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Diss Factsheets

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
20 Nov - 19 Apr 2016
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2016
Report date:
2016

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
adopted 22 Jan 2001
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
Government of India, Department of Science and Technology, New Delhi, India
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Allyl heptanoate
EC Number:
205-527-1
EC Name:
Allyl heptanoate
Cas Number:
142-19-8
Molecular formula:
C10H18O2
IUPAC Name:
allyl heptanoate

Test animals

Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Advinus Therapeutics Ltd, Bengaluru, India
- Age at study initiation: 14 - 15 weeks
- Weight at study initiation: 251.78 - 252.76 g
- Housing: individually in standard polysulfone rat cages (L 425 x B 266 x H 185 mm) on steam sterilized clean corn cob
- Diet: Teklad Certified (2014CM) Global 14% Protein Rodent Maintenance Diet - Powder (Harlan Laboratories B.V., Venray, The Netherlands), ad libitum
- Water: deep bore-well water passed through activated charcoal filter and exposed to UV rays in ‘Aquaguard’ on-line water filter-cum-purifier (Eureka Forbes Ltd., Mumbai, India), ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 23
- Humidity (%): 65 - 67
- Air changes (per hr):12 - 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: feed
Vehicle:
acetone
Details on exposure:
DIET PREPARATION
- Rate of preparation of diet: The test substance fortified diet was prepared twice during the conduct of the study and were used within the established stability period of 15 days.
- Mixing appropriate amounts with Teklad powder feed
The required quantities of the test substance (1.001 , 4.003 and 15.004 g for low, mid and high dose) were weighed and mixed with 10 mL of acetone. This was mixed manually with approximately 1.0 kg of powder food in stainless steel drum for 2 minutes and then added in portions to the remaining portion of the food (approximately 9 kg) and was mixed in a ribbon blender for 20 minutes.
- Storage temperature of food: The experimental feed was stored in the polyethylene bags within labeled stainless steel drums in the experimental room.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The homogeneity and active ingredient analysis was carried from the samples of first preparation. For this, samples were taken from top, middle and bottom layers of the fortified diet of each dose group to determine the homogeneity and active ingredient of the test substance in the experimental fortified diet. Further, active ingredient analysis was carried out at termination of treatment period (6 days before termination of treatment for batch I). For this, one composite sample from each dose was taken to determine the active ingredient concentration by GC analysis. For the control group, one composite sample was collected as scheduled above. The results of analysis indicated that the test substance concentrations in the fortified diet samples were found to be in acceptable range, as the percent agreement of the analyzed concentrations were within ± 20% of the nominal dose concentration. Homogeneity of the dose formulation was also considered acceptable as the relative standard deviation from three replicates (1 replicate from top layer, 1 replicate from middle layer and 1 replicate from the bottom layer of the dietary preparation) at each dose level were <15%. The test substance was found to be stable in the diet for 15 days at room temperature.
Details on mating procedure:
- Impregnation procedure: cohoused
- M/F ratio per cage: 1/1
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as Day 0 of pregnancy
Duration of treatment / exposure:
Day 5 - 20 of gestation
Frequency of treatment:
continuously (via diet)
Duration of test:
20 days
Doses / concentrationsopen allclose all
Dose / conc.:
100 ppm
Remarks:
equivalent to 6.95 mg/kg bw/day
Dose / conc.:
400 ppm
Remarks:
equivalent to 25.71 mg/kg bw/day
Dose / conc.:
1 500 ppm
Remarks:
equivalent to 77.40 mg/kg bw/day
No. of animals per sex per dose:
24
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The dose levels were selected based on the results of a dose range-finding study. The study was carried out using seven Day ‘0’ pregnant rats per group at dose levels of 200, 1000 and 5000 ppm. Rats were treated from GD 5 to GD 20 and observed for clinical signs, mortality, body weight changes and food intake. The caesarean section was performed on GD 20. The dams were observed to obtain maternal and litter data and the fetuses were subjected to external examination. No clinical signs, mortality and morbidity were observed at any of the doses tested. The food consumption was significantly lower at 1000 and 5000 ppm with concomitant reduced body weight gains at 5000 ppm mainly due to palatability reasons. The reduced body weights resulted in lower pregnancy rates at 5000 ppm. However there were no effects on uterine/litter parameters at any of the dose levels tested. Based on the results of the study 100, 400 and 1500 ppm were selected for the main study.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily (once daily on holidays)
- Cage side observations included: mortality/viability

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily

BODY WEIGHT: Yes
- Time schedule for examinations: All females included in the study were weighed on gestation days 0, 3, 5, 8, 11, 14, 17 and 20.

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/rat/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on GD 20
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: gross evaluation of placenta, pregnancy status
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: approximately half per litter
- Skeletal examinations: Yes: approximately half per litter
- Head examinations: Yes: approximately half per litter

OTHER: total number of fetuses, number of viable fetuses, number of non-viable fetuses, individual fetal body weight, fetus sex, sex ratio
Statistics:
The data on maternal body weight, body weight change, gravid uterine weight, body weight change corrected for gravid uterine weight, maternal food consumption, number of corpora lutea, number of implantations, litter size, litter weight, male and female fetus number and weight were analyzed using ANOVA model, after testing for homogeneity for intra group variance using Levene’s test.
If the intra group variances are heterogeneous ANOVA was performed after suitable transformation of data. Dunnett’s pairwise comparison of the treated group means with the control group mean was performed, if the group differences were found significant.
Incidence of pre-implantation loss, post implantation loss, number of early, late, total resorptions, was analyzed using Kruskal Wallis.
Overall number and percentage of external, visceral and skeletal malformations, sex ratio, number of dams with any resorptions were analyzed using 2 X 2 Contingency Table.
Indices:
Embryonic resorption index (%) = (No. of early resorptions / No. of implantations) x 100
Fetal resorption index (%) = (No. of late resorptions / No. of implantations) x 100
Pre-implantation loss per group (%) = (No. of corpora lutea - No. of implantations / No. of corpora lutea) x 100
Post-implantation loss per group (%) = (No. of (early + late) resorptions / Total No. of implantations) x 100
Implantation index (%) = (No. of implantations sites / No. of corpora lutea) x 100
Percentage of live fetuses per group (Live fetus index) = (No. of live fetuses / Total No. of fetuses) x 100
Percentage of dead fetuses per group (Dead fetus index) = (No. of dead fetuses / Total No. of fetuses) x 100
Historical control data:
The results of the study will be discussed taking into consideration the historical control data of this lab. Historical control data was obtained from 10 prenatal developmental toxicity studies conducted from 2011 until 2015. Studies were performed in female Wistar rats at the age of 11 -15 weeks.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
There were no clinical signs in any of the rats at the tested dose levels.
Mortality:
no mortality observed
Description (incidence):
There were no mortalities in any of the rats at the tested dose levels.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Maternal body weights were not affected by the treatment at the doses of 100 and 400 ppm.
At 1500 ppm, the group means of maternal body weights were significantly reduced on GD 8, 14, 17 and 20. However, these reductions in body weights at 1500 ppm were less than 10% as compared to control group and hence not considered to be adverse.
There was significant reduction in intermittent body weight gains during GD 5 - 8 at 400 ppm, and during GD 5 - 8, 11 - 14, 14 - 17 and 17 - 20 at 1500 ppm as compared to control group.
The maternal body weight gain was significantly reduced during treatment period (GD 5 - 20) and throughout gestation (GD 0 - 20) at 1500 ppm as compared to control group (reduced up to 39% and 34%, respectively).
The corrected body weight gain was also significantly lower at 400 and 1500 ppm.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
The significant increase in food intake during GD 11 - 14 at 100 ppm was considered as an incidental finding as the maternal body weights were unaffected at this dose.
The food intake was significantly reduced during GD 5 - 8 and 17 - 20 at 400 ppm and during GD 5 - 8, 8 - 11, 11 - 14, 14 - 17 and 17 - 20 at 1500 ppm compared to the vehicle control group.
The food intake was significantly reduced during treatment period (GD 5 - 20) and throughout gestation (GD 0 - 20) at 1500 ppm as compared to control group.
Reduction in food intake was mainly due to palatability reasons and this was associated with reduced body weights in the respective dose groups.
Food efficiency:
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):
Mean gravid uterine weights were statistically comparable to the control group at all dose levels and were not affected by the treatment.
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no gross pathological findings in any of the rats at the tested dose levels.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined

Maternal developmental toxicity

Number of abortions:
not specified
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
Pre- and post-implantation loss rates were statistically comparable to the control group at all dose levels and were not affected by treatment with the test substance.
Total litter losses by resorption:
not specified
Early or late resorptions:
no effects observed
Description (incidence and severity):
Early and late resorptions were statistically comparable to the control group at all dose levels and were not affected by treatment with the test substance.
Dead fetuses:
no effects observed
Description (incidence and severity):
There were no dead fetuses in any of the dose groups.
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
All 24 dams of each dose group were sacrificed at cesarean section on GD 20.
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified
Changes in number of pregnant:
effects observed, non-treatment-related
Description (incidence and severity):
2 rats each of the control and high dose group as well as 1 rat each of the low and mid dose group were non-pregnant at cesarean section on GD 20.
Details on maternal toxic effects:
The maternal uterine parameters which includes mean gravid uterine weights, mean numbers of corpora lutea, implantations, early and late resorptions, pre and post-implantation loss rates and were statistically comparable to the control group at all dose levels and were not affected by treatment with the test substance.

Effect levels (maternal animals)

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 500 ppm
Based on:
test mat.
Basis for effect level:
body weight and weight gain
changes in number of pregnant
changes in pregnancy duration
clinical signs
dead fetuses
early or late resorptions
food consumption and compound intake
gross pathology
maternal abnormalities
mortality
necropsy findings
organ weights and organ / body weight ratios
pre and post implantation loss
Key result
Dose descriptor:
NOAEL
Effect level:
>= 77.4 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
changes in number of pregnant
changes in pregnancy duration
clinical signs
dead fetuses
early or late resorptions
food consumption and compound intake
gross pathology
maternal abnormalities
mortality
necropsy findings
organ weights and organ / body weight ratios
pre and post implantation loss
total litter losses by resorption

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
The mean fetal weights of male fetuses of the high dose group were significantly lower, however the decrease was within the historical control range and hence considered incidental.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
Number of live fetuses was statistically comparable to control group at all the tested doses.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
Sex ratio was statistically comparable to control group at all the tested doses.
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
The mean litter size was statistically comparable to control group at all the tested doses.
Changes in postnatal survival:
not examined
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
There were no observations in the control and treatment groups considering normal variants, minor anomalies and major malformations.
Skeletal malformations:
no effects observed
Description (incidence and severity):
Incidences of normal variants were comparable between the control and the treatment groups. However, statistically significant increase in the percent incidences of delayed skeletal ossification and incomplete/poor ossification in some of the bone components was observed in the treatment groups. These findings were randomly distributed across treatment groups and were not dose-dependent. Further, these normal variants are commonly observed in rat fetuses (comparable with historical control data) and were not considered as biological significant.
There was significant increase in dumbbell thoracic vertebral centra 1/13 at 100 and 400 ppm as compared to control group. This finding was considered not treatment-related as the values were comparable to historical control data.
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
There were 2 incidences of median lobe extra lobation in liver at 400 ppm and a single incidence of slight kidney renal pelvis dilation at 100 ppm. These variations were commonly observed in colonies of rats from the laboratory and hence were not attributed to treatment.

Effect levels (fetuses)

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 500 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
changes in sex ratio
changes in litter size and weights
external malformations
skeletal malformations
visceral malformations
Key result
Dose descriptor:
NOAEL
Effect level:
>= 77.4 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
changes in sex ratio
changes in litter size and weights
external malformations
skeletal malformations
visceral malformations

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
Based on the results of this study, the NOAEL for maternal and fetal developmental toxicity was set at ≥ 1500 ppm (equivalent to 77.40 mg/kg bw/day).