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Registration Dossier
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EC number: 814-509-8 | CAS number: 62132-67-6
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2021-JUL-11 to 2021-OCT-28
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 022
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
- 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
- Version / remarks:
- November 2000
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- 1-Dodecene, Dimer
- Cas Number:
- 62132-67-6
- IUPAC Name:
- 1-Dodecene, Dimer
- Test material form:
- liquid
- Details on test material:
- Name of substance: 1-Dodecene, dimers (Synfluid Dimer C12 PAO, Polyalphaolefin)
CAS# 62132-67-6
EC# 814-509-8
Batch # DBA0146456
Storage: At ambient temperature (15 to 25°C)
Expiration date: 2023-MAY-01
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source (i.e. manufacturer or supplier) and lot/batch number of test material: Chevron Phillips Chemical Company LP; Batch No. DBA0146456
- Purity, including information on contaminants, isomers, etc.: 100 % (UVCB)
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At ambient temperature (15 to 25°C)
- Stability and homogeneity of the test material in the vehicle/solvent under test conditions (e.g. in the exposure medium) and during storage: Stable for one day at ambient temperature (15 to 25°C) and 17 days when stored refrigerated (2 to 8°C)
FORM AS APPLIED IN THE TEST (if different from that of starting material) : Clear and bright liquid
OTHER SPECIFICS
- Expiration date: 2023-MAY-01
Test animals
- Species:
- rat
- Strain:
- Wistar
- Remarks:
- RccHan®:WIST
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Envigo RMS Limited
- Age at study initiation: 11 to 12 weeks
- Weight at study initiation: 169 to 238 grams
- Fasting period before study: Not specified
- Housing: Individually in polycarbonate cages with a stainless steel mesh lid
- 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: at least 3 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 40-70%
- Air changes (per hr): Filtered fresh air which was passed to atmosphere and not recirculated
- Photoperiod (hrs dark / hrs light): 12 hrs dark / 12 hrs light
IN-LIFE DATES: From: 2021-JUL-15 To: 2021-AUG-06
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
Formulations were prepared weekly and required amount of the test material was weighed out. Starting with the lowest concentration, approximately 50% of the final volume of vehicle was added to the test material and magnetically stirred until it was uniformly mixed. The remaining vehicle was added to achieve the required volume and the formulation was mixed using a magnetic stirrer until homogeneous. The formulation was then transferred to the final containers, via syringe, whilst 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): Not specified
- Concentration in vehicle: 0, 25, 75, or 250 mg/mL for the control, 100, 300, and 1000 mg/kg/day dose groups, respectively
- Amount of vehicle (if gavage): 4 mL/kg
- Lot/batch no. (if required): Not specified
- Purity: Not specified - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Stability and homogeneity:
Homogeneity and stability of formulations during storage were confirmed as part of another study (Labcorp Study Number 8457609). In that study, formulations in the range 2.5 mg/mL to 250 mg/mL were determined to be stable for one day at ambient temperature (15 to 25°C); 17 days when stored refrigerated (2 to 8°C).
Concentration analysis:
Samples of each formulation prepared for administration in the first and last weeks of treatment were analyzed for achieved concentration of the test material using gas chromatography with flame ionization detection. - Details on mating procedure:
- - Impregnation procedure: purchased timed pregnant
Natural mating with Han Wistar of established fertility at the supplier’s facility. Males and females were not related. Positive evidence of mating was considered to be Gestation Day 0. Animals arrived 2 days after mating. - 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 - Corn oil)
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Remarks:
- Group 2 (Low dose)
- Dose / conc.:
- 300 mg/kg bw/day (nominal)
- Remarks:
- Group 3 (Intermediate dose)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Remarks:
- Group 4 (High dose)
- No. of animals per sex per dose:
- 22/dose
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:
Dose levels selected were based on the results of a preliminary study (Labcorp Study Number 8457611) which investigated doses of 0, 100, 300, and 1000 mg/kg/day. There was no evidence of maternal toxicity, on the outcome of pregnancy, and all fetuses were observed to be macroscopically normal. Adjusted maternal body weight change (GD 6 21) at 300 or 1000 mg/kg/day was low (48% or 63% of Control, respectively) but attributed at 1000 mg/kg/day to the marginally high litter size, which was due to chance, when compared with Control.
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 1000 mg/kg/day were investigated in the current OECD 414 study.
- 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: time not specified but to minimize any potential confounding effect of the time of day of blood sampling, the time of blood sampling was controlled to allow satisfactory inter-group comparisons.
- Other:
- Animal model: The rat was chosen as the test species because of the requirement for a rodent species by regulatory agencies. The RccHan®:WIST. (Han Wistar) strain was used because of the historical control data available at the CRO.
- Route of administration: The oral gavage route of administration was chosen to simulate the conditions of possible human exposure
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Animals were inspected visually at least twice daily for evidence of ill-health or reaction to treatment and cages were inspected daily for evidence of animal ill-health.
Signs associated with dosing: Detailed observations were recorded daily during the treatment period (Pre-dose ; One to two hours post-dosing; As late as possible in the working day)
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: A detailed physical examination was performed on each animal on Days 3, 6, 12, 18, and 21 after mating.
BODY WEIGHT: Yes
- Time schedule for examinations: The weight of each adult was determined on Days 3 and 6-21 after mating.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
The weight of food supplied to each adult, that remaining, and an estimate of any spilled was recorded for the following periods: Days 3-5, 6-8, 9-11, 12-14, 15-17, and 18-20 after mating inclusive.
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 21
- Organs examined: Gravid uterine weight (including cervix and ovaries) and Thyroid weighed.
All adult animals were sacrificed via carbon dioxide asphyxiation and subjected to a detailed necropsy. A full macroscopic examination of the tissues was performed and all external features and orifices examined visually. Any abnormality in the appearance or size of any organ and tissue (external and cut surface) was recorded. For bilateral organs, left and right organs were weighed together. Requisite organs were weighed for animals killed at scheduled intervals.
OTHER:
Histology:
Tissues were routinely preserved in 10% Neutral Buffered Formalin, dehydrated, embedded in paraffin wax, and sectioned at a nominal four to five micron thickness. For bilateral organs, sections of both organs were prepared. A single section was prepared from each of the remaining tissues required. Sections were stained with hematoxylin and eosin. - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes (including cervix and ovaries)
- 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:
- - Serum: Yes
- Volume collected : 1.0 mL
Thyroid Hormone Analysis:
Blood samples were collected from all adult animals at termination on GD 21 (necropsy). 1.0 mL of blood was collected from the sublingual vein under isoflurane anaesthesia and stored in tubes with clotting activator. Samples were kept at ambient temperature (15 to 25°C) for a minimum of 30 minutes and then centrifuged at 2000 g for ten minutes at 4°C. Serum was then transferred to appropriately labelled polypropylene “cryo” tubes using plastic disposable pipettes and mixed by gentle ten-fold inversion. Following mixing, each serum sample was divided in two aliquots (aliquot 1: 0.2 mL serum for T3/T4; aliquot 2: residual serum for TSH). The samples were then analyzed for Triiodothyronine (T3); Thyroxine (T4); and Thyroid stimulating hormone (TSH) concentrations. - 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:
- Please see 'Any other information on materials and methods incl. tables' for information on statistics.
- Indices:
- 1) Pre-implantation loss (%) = (Number of corpora lutea - Number of implantations) / (Number of corpora lutea) x 100
2) Post-implantation loss (%) = (Number of implantations - Number of live fetuses) / (Number of implantations) x 100 - Historical control data:
- Historical control data is presented in Tables 13 to 15 in the section 'Any other information on results incl. tables'.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No adverse treatment-related clinical signs of toxicity were observed through the study period.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Overall body weight gain (GD 6-21) and adjusted body weight change (GD 6-21) was unaffected by treatment at 100, 300 or 1000 mg/kg/day.
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- Overall food consumption was unaffected by treatment at 100, 300 or 1000 mg/kg/day.
While overall food consumption was statistically significantly high at 300 or 1000 mg/kg/day, the differences were marginal (106% or 112% of Control, respectively) and therefore considered to be incidental rather than treatment-related. - Food efficiency:
- not examined
- 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:
- no effects observed
- Description (incidence and severity):
- No effect of treatment was observed on serum concentrations of T3, T4, and TSH.
- 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):
- No treatment-related changes were observed in the thyroids (with parathyroids).
- 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 microscopic findings in the thyroids.
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- The number of implantations and the extent of pre- and post-implantation losses (%) were unaffected by treatment at 100, 300 or 1000 mg/kg/day.
- Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- The number of resorptions were unaffected by treatment at 100, 300 or 1000 mg/kg/day.
- Early or late resorptions:
- no effects observed
- Description (incidence and severity):
- The number of resorptions were unaffected by treatment at 100, 300 or 1000 mg/kg/day.
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- no effects observed
- Changes in number of pregnant:
- effects observed, non-treatment-related
- Description (incidence and severity):
- One Control animal (No. 11), two animals treated at 100 mg/kg/day (No’s 33 and 39), one animal treated at 300 mg/kg/day (No. 65), and one animal treated at 1000 mg/kg/day (No. 84) were not pregnant.
- Other effects:
- no effects observed
- Description (incidence and severity):
- Placental weights were unaffected by treatment at 100, 300, or 1000 mg/kg/day.
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- ca. 1 000 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:
- no effects observed
- Description (incidence and severity):
- Fetal weights were unaffected by treatment at 100, 300, or 1000 mg/kg/day.
- Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- The number of live young was unaffected by treatment at 100, 300, or 1000 mg/kg/day.
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- The ratio of male to female fetuses was unaffected by treatment at 100, 300, or 1000 mg/kg/day.
- Changes in litter size and weights:
- no effects observed
- Description (incidence and severity):
- Total litter weights were unaffected by treatment at 100, 300, or 1000 mg/kg/day.
One Control animal (No. 11), two animals treated at 100 mg/kg/day (No’s 33 and 39), one animal treated at 300 mg/kg/day (No. 65) and one animal treated at 1000 mg/kg/day (No. 84) were not pregnant and one animal at 300 mg/kg/day had no live fetuses. Therefore, assessment of litter response was performed on 21 litters at 0 or 1000 mg/kg/day and on 20 litters at 100 or 300 mg/kg/day. - Anogenital distance of all rodent fetuses:
- no effects observed
- Description (incidence and severity):
- Ano-genital distance was unaffected subsequent to parental exposure to the test material at 100, 300, or 1000 mg/kg/day.
- Changes in postnatal survival:
- no effects observed
- External malformations:
- no effects observed
- Description (incidence and severity):
- No major or minor treatment-related fetal abnormalities were observed.
- Skeletal malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Two female fetuses in one litter (Dam/Litter No. 67) at 1000 mg/kg/day exhibited abnormalities of the head (one fetus had Microphthalmia (left eye) and one fetus had Brachygnathia and other related cranial abnormalities (jaw, palate, ear and nose)). However, given that only a single litter was affected and in the absence of related aetiology to other malformations at 1000 mg/kg/day or lower, these observations were not considered treatment-related.
- Visceral malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- An increase in the incidence of the minor visceral abnormality subdural brain haemorrhage compared to control animals was observed at 1000 mg/kg/day (six fetuses in five litters). This exceeded the Historical Control Data (HCD) range (fetuses; 0-3, litters; 0-3) but was considered to have occurred during the necropsy procedure and therefore, was unrelated to treatment with the test material.
- Other effects:
- not examined
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- ca. 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Developmental Toxicity
Fetal abnormalities
- Key result
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Any other information on results incl. tables
Formulation Analysis
Analyzed mean concentrations of 1-Dodecene, dimers were within 7% of the nominal concentration, confirming the accuracy of formulation. The difference from mean remained within 2%, confirming precise analysis.
Table 2. Results of Formulation Analysis |
|||||||||
Occasion |
Group |
Nominal concentration (mg/mL) |
Analyzed concentration (mg/mL) |
RME (%) |
Difference from mean (%) |
Procedural recoveries |
|||
Analysis 1 |
Analysis 2 |
Mean |
Analyzed (%) |
Mean |
|||||
First Week |
1 |
0 |
ND |
ND |
- |
- |
- |
- |
100.4 |
2 |
25 |
27.1 |
26.1 |
26.6 |
+6.4 |
±1.90 |
108.01 |
||
3 |
75 |
78.1 |
77.3 |
77.7 |
+3.6 |
±0.47 |
100.4 |
||
4 |
250 |
265 |
262 |
264 |
+5.6 |
±0.47 |
100.3 |
||
|
|
|
|
|
|
|
|||
Last Week |
1 |
0 |
ND |
ND |
- |
- |
- |
- |
100.4 |
2 |
25 |
25.6 |
26.0 |
25.7 |
+2.8 |
±0.28 |
108.01 |
||
3 |
75 |
69.3 |
71.1 |
77.1 |
+2.8 |
±1.28 |
100.4 |
||
4 |
250 |
242 |
239 |
241 |
-3.6 |
±0.51 |
100.3 |
||
RME Relative mean error, representing the deviation from nominal
ND Not detected
1 Result above the range established during the validation therefore excluded as per SOP.
Table 3. Body weight and Body weight change - Group mean values (g) during Gestation |
||||||||||||||||||||
Dose Group |
|
Day |
Change |
|||||||||||||||||
3 |
6 |
7 |
8 |
9 |
10 |
11 |
12 |
13 |
14 |
15 |
16 |
17 |
18 |
19 |
20 |
21 |
3-6 |
6-21 |
||
Statistics Test |
|
Av |
Av |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Av |
Wi |
Group 1 Control 0 mg/kg/day |
Mean |
208 |
222 |
222 |
224 |
228 |
233 |
237 |
241 |
243 |
247 |
254 |
262 |
271 |
282 |
290 |
300 |
306 |
14 |
85 |
SD |
15.7 |
15.3 |
16.0 |
16.6 |
15.5 |
16.3 |
15.8 |
15.2 |
16.3 |
16.9 |
17.9 |
19.0 |
18.9 |
21.0 |
21.7 |
23.1 |
23.7 |
4.4 |
14.4 |
|
N |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
|
|
||||||||||||||||||||
Group 2 100 mg/kg/day |
Mean |
202 |
214 |
216 |
219 |
222 |
227 |
232 |
236 |
239 |
243 |
249 |
257 |
265 |
276 |
285 |
294 |
302 |
12 |
87 |
SD |
10.3 |
10.1 |
9.8 |
9.6 |
10.2 |
10.2 |
11.3 |
11.0 |
11.3 |
12.1 |
12.5 |
12.6 |
13.2 |
15.9 |
17.1 |
17.8 |
18.3 |
4.5 |
16.5 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
|
|
||||||||||||||||||||
Group 3 300 mg/kg/day |
Mean |
204 |
217 |
216 |
219 |
223 |
227 |
233 |
238 |
241 |
245 |
252 |
259 |
269 |
280 |
288 |
299 |
304 |
13 |
88 |
SD |
17.1 |
16.2 |
16.0 |
17.9 |
18.0 |
18.7 |
18.3 |
18.3 |
18.2 |
18.5 |
19.7 |
19.9 |
20.5 |
21.3 |
21.7 |
23.1 |
23.8 |
3.3 |
11.9 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
|
|
||||||||||||||||||||
Group 4 1000 mg/kg/day |
Mean |
204 |
214 |
215 |
219 |
223 |
226 |
231 |
235 |
238 |
242 |
249 |
255 |
265 |
277 |
286 |
296 |
304 |
10 |
90 |
SD |
14.1 |
14.1 |
14.2 |
14.5 |
14.3 |
14.7 |
14.4 |
14.3 |
13.7 |
14.3 |
14.6 |
15.1 |
15.9 |
16.6 |
17.8 |
18.2 |
18.7 |
5.1 |
7.8 |
|
N |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
|
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
Table 4. Gravid uterine weight, adjusted body weight and adjusted body weight change - group mean values (kg) 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 |
222 |
306 |
84 |
68.7 |
237 |
16 |
SD |
15.3 |
23.5 |
14.0 |
15.63 |
18.1 |
11.0 |
|
N |
21 |
21 |
21 |
21 |
21 |
21 |
|
|
|||||||
Group 2 (Control – 100 mg/kg/day) |
Mean |
214 |
302 |
87 |
63.6 |
238 |
24 |
SD |
10.1 |
18.4 |
16.5 |
20.18 |
13.6 |
8.7 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
|
|
|||||||
Group 3 (Control – 300 mg/kg/day) |
Mean |
217 |
304 |
87 |
67.1 |
237 |
20 |
SD |
16.2 |
24.0 |
12.0 |
15.57 |
22.4 |
11.0 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
|
|
|||||||
Group 4 (Control – 1000 mg/kg/day) |
Mean |
214 |
303 |
89 |
71.7 |
231 |
17 |
SD |
14.1 |
18.9 |
7.8 |
10.13 |
14.2 |
7.9 |
|
N |
21 |
21 |
21 |
21 |
21 |
21 |
|
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
Table 5. Food consumption - Group Mean Values (g/animal/day) during Gestation (Females) |
||||||||
Dose Group |
|
Day |
Mean |
|||||
3-6 |
6-9 |
9-12 |
12-15 |
15-18 |
18-21 |
6-21 |
||
Statistics Test |
|
Av |
Wi |
Wi |
Wi |
Wi |
Sh |
Wi |
Group 1 (Control – 0 mg/kg/day) |
Mean |
17 |
16 |
17 |
18 |
20 |
16 |
17 |
SD |
1.8 |
2.1 |
1.1 |
1.5 |
2.0 |
1.9 |
1.2 |
|
N |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
|
|
||||||||
Group 2 (Control – 100 mg/kg/day) |
Mean |
16 |
15 |
17 |
18 |
19 |
17 |
17 |
SD |
2.5 |
1.4 |
1.5 |
1.6 |
2.1 |
1.1 |
1.2 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
|
|
||||||||
Group 3 (Control – 300 mg/kg/day) |
Mean |
17 |
16 |
19* |
19 |
20 |
18 |
18* |
SD |
1.7 |
1.8 |
1.8 |
1.9 |
1.8 |
2.6 |
1.7 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
|
|
||||||||
Group 4 (Control – 1000 mg/kg/day) |
Mean |
17 |
17* |
18* |
19 |
21 |
18 |
19** |
SD |
1.8 |
1.8 |
1.8 |
1.6 |
2.0 |
3.9 |
1.4 |
|
N |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
|
* p<0.05
** p<0.01
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
Sh: Treated groups compared with Control using Shirley’s test
Table 6. Group Mean Serum T3, T4, and TSH Concentration Data in Pregnant Rats |
||||
Dose Group (mg/kg/day) |
Parameters |
Gestational Day 21 Termination |
||
T3 (pg/mL) |
T4 (pg/mL) |
TSH (pg/mL) |
||
Group 1 (Control – 0 mg/kg/day) |
Mean |
470 |
21700 |
690 |
SD |
127 |
5280 |
308 |
|
CV% |
27.0 |
24.3 |
44.6 |
|
N |
21 |
21 |
21 |
|
|
||||
Group 2 (Control – 100 mg/kg/day) |
Mean |
473 |
21900 |
639 |
SD |
162 |
6310 |
247 |
|
CV% |
34.2 |
28.8 |
38.7 |
|
N |
20 |
20 |
20 |
|
|
||||
Group 3 (Control – 300 mg/kg/day) |
Mean |
522 |
21000 |
635 |
SD |
130 |
5100 |
261 |
|
CV% |
24.9 |
24.3 |
41.0 |
|
N |
20 |
20 |
21 |
|
|
||||
Group 4 (Control – 1000 mg/kg/day) |
Mean |
509 |
22100 |
696 |
SD |
96.3 |
4570 |
215 |
|
CV% |
18.9 |
20.7 |
31.0 |
|
N |
21 |
21 |
21 |
|
Table 7. Litter data - Group Mean Values on Day 21 of Gestation |
||||||||||||
Group |
|
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 |
11.7 |
10.1 |
0.2 |
0.1 |
0.4 |
14.4 |
3.2 |
4.0 |
5.7 |
9.7 |
41.9 |
SD |
1.85 |
2.74 |
0.54 |
0.36 |
0.59 |
16.89 |
5.02 |
2.01 |
2.13 |
2.51 |
17.77 |
|
N |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
|
|
||||||||||||
Group 2 (Control – 100 mg/kg/day) |
Mean |
12.2 |
9.6 |
0.3 |
0.2 |
0.4 |
21.2 |
4.1 |
4.4 |
4.8 |
9.2 |
51.0 |
SD |
1.51 |
3.12 |
0.91 |
0.37 |
0.94 |
24.75 |
10.28 |
1.96 |
2.40 |
3.20 |
18.98 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
|
|
||||||||||||
Group 3 (Control – 300 mg/kg/day) |
Mean |
11.8 |
10.5 |
0.8 |
0.2 |
1.0 |
12.4 |
8.2 |
5.2 |
4.4 |
9.6 |
53.4 |
SD |
1.54 |
2.69 |
0.91 |
0.41 |
1.00 |
19.30 |
8.48 |
2.11 |
1.76 |
2.42 |
14.21 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
|
|
||||||||||||
Group 3 (Control – 1000 mg/kg/day) |
Mean |
12.3 |
11.0 |
0.6 |
0.0 |
0.6 |
11.6 |
4.9 |
5.0 |
5.4 |
10.4 |
49.8 |
SD |
1.77 |
1.90 |
0.87 |
0.00 |
0.87 |
13.21 |
7.42 |
1.63 |
2.29 |
1.86 |
17.39 |
|
N |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
|
Wi: Treated groups compared with Control using Williams’ test
Table 8. 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 Weight |
Overall Fetal Weight |
Statistics test |
|
Wi |
Wi |
Sh |
Sh |
Sh |
Group 1 (Control – 0 mg/kg/day) |
Mean |
0.47 |
48.68 |
5.22 |
4.99 |
5.09 |
SD |
0.066 |
12.359 |
0.689 |
0.686 |
0.678 |
|
N |
21 |
21 |
21 |
21 |
21 |
|
|
||||||
Group 2 (Control – 100 mg/kg/day) |
Mean |
0.46 |
47.58 |
5.38 |
5.09 |
5.26 |
SD |
0.071 |
16.028 |
0.382 |
0.398 |
0.381 |
|
N |
20 |
20 |
20 |
20 |
20 |
|
|
||||||
Group 3 (Control – 300 mg/kg/day) |
Mean |
0.47 |
49.79 |
5.37 |
5.06 |
5.22 |
SD |
0.053 |
12.391 |
0.288 |
0.307 |
0.302 |
|
N |
20 |
20 |
20 |
20 |
20 |
|
|
||||||
Group 4 (Control – 1000 mg/kg/day) |
Mean |
0.46 |
53.47 |
5.31 |
5.00 |
5.16 |
SD |
0.035 |
8.396 |
0.255 |
0.336 |
0.289 |
|
N |
21 |
21 |
21 |
21 |
21 |
|
Wi: Treated groups compared with Control using Williams’ test
Sh: Treated groups compared with Control using Shirley’s test
Table 9. Ano-genital Distance - Group Mean Absolute and Adjusted Values for Fetuses on Day 21 of Gestation |
|||
Dose Group (mg/kg/day) |
|
Fetal Weight (g) |
Ano-genital / distance (mm) |
Statistics test |
Sh |
Sh |
|
Males |
|||
Group 1 (Control – 0 mg/kg/day) |
Mean |
5.22 |
3.47 |
SD |
0.69 |
0.21 |
|
N |
21 |
21 |
|
|
|||
Group 2 (Control – 100 mg/kg/day) |
Mean |
5.38 |
3.48 |
SD |
0.38 |
0.16 |
|
N |
20 |
20 |
|
|
|||
Group 3 (Control – 300 mg/kg/day) |
Mean |
5.37 |
3.61 |
SD |
0.29 |
0.40 |
|
N |
20 |
20 |
|
|
|||
Group 4 (Control – 1000 mg/kg/day) |
Mean |
5.31 |
3.46 |
SD |
0.26 |
0.19 |
|
N |
21 |
21 |
|
Females |
|||
Group 1 (Control – 0 mg/kg/day) |
Mean |
4.99 |
2.21 |
SD |
0.69 |
0.11 |
|
N |
21 |
21 |
|
|
|||
Group 2 (Control – 100 mg/kg/day) |
Mean |
5.09 |
2.25 |
SD |
0.40 |
0.14 |
|
N |
19 |
19 |
|
|
|||
Group 3 (Control – 300 mg/kg/day) |
Mean |
5.06 |
2.23 |
SD |
0.31 |
0.15 |
|
N |
20 |
20 |
|
|
|||
Group 4 (Control – 1000 mg/kg/day) |
Mean |
5.00 |
2.24 |
SD |
0.34 |
0.13 |
|
N |
21 |
21 |
|
Sh: Treated groups compared with Control using Shirley’s test
Table 10. Summary of Fetal examinations - Major Abnormalities – Group Incidences |
|||||||||
|
|
Fetuses |
Litters |
||||||
Group |
Group 1 0 mg/kg/day |
Group 2 100 mg/kg/day |
Group 3 300 mg/kg/day |
Group 4 1000 mg/kg/day |
Group 1 0 mg/kg/day |
Group 2 100 mg/kg/day |
Group 3 300 mg/kg/day |
Group 4 1000 mg/kg/day |
|
Number Examined |
204 |
183 |
191 |
219 |
21 |
20 |
20 |
21 |
|
Total Number Affected |
1 |
0 |
1 |
2 |
1 |
0 |
1 |
1 |
|
Head |
|
||||||||
Skeletal |
Fused premaxillae |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
Single medial lower incisor socket |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
|
Absent upper incisor socket(s) |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
|
Fused mandibles |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
|
Displaced tympanic annula |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
|
Brachygnathia |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
|
Basisphenoid partially fused to tympanic annula |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
|
Misshapen basisphenoid |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
|
Partially fused nasals |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
|
Misshapen palatine bones |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
|
Visceral |
Microphthalmia |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
Cervical/Thoracic |
|
||||||||
Visceral |
Complete situs inversus |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0 |
Appendicular |
|
||||||||
External |
Malrotated hindlimb(s) |
1 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Table 12. Summary of Fetal examinations - Minor Visceral Abnormality and Necropsy Findings – Group Incidences |
|||||||||
Group |
|
Fetuses |
Litters |
||||||
Group 1 0 mg/kg/day |
Group 2 100 mg/kg/day |
Group 3 300 mg/kg/day |
Group 4 1000 mg/kg/day |
Group 1 0 mg/kg/day |
Group 2 100 mg/kg/day |
Group 3 300 mg/kg/day |
Group 4 1000 mg/kg/day |
||
Number Examined |
106 |
96 |
99 |
114 |
21 |
20 |
20 |
21 |
|
Number of Heads Examined at Detailed Visceral Examination |
|
106 |
96 |
100 |
114 |
21 |
20 |
20 |
21 |
Head abnormalities (fixed visceral) |
|
||||||||
Eyes |
folded retina |
1 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
dilated orbital sinus |
0 |
1 |
1 |
0 |
0 |
1 |
1 |
0 |
|
Brain |
subdural haemorrhage |
0 |
1 |
1 |
6 |
0 |
1 |
1 |
5 |
Total affected by one or more of the above |
|
1 |
2 |
2 |
6 |
1 |
2 |
2 |
5 |
Necropsy observations (fresh visceral) |
|
||||||||
Thymus |
partially undescended lobe |
1 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
Umbilical artery |
left |
2 |
7 |
6 |
8 |
2 |
5 |
5 |
5 |
Total affected by one or more of the above |
|
3 |
7 |
6 |
8 |
3 |
5 |
5 |
5 |
Table 13. Fetal examinations - Major Historical Control Data (July 2015 – present) |
|||||||||||
|
|
Study # 8457610 |
HCD Range |
||||||||
|
|
Fetuses |
Litters |
Fetuses |
Litters |
||||||
Group |
Group 1 0 mg/kg/day |
Group 2 100 mg/kg/day |
Group 3 300 mg/kg/day |
Group 4 1000 mg/kg/day |
Group 1 0 mg/kg/day |
Group 2 100 mg/kg/day |
Group 3 300 mg/kg/day |
Group 4 1000 mg/kg/day |
|||
Number Examined |
204 |
183 |
191 |
219 |
21 |
20 |
20 |
21 |
|||
Head |
|
|
|
||||||||
Skeletal |
Fused premaxillae |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0-0 |
0-0 |
Single medial lower incisor socket |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0-1 |
0-1 |
|
Absent upper incisor socket(s) |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0-0 |
0-0 |
|
Fused mandibles |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0-0 |
0-0 |
|
Displaced tympanic annula |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0-0 |
0-0 |
|
Brachygnathia |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0-1 |
0-1 |
|
Basisphenoid partially fused to tympanic annula |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0-0 |
0-0 |
|
Misshapen basisphenoid |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0-0 |
0-0 |
|
Partially fused nasals |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0-0 |
0-0 |
|
Misshapen palatine bones |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0-1 |
0-1 |
|
Visceral |
Microphthalmia |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0-0 |
0-0 |
Cervical/Thoracic |
|
|
|
||||||||
Visceral |
Complete situs inversus |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0 |
0-0 |
0-0 |
Table 14. Fetal examinations - Minor Skeletal Historical Control Data (July 2015 – present) |
|||||||||||
Group |
|
Study # 8457610 |
HCD Range |
||||||||
Fetuses |
Litters |
Fetuses |
Litters |
||||||||
Group 1 0 mg/kg/day |
Group 2 100 mg/kg/day |
Group 3 300 mg/kg/day |
Group 4 1000 mg/kg/day |
Group 1 0 mg/kg/day |
Group 2 100 mg/kg/day |
Group 3 300 mg/kg/day |
Group 4 1000 mg/kg/day |
||||
Number Examined |
98 |
87 |
91 |
105 |
21 |
20 |
20 |
21 |
441 |
77 |
|
Minor skeletal abnormalities |
|
|
|
||||||||
Sternebrae |
bipartite ossified |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0 |
0-0 |
0-0 |
Costal cartilage |
2nd not connected to sternum |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0-0 |
0-0 |
Rib and vertebral configuration |
|
||||||||||
13thRib |
short without costal cartilage |
0 |
0 |
1 |
2 |
0 |
0 |
1 |
2 |
0-0 |
0-0 |
Number of 14thRibs |
full supernumerary |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0-3 |
0-2 |
Pelvic girdle |
unilateral caudal shift |
0 |
0 |
1 |
2 |
0 |
0 |
1 |
1 |
0-4 |
0-3 |
Delayed/Incomplete ossification/unossified |
|
||||||||||
Sterrnebrae |
1stto 4th |
0 |
1 |
2 |
1 |
0 |
1 |
2 |
1 |
0-13 |
0-4 |
Table 15. Fetal examinations - Minor Visceral Historical Control Data (July 2015 – present) |
|||||||||||
Group |
|
Study # 8457610 |
HCD Range |
||||||||
Fetuses |
Litters |
Fetuses |
Litters |
||||||||
Group 1 0 mg/kg/day |
Group 2 100 mg/kg/day |
Group 3 300 mg/kg/day |
Group 4 1000 mg/kg/day |
Group 1 0 mg/kg/day |
Group 2 100 mg/kg/day |
Group 3 300 mg/kg/day |
Group 4 1000 mg/kg/day |
||||
Number Examined |
106 |
96 |
99 |
114 |
21 |
20 |
20 |
21 |
774 |
77 |
|
|
106 |
96 |
100 |
114 |
21 |
20 |
20 |
21 |
360 |
68 |
|
Head abnormalities (fixed visceral) |
|
|
|
||||||||
Eyes |
dilated orbital sinus |
0 |
1 |
1 |
0 |
0 |
1 |
1 |
0 |
0-0 |
0-0 |
Brain |
subdural haemorrhage |
0 |
1 |
1 |
6 |
0 |
1 |
1 |
5 |
0-3 |
0-3 |
Necropsy observations (fresh visceral) |
|
||||||||||
Umbilical artery |
Left |
2 |
7 |
6 |
8 |
2 |
5 |
5 |
5 |
3-17 |
2-12 |
Applicant's summary and conclusion
- Conclusions:
- Based on the lack of adverse treatment-related effects observed, the No Observed Effect Level (NOEL) of 1-Dodecene, dimers (CAS No. 62132-67-6) for maternal toxicity, embryo-fetal survival, growth and development in rats was determined to be 1000 mg/kg/day.
- Executive summary:
A key OECD Guideline 414 pre-natal developmental toxicity study was conducted to evaluate the potential effects of the test material (1-Dodecene, dimers (CAS No. 62132-67-6)) on embryo-fetal survival and development when administered during the organogenesis and fetal growth phases of pregnancy in the rat.
The test material was administered to time-mated female Hans Wistar rats (22/dose) once daily via oral gavage in a corn oil vehicle at doses of 0, 100, 300, or 1000 mg/kg bw/day from Day 6 to 20 after mating. The control group received corn oil only. Clinical observations, body weight, and food consumption were recorded and animals were sacrificed on Day 21 after mating. Adult females were examined macroscopically at necropsy on Day 21 after mating, blood samples were taken for thyroid hormone analysis and the gravid uterus and thyroid weights were recorded. All fetuses were examined macroscopically at necropsy and the ano-genital distance measured. Fetal pathology investigations were undertaken on all fetuses by detailed internal visceral examination or skeletal examination.
No mortality or adverse treatment-related clinical signs of toxicity were observed through the study period. Overall body weight gain (GD 6-21), adjusted body weight change (GD 6-21), gravid uterine weight, and overall food consumption was unaffected by treatment at 100, 300 or 1000 mg/kg/day. While overall food consumption was statistically significantly high at 300 or 1000 mg/kg/day, the differences were marginal (106% or 112% of Control, respectively) and therefore considered to be incidental rather than treatment-related. There was no effect of treatment observed on serum concentrations of T3, T4, and TSH and no treatment-related changes were observed in the thyroids (with parathyroids). Gross necropsy did not reveal any remarkable treatment-related findings and no microscopic effects were observed in the thyroids.
Implantation losses, the numbers of resorptions and live young and the ratio of male to female offspring was unaffected by treatment.
Placental, fetal and total litter weights were also unaffected by treatment and no effect of treatment was observed on fetal ano‑genital distance. No major or minor treatment-related fetal abnormalities were observed. Two female fetuses in one litter (Dam/Litter No. 67) at 1000 mg/kg/day exhibited abnormalities of the head (one fetus had Microphthalmia (left eye) and one fetus had Brachygnathia and other related cranial abnormalities (jaw, palate, ear and nose)). However, given that only a single litter was affected and in the absence of related aetiology to other malformations at 1000 mg/kg/day or lower, these observations were not considered treatment-related. An increase in the incidence of the minor visceral abnormality subdural brain haemorrhage compared to control animals was observed at 1000 mg/kg/day (six fetuses in five litters). This exceeded the Historical Control Data (HCD) range (fetuses; 0-3, litters; 0-3) but was considered to have occurred during the necropsy procedure and therefore, was unrelated to treatment with the test material.
Based on the lack of adverse treatment-related effects observed, the No Observed Effect Level (NOEL) of 1-Dodecene, dimers (CAS No. 62132-67-6) for maternal toxicity, embryo-fetal survival, growth and development in rats was determined to be 1000 mg/kg/day.
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