0-0
0-1 |
Table 11. Fetal Examinations - Minor Skeletal Historical Control Data |
|||||||||||
Group |
|
8461367 |
HCD Range |
||||||||
Fetuses |
Litters |
Fetuses |
Litters |
||||||||
Group 1 (Control – 0 mg/kg/day |
Group 2 (Control – 100 mg/kg/day) |
Group 3 (Control – 300 mg/kg/day) |
Group 4 (Control – 600 mg/kg/day) |
Group 1 (Control – 0 mg/kg/day |
Group 2 (Control – 100 mg/kg/day) |
Group 3 (Control – 300 mg/kg/day) |
Group 4 (Control – 600 mg/kg/day) |
||||
Number Examined |
89 |
87 |
95 |
86 |
19 |
20 |
21 |
19 |
635 |
119 |
|
Minor skeletal abnormalities |
|
|
|
|
|
|
|
|
|
|
|
Vertebral element abnormality |
thoracic |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0-1 |
0-1 |
scoliosis minimal |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0-0 |
0-0 |
|
Ribs |
Medially thickened/kinked |
0 |
3 |
6 |
22 |
0 |
2 |
5 |
8 |
0-2 |
0-2 |
absent |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0-0 |
0-0 |
|
Sternebrae |
Biparte ossified |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0-0 |
0-0 |
Misaligned ossification sites |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0 |
0-1 |
0-1 |
|
Misaligned hemicentres |
0 |
1 |
0 |
4 |
0 |
1 |
0 |
3 |
0-3 |
0-3 |
|
Misshapen |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0 |
0-2 |
0-1 |
|
Costal cartilage |
Partially fused |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0-2 |
0-2 |
Misaligned |
0 |
1 |
0 |
4 |
0 |
1 |
0 |
3 |
0-4 |
0-3 |
|
Branched |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0 |
0-0 |
0-0 |
|
7th not connected to sternum |
0 |
0 |
0 |
2 |
0 |
0 |
0 |
1 |
0-1 |
0-1 |
|
Appendicular |
Misshapen cranial margin scapula(e) |
0 |
1 |
0 |
0 |
0 |
1 |
6 |
0 |
0-1 |
0-1 |
Table 12. Fetal Examinations - Minor Skeletal Historical Control Data |
|||||||||||
Group |
|
8461367 |
HCD Range |
||||||||
Fetuses |
Litters |
Fetuses |
Litters |
||||||||
Group 1 (Control – 0 mg/kg/day |
Group 2 (Control – 100 mg/kg/day) |
Group 3 (Control – 300 mg/kg/day) |
Group 4 (Control – 600 mg/kg/day) |
Group 1 (Control – 0 mg/kg/day |
Group 2 (Control – 100 mg/kg/day) |
Group 3 (Control – 300 mg/kg/day) |
Group 4 (Control – 600 mg/kg/day) |
||||
Number Examined |
89 |
87 |
95 |
86 |
19 |
20 |
21 |
19 |
635 |
119 |
|
Rib and vertebral configuration |
|
||||||||||
Cervical rib |
short supernumerary |
4 |
0 |
4 |
12 |
4 |
0 |
2 |
9 |
0-3 |
0-3 |
13th rib |
short |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0-0 |
0-0 |
Number of 14th ribs |
short supernumerary |
11 |
21 |
21 |
36 |
7 |
12 |
13 |
13 |
4-33 |
3-16 |
full supernumerary |
1 |
0 |
0 |
5 |
1 |
0 |
0 |
3 |
0-3 |
0-2 |
|
total |
11 |
21 |
21 |
37 |
7 |
12 |
13 |
13 |
4-33 |
3-16 |
|
Thoracolumbar vertebrae |
20 |
1 |
0 |
0 |
5 |
1 |
0 |
0 |
4 |
0-3 |
0-2 |
Pelvic girdle |
unilateral cranial shift |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0-0 |
0-0 |
unilateral caudal shift |
0 |
3 |
1 |
2 |
0 |
2 |
1 |
2 |
0-4 |
0-3 |
|
Delayed/Incomplete ossification / unossified |
|
||||||||||
Cranial |
cranial centres |
1 |
1 |
4 |
9 |
1 |
1 |
2 |
4 |
0-4 |
0-3 |
Sternebrae |
5th and/ or 6th |
8 |
13 |
13 |
71 |
4 |
9 |
9 |
19 |
0-11 |
0-7 |
1st to 4th |
2 |
1 |
0 |
12 |
2 |
1 |
0 |
8 |
0-13 |
0-4 |
|
total |
10 |
14 |
13 |
73 |
5 |
9 |
9 |
19 |
1-15 |
1-9 |
|
Vertebrae |
Cervical |
0 |
0 |
1 |
22 |
0 |
0 |
1 |
12 |
0-0 |
0-0 |
thoracic |
1 |
0 |
0 |
4 |
1 |
0 |
0 |
3 |
0-0 |
0-0 |
|
Increased ossification |
|
||||||||||
Talus |
ossified |
0 |
1 |
0 |
0 |
0 |
1 |
0 |
0 |
0-0 |
0-0 |
Table 13. Fetal Examinations - Visceral Historical Control Data |
|||||||||||
Group |
|
8461367 |
HCD Range |
||||||||
Fetuses |
Litters |
Fetuses |
Litters |
||||||||
Group 1 (Control – 0 mg/kg/day |
Group 2 (Control – 100 mg/kg/day) |
Group 3 (Control – 300 mg/kg/day) |
Group 4 (Control – 600 mg/kg/day) |
Group 1 (Control – 0 mg/kg/day |
Group 2 (Control – 100 mg/kg/day) |
Group 3 (Control – 300 mg/kg/day) |
Group 4 (Control – 600 mg/kg/day) |
||||
Number Examined |
94 |
93 |
105 |
99 |
18 |
19 |
21 |
20 |
992 |
119 |
|
Necropsy observations (fresh visceral) |
|
||||||||||
Thymus |
partially undescended lobe |
0 |
1 |
0 |
0 |
0 |
1 |
0 |
0 |
0-5 |
0-5 |
Abdominal cavity |
blood in |
0 |
1 |
0 |
2 |
0 |
1 |
0 |
1 |
0-2 |
0-2 |
Kidney(s) |
haemorrhage |
0 |
1 |
0 |
0 |
0 |
1 |
0 |
0 |
0-0 |
0-0 |
Necropsy observations (external) |
|
||||||||||
Skin |
subcutaneous edema |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0-0 |
0-0 |
Applicant's summary and conclusion
- Conclusions:
- Based on the results observed in this prenatal developmental toxicity study in the rat, the No Observed Adverse Effect Level (NOAEL) for systemic toxicity was determined to be 600 mg/kg/day and the NOAEL for embryo-foetal development was determined to be 300 mg/kg/day.
- Executive summary:
A key OECD Guideline 414 prenatal developmental toxicity study in rats was conducted to evaluate the effect/s of the test material (Benzaldehyde; CAS# 100-52-7) on embryo-fetal survival and development when administered during the organogenesis and fetal growth phases of pregnancy.
The test material was administered via oral gavage to three groups of 22 time-mated female Han Wistar rats at doses of 100, 300 or 600 mg/kg/day once daily from Day 6 to 20 after mating. A similarly constituted Control group received the vehicle, 0.5% methylcellulose with 0.5% Tween-80 in purified water at the same volume dose as the treated groups. Animals were killed on Day 21 after mating for reproductive assessment and fetal examination/s.
Clinical observations, body weight, and food consumption were recorded and all adult females were examined macroscopically at necropsy on Day 21 after mating. Blood samples were taken for thyroid hormone analysis and the gravid uterus weight and thyroid weight was recorded. Microscopic pathology investigations were also undertaken. Ano-genital distance was measured for fetuses and all fetuses were examined macroscopically at necropsy and subsequently by detailed internal visceral examination of the head or skeletal examination.
No mortality or treatment-related signs of clinical toxicity were observed at routine examination or following dose administration through the study period. One female (4F 71) in the 600 mg/kg/day dose group was euthanized (for welfare reasons) on Day 11 of gestation, due to general poor clinical condition with clinical signs of decreased activity, piloerection, hunched posture and abnormal (swaying) gait. This female was also abnormally cold to touch and had a distended abdomen. Macroscopic examination revealed abnormal, pale contents in the stomach and a distended stomach. The female was found to be pregnant with 12 live fetuses. Since no other premature deaths occurred on study and no similar signs were observed among the remaining females, this premature death was not considered to be treatment-related.
Body weight gain, adjusted maternal body weight gain and food consumption were unaffected by treatment. At 600 mg/kg/day mean gravid uterine weight was slightly, but not statistically significantly, lower than Control.
Mean serum T3 or T4 concentration of maternal females in the 100 or 300 mg/kg/day remained unaffected post-treatment. Statistically significantly low mean serum T3 and T4 concentrations were observed at 600 mg/kg/day when compared to control animals (reduction of 24% and 26%, respectively). In the absence of any differences in thyroid weight or microscopic changes and no effect of treatment on TSH concentration at the highest dose level tested, it was considered that thyroid gland function was highly unaffected by treatment and these differences were adaptive not adverse. Thyroid weights were unaffected by treatment and gross necropsy did not reveal any remarkable treatment-related findings. There were no treatment-related microscopic findings observed either.
Litter data as assessed by the mean number of implantations, resorptions, extent of pre-and post-implantation losses, live young and sex ratio were unaffected by treatment with the test material. Mean total litter weights were slightly, but not statistically significantly, lower than Control at 600 mg/kg/day. Male, female and overall fetal weights were statistically significantly low at 600 mg/kg/day when compared to Controls (overall fetal weight was 16% lower than Controls). There was no effect of treatment on fetal weights at 100 or 300 mg/kg/day. Mean placental weights were unaffected by treatment and no effect of treatment on fetal ano-genital distance was observed.
At 600 mg/kg/day there were 8 fetuses in 4 litters affected with major eye abnormalities; anophthalmia and microphthalmia with absent optic nerve observed at fixed visceral examination and small orbital socket(s) observed at skeletal examination, all exceeding the Historical Control Data (HCD) range. In addition, at 600 mg/kg/day there was an increase in the incidence of minor skeletal abnormalities/variants compared to concurrent control which exceeded the HCD range; medially thickened/kinked ribs (the incidence was also increased to a lesser extent at 100 or 300 mg/kg/day), short supernumerary cervical ribs, supernumerary 14th rib(s), 20 thoracolumbar vertebrae, incompletely ossified cranial centres, sternebrae and cervical vertebrae These findings, although treatment-related, were not considered adverse.
At 100 and 600 mg/kg/day, there were 5 fetuses with apparent malrotation of the hindlimb(s) noted at necropsy external examination. At subsequent skeletal examination, although the limbs still appeared slightly malrotated, both the bones and cartilage of the hindlimbs were normal. This finding was therefore considered to be incidental and not treatment-related.
Based on the results observed in this prenatal developmental toxicity study in the rat, the No Observed Adverse Effect Level (NOAEL) for systemic toxicity was determined to be 600 mg/kg/day and the NOAEL for embryo-foetal development was determined to be 300 mg/kg/day.
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