Allyl hexanoate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

one-generation reproductive toxicity

Remarks:

based on generations indicated in Effect levels (migrated information)

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

2009-11-03 to 2010-02-26

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study reliable without restrictions

Qualifier:

according to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

signed 2009-11-12

Limit test:

no

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories Germany GmbH, Sandhofer Weg 7, D-97633 Sulzfeld
- Age at study initiation: (P) 9-10 wks
- Weight at study initiation: (P) Males: 311.0-443.8 g; Females: 215.6-275.5 g
- Housing: Except during the mating period, the parental males and females were kept singly in MAKROLON cages (type III) with a basal surface of approximately 39 cm x 23 cm and a height of approximately 15 cm.
- Diet: Commercial ssniff® R-Z V1324; ad libitum. Food residue was removed and weighed.
- Water: Tap water (in drinking bottles) was offered ad libitum.
- Acclimation period: 19 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C ± 2°C (maximum range)
- Humidity (%): 55% ± 15%
- Photoperiod: 12 hours dark/light cycle

IN-LIFE DATES:
- Termination of the in-life phase: 2010-01-01

Route of administration:

oral: gavage

Vehicle:

other: sesame oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: The test item was diluted in the vehicle to the appropriate concentrations and was administered orally (5 mL/kg b.w./day) once daily. The test item-vehicle mixtures were freshly prepared every day.

VEHICLE
- Volume of vehicle (if gavage): 5mL/kg body weight/day
- Lot/batch no. (if required): 90903229

Details on mating procedure:

- M/F ratio per cage: monogamous (1 male and 1 female rat per cage); 4 groups of sexually mature male and female rats were randomly paired for mating.
- Length of cohabitation: until copulation occurred or 2 weeks had elapsed
- Proof of pregnancy: Each morning, females were examined for presence of sperm in the vaginal lavage or for the presence of a vaginal plug referred to as day 0 of pregnancy.
- After 14 days of unsuccessful pairing: replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: no
This procedure was repeated until at least 8 pregnant dams were available for each group.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Stability and concentration were analysed immediately after preparation of the mixture as well as 8 and 24 hours after storage of the test item preparations at room temperature and during the last administration of the test item to the group, always before administration to the last animal/dose level group.

Duration of treatment / exposure:

Males: 2 weeks prior to mating, during the mating period and approximately 2 weeks post mating up to and including the day before sacrifice. Treatment of the males was conducted over a period of 29 days.
Females: Throughout the study beginning 2 weeks prior to mating and continuing up to, and including, day 3 post-partum or the day before sacrifice.

Frequency of treatment:

once daily

Details on study schedule:

indicated under "duration of treatment"

Remarks:

Doses / Concentrations:
10 mg/kg body weight/day
Basis:
nominal conc.
(low dose)

Remarks:

Doses / Concentrations:
30 mg/kg body weight/day
Basis:
nominal conc.
(intermediate dose)

Remarks:

Doses / Concentrations:
100 mg/kg body weight/day
Basis:
nominal conc.
(high dose)

No. of animals per sex per dose:

80 animals (40 males and 40 females), a sufficient number in order to grant at least 8 pregnant females per group.
10 male and 10 female rats were assigned to one of the 4 test groups, respectively.

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The dose levels for this study were selected based on the results of a 7-day dose-range finding study.

Positive control:

No positive control substance was tested.

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Each animal was observed for clinical signs at least once daily throughout the test period. The frequency was increased when signs of toxicity were observed. Relevant behavioural changes, signs of difficult or prolonged parturition and all signs of toxicity, including mortality, were recorded. Animals which died or were sacrificed prematurely during the study would have been necropsied as soon as possible after exitus. However, no parental animal died prematurely or were prematurely sacrificed.

BODY WEIGHT: Yes
- Time schedule for examinations: Parental male and female animals were weighed on the first day of dosing, weekly thereafter and at study termination. During gestation, females were weighed on days 0, 7, 14 and 20 and within 24 hours of parturition (day 0 or 1 post-partum) and on day 4 post-partum during lactation. Body weights were recorded individually for each adult animal.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
Food consumption of each animal was recorded weekly during the pre-mating period, daily during gestation and on day 4 post-partum. Food intake per rat (g/rat/week) was calculated using the total amount of food given to and left by each rat in each group on completion of a treatment week.

- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION AND COMPOUND INTAKE: Yes
- Time schedule for examinations: Drinking water consumption was monitored daily by visual appraisal throughout the study.

OTHER: Yes
The females were allowed to litter normally. The day on which parturition commenced was designated as day 0 of lactation. The pre-coital time, the number of pregnancies, and the duration of gestation in days were evaluated.
Evaluation/parameters:
- Corpora lutea: number per dam, absolute number per group, mean per group
- Implantation sites: number per dam, distribution in the uterine horns, absolute number per group, mean per group
- Number of pups absolute: at birth (alive and dead), after 4 days of life
- Number of pups per dam: at birth
- Number of male and female pups: at birth, after 4 days of life
- Offspring sex ratio
- Number of stillbirths: absolute, per dam

Oestrous cyclicity (parental animals):

not examined

Sperm parameters (parental animals):

not examined

Litter observations:

STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
- Number and sex of pups: Live pups were counted and the sex was determined.
- Stillbirths, live births, postnatal mortality, presence of gross anomalies: Each litter was examined as soon as possible after delivery to establish the number of stillbirth, live births, runts (pups were considered as runts if their weight was less than 70% of the mean litter weight) and the presence of gross abnormalities.
- Weight gain: Live pups were weighed individually within 24 hours of parturition (day 0 or 1 postpartum) and on day 4 post-partum during lactation.
- Physical or behavioural abnormalities: Any abnormal behaviour of the pups was recorded.

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals after a minimum total dosing period of 28 days.
- Maternal animals: Dams with offspring were sacrificed on day 4 post-partum, or shortly thereafter. Females which did not show any evidence of copulation were sacrificed 24 days after the last day of mating.

GROSS NECROPSY
- All animals were examined macroscopically for any abnormalities or pathological changes.
- Male animals: Testes and epididymides of all male adult animals were weighed. Testes, epididymides, accessory sex organs (coagulating gland, prepuital gland, prostate, seminal vesicle) and all organs showing macroscopic lesions of all adult males were preserved. The testes and epididymides were preserved in Bouin’s fixative; the remaining tissues were preserved in 7% buffered formalin.
- Female animals: The number of corpora lutea and implantation sites was recorded in the female adult animals. Special attention was paid to the organs of the reproductive system. Apparently non-pregnant uteri were placed in a 10% aqueous solution of ammonium sulfide for about 10 minutes to stain possible implantation sites in the endometrium according to SALEWSKI. The ovaries, accessory sex organs and all organs showing macroscopic lesions of all adult femals were preserved in 7% buffered formalin.

HISTOPATHOLOGY / ORGAN WEIGHTS
Detailed histopathologic examination was performed on the following organs and tissues of the animals of group 4 (high dose) and group 1 (control) following H&E and PAS staining:
- ovaries
- testes
- epididymides

Postmortem examinations (offspring):

SACRIFICE
- Dead pups and pups killed at day 4 post-partum, or shortly thereafter, were carefully examined externally for gross abnormalities.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows:

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations

HISTOPATHOLOGY / ORGAN WEIGTHS
not examined

Statistics:

For all numerical values homogeneity of variances was tested by using the BARTLETT chi-square test. If the variances were homogeneous, the DUNNETT test (p ≤ 0.01) was used to compare the experimental groups with the control group.
In case of heterogeneity of variances, the STUDENT's t-test was carried out, limit of significance was p ≤ 0.01.
For the comparison of classification measurements (for example the fertility index) the FISHER's exact test, n < 100 or chi2-test with Yates' correction for continuity, n ≥ 100 (p ≤ 0.05 and p ≤ 0.01) were employed.

Reproductive indices:

For each group the following indices were determined:
a) Fertility Index Female = number of pregnancies/number of matings x 100;
b) Gestation Index = number of litters with live pups/number of pregnancies x 100.

Offspring viability indices:

For each litter and group the following indices were determined:
a) Live birth Index = number of pups born alive/total number of pups born x 100;
b) Sex Ratio = number of males/number of females;
c) Percentage by Sex = number of males (females)/total number of animals x 100;
d) Viability Index = number of pups alive on day 4/number of pups alive and kept on day 0 x 100;
e) Post-implantation loss = implantations - no. pups born alive/implantations x 100.

Clinical signs:

effects observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Other effects:

no effects observed

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
No test item-related mortality was noted. Treatment with 100 mg Allyl heptanoate (Sym09/611041)/kg b.w./day led to salivation in 3/10 female rats on a few test days during the pre-mating, mating and/or gestation period.
One female animal (female no. 31) treated with 10 mg Allyl heptanoate (Sym09/611041)/kg b.w./day died prematurely and was found dead in the morning of test day 16, i.e. one day after start of the mating period. At necropsy, dark red discoloured lungs were noted in this female rat, hence, the death is considered to be possibly caused by misgavage. Additionally, the death is not regarded to be test item related as none of the intermediate- or high-dosed animals died prematurely during the course of the study.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Males: No test item-related changed were noted.
Females: Treatment with 100 mg Allyl heptanoate (Sym09/611041)/kg b.w./day led to a slightly increased mean body weight in the female animals starting in test week 2 of the pre-mating period lasting until the end of the gestation period (statistically significant on gestation days 3 to 9 and 12 to 15).

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
No influence was noted on the food intake of males and females during the pre-mating period and of females during the pre-mating, gestation and lactation periods at any of the tested dose levels.

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
no data

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
no data

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
Examination of female fertility: No test item-related influence was noted at any of the tested dose level.
Evaluation of the pre-coital time: No test item-related influence was noted.
Evaluation of female reproduction parameters: There were no test item-related differences in any of the reproduction parameters examined between the control group and the animals treated with 10, 30 or 100 mg Allyl heptanoate (Sym09/611041)/kg b.w./day.

ORGAN WEIGHTS (PARENTAL ANIMALS)
No test item-related influence was noted for the relative and absolute epididymides and testes weights of the male animals treated with 10, 30 or 100 mg Allyl heptanoate/kg b.w./day.

GROSS PATHOLOGY (PARENTAL ANIMALS)
Macroscopic post mortem findings: Treatment with 30 mg Allyl heptanoate (Sym09/611041)/kg b.w./day led to a white flocculation in the urinary bladder in 2/10 male rats and a partly thickened liver (adhered to diaphragm) in 1/10 female rats. A white flocculation in the urinary bladder was noted in 4/10 males treated with 100 mg Allyl heptanoate (Sym09/611041)/kg b.w./day. The liver of 6/10 high dosed females was indurated and/or thickened. Several yellow foci were noted in five of these females, reticulated yellowish discolourations were recorded in one female animal.
The spleen was enlarged in 5/10 high-dosed females.
No test item-related influence was noted on the absolute and relative epididymides and testes weights of male animals.

HISTOPATHOLOGY (PARENTAL ANIMALS)
The histomorphological examination of ovaries, testes and epididymides of the parental animals treated with 100 mg Allyl heptanoate (Sym09/611041)/kg b.w./day did not reveal any microscopical changes.

Dose descriptor:

NOAEL

Effect level:

30 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Effects observed at this dose in two treated males and one treated female in the 30 mg/kg bw dose group were considered as non-adverse effects.

Dose descriptor:

NOEL

Effect level:

9.2 mg/kg bw/day (nominal)

Based on:

other: allyl hexanoate

Sex:

male/female

Basis for effect level:

other: see read across statement (section 13)

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Histopathological findings:

not specified

VIABILITY (OFFSPRING)
No test item-related mortality occurred.

CLINICAL SIGNS (OFFSPRING)
No abnormal behaviour was noted.

BODY WEIGHT (OFFSPRING)
No test item-related influence was noted on the mean and total litter weight at any dose level.

SEXUAL MATURATION (OFFSPRING)
no data

ORGAN WEIGHTS (OFFSPRING)
no data

GROSS PATHOLOGY (OFFSPRING)
External examinations at dissection revealed no external abnormalities in any of the pups examined.

HISTOPATHOLOGY (OFFSPRING)
no data

Dose descriptor:

NOEL

Generation:

F1

Effect level:

100 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No test item-related influence was noted at any of the tested dose levels on the growth and development of the offspring from conception to day 4 post-partum.

Dose descriptor:

NOEL

Generation:

F1

Effect level:

92 mg/kg bw/day (nominal)

Based on:

other: allyl hexanoate

Sex:

male/female

Basis for effect level:

other: see read across statement (section 13)

Reproductive effects observed:

not specified

- Dose verification (content of Allyl heptanoate (Sym09/611041) in samples in the concentration range of 20 to 200 mg/mL) was successful.

- Homogeneity of samples during the application period was given.

- Stability of the test item Allyl heptanoate (Sym09/611041) over a period of 113 days at -20 ± 2 °C was confirmed (sampling at LPT Laboratory of Pharmacology and Toxicology until further sample dilution and analysis at the test facility).

For further information please refer to the appendix of this robust study summary.

Conclusions:

Under the present test conditions the following effect levels were noted for the test item Allyl Heptanoate (Sym09/611041) administered during the pre-mating and mating periods to parental males, during the pre-mating, mating, gestation and lactation periods until day 3 post-partum to parental female animals.
- Parental generation: The no-observed-effect level (NOEL) was 10 mg/kg b.w./day, p.o.
- Effects on the development of the conceptus and the F1 offspring (pups): The no-observed-effect level (NOEL) was above 100 mg/kg b.w./day, p.o.

Executive summary:

The results indicate that the content of Allyl heptanoate in the dosing suspensions corresponded reasonably well with the nominal concentrations in the concentration range of 6 to 20 g/L, and were shown to be stable and homogeneous during the application period.

Three dose levels (10, 30 and 100 mg/kg bw/day) of the test item Allyl Heptanoate (Sym09/611041) were administered during the pre-mating and mating periods to parental males, and during the pre-mating, mating, gestation and lactation periods until day 3 post-partum to parental female animals.

In parental animals, macroscopic changes were noted in the urinary bladder (males) or in the liver and spleen (females) of the animals treated with 30 or 100 mg Allyl heptanoate (Sym09/611041)/kg bw/day. The body weight of the high-dosed female rats (100 mg/kg) was slightly increased during the pre-mating and gestation period. Hence, the no-observed-effect level (NOEL) was 10 mg/kg bw/day, p.o.

No test item-related influence was noted at any of the tested dose levels on the growth and development of the offspring from conception to day 4 post-partum. Hence, the no-observed-effect level (NOEL) was above 100 mg/kg bw/day, p.o.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

92 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

GLP study, according to OECD TG 421 without deviations.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Three dose levels (10, 30 and 100 mg/kg bw/day) of the test item allyl heptanoate (see read across statement, section 13) were administered during the pre-mating and mating periods to parental males, and during the pre-mating, mating, gestation and lactation periods until day 3 post-partum to parental female animals. In parental animals, macroscopic changes were noted in the urinary bladder (males) or in the liver and spleen (females) of the animals treated with 30 or 100 mg allyl heptanoate/kg bw/day. The body weight of the high-dosed female rats (100 mg/kg) was slightly increased during the pre-mating and gestation period. Hence, the no-observed-effect level (NOEL) was 10 mg/kg bw/day, p.o. (9.2 mg/kg bw/day allyl hexanoate). No test item-related influence was noted at any of the tested dose levels on the reproductive parental performance, the growth and development of the offspring from conception to day 4 post-partum. Hence, the no-observed-effect level (NOEL) was 100 mg/kg bw/day, p.o. (92 mg/kg bw/day allyl hexanoate).

Short description of key information:
NOEL (parental/systemic) = 9.2 mg/kg bw/day allyl hexanoate (data derived from allyl heptanoate parental/systemic NOEL = 10 mg/kg bw/day)
NOEL (reproductive/developmental) = 92 mg/kg bw/day allyl hexanoate (data derived from allyl heptanoate reproductive/developmental NOEL = 100 mg/kg bw/day)

Justification for selection of Effect on fertility via oral route:
Only one reproduction/developmental toxicity screening study of allyl heptanoate is available for the toxicity to reproduction endpoint. Since allyl-heptanoate is a homologue of allyl-hexanoate, only with an additional methyl group in the aliphatic chain, it is considered that read-across from allyl-heptanoate is acceptable (see read across statement, section 13).

Effects on developmental toxicity

Description of key information

LOAEL (maternal) = 27 mg/kg bw/day allyl hexanoate (data derived from allyl alcohol maternal LOAEL = 10 mg/kg bw/day)
NOAEL (developmental) = 27 mg/kg bw/day allyl hexanoate (data derived from allyl alcohol developmental NOAEL = 10 mg/kg bw/day)

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP study performed according to guidelines

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

other: Crl: CD (SD)IGS BR

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Inc, Raleigh, North Carolina
- Age at study initiation: no data
- Weight at study initiation: minimum of 220 g
- Fasting period before study: no data
- Housing: All rats were individually housed in stainless steel wire-mesh cages and suspended above cage board. The cage-board was changed three times per week. Rats were paired for mating in the cage of the male. Following confirmation of mating, females were returned to individual suspended wire-mesh cages.
- Diet (e.g. ad libitum): PMI Nutrition international LLC, Certified Rodent LabDiet 5002, ad libitum. A supplemental feed (approximately 50/50 mixture of Hills Prescription Diet canine feed and water) was also used as many animals were not consuming sufficient amounts of food. This supplemental feed was provided to all animals that consumed less than 10 g/day beginning on 23/09/04.
- Water (e.g. ad libitum): Reverse osmosis-purified (on-site) drinking water delivered by an automatic watering system, ad libitum.
- Acclimation period: 13 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3
- Humidity (%): 50±20
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

other: deionized water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Test substance formulations were prepared by measuring the volume of test substance based on its specific gravity to obtain the correct mg/mL concentration. These volumes were placed into a calibrated container. 70 % of the vehicle was added to these calibrated containers and mixed with a magnetic stirrer until uniform

VEHICLE
- Concentration in vehicle: 2, 7, 10 mg/mL
- Amount of vehicle (if gavage): 5 mL/kg

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Gas chromatography was used to verify dose concentrations. Stability in dosing vehicle was similarly confirmed.

Details on mating procedure:

- Impregnation procedure: cohoused
- M/F ratio per cage: 1/1
- Proof of pregnancy: observation of vaginal plug or presence of sperm after vaginal lavage, referred to as day 0 of pregnancy

Duration of treatment / exposure:

Dosed on gestation days 6-19.

Frequency of treatment:

Once daily during gestation days 6-19.

Duration of test:

20 days

Remarks:

Doses / Concentrations:
0, 10, 35, 50 mg/kg bw/day
Basis:
analytical conc.

No. of animals per sex per dose:

25 animals per dose

Control animals:

yes, concurrent vehicle

Details on study design:

Daily observations of maternal clinical effects. Body weights and food consumption noted at appropriate intervals. 25 mated females/group were dosed once daily during gestation days 6-19. Animals dying during this period are necropsied. Laparohysterectomies carried out on gestation day 20 and gravid uterine weights and liver weights were recorded. Foetal weights and morphological examination and visceral dissection was carried out.

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Checked for moribundity and mortality.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Individual detailed clinical observations recorded from gestation days 0 through 20.

BODY WEIGHT: Yes
- Time schedule for examinations: Individual maternal body weights were recorded on gestation days 0 and 6-20 (daily).

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: liver, uterus, ovaries

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, and distribution
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Placental examination: Yes

Fetal examinations:

Viable foetuses were examined for external abnormalities, weighed and sexed. The following examinations conducted on each foetus included (and any findings recorded): eyes, palate and external orifices. All non-viable foetuses were examined (only if autolysis was minimal or absent) and in addition the crown-rump length measured, weighed and sexed. For late resorptions, crown-rump measurements and degree of autolysis were noted.

All viable foetuses underwent the following examinations:
- Visceral examination (including heart and major blood vessels)
- Internal examination to determine the sex of each foetus
- Foetal kidneys were examined for development of renal papillae
- The heads from half of the foetuses of each litter underwent a soft-tissue examination, the heads of the other half were examined by mid-coronal slice.
- Developmental variations and malformations were recorded

Statistics:

Implant and foetal data were summarised on both group and proportional litter bases

Indices:

Post implantation losses:
- post implantation loss/litter (dead foetuses + resorptions per group/gravid females per group)
- summation/group (sum of post implantation losses per litter/litters per group)

Foetal abnormalities:
- Viable foetuses affected/litter (viable foetuses affected per litter/viable foetuses per litter)
- Summation/group (sum of viable foetuses affected per litter/litters per group)

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
- In the 35 and 50 mg/kg bw/day groups, one and six females were found dead during gestation days 9-20.
- Clinical observations in all dose groups include: salivation, poor grooming (due to declining health), extremities cool to the touch, rocking, swaying while walking and hypoactivity. One female from the 35 mg/kg bw/day group also displayed shallow respiration. Two females from the 50 mg/kg bw/day group also had decreased defecation on days 8 and 10 of the gestation period.
- Necropsies of animals that had died after dosing at 50 mg/kg bw/day revealed a distended stomach, dark red stomach contents (with dark red areas on stomach lining). One female from the 35 mg/kg bw/day group had white and yellow patches on the liver and an entirely resorbed litter. Of the surviving females who underwent a scheduled necropsy, yellow/white areas on the liver, liver adhesions and misshapen/mottled livers were seen. In addition females from the 35 and 50 mg/kg bw/day group had enlarged spleens and females from the 35 mg/kg bw/day group had thickened pericardium and/or pericardium adhesions. One female from the 10 mg/kg bw/day group displayed yellow areas on the liver.
- A statistically significant loss in mean body weight gain was observed during days 6-9 of the gestation period in females of the 35 and 50 mg/kg bw/day group (when compared to the control group). In addition, mean body weights of the 50 mg/kg bw/day dose group were also significantly lower than the control group on day 8-11 of the gestation period and continued to be reduced for the remainder of the study.
- Group mean liver weights were reduced at 35 and 50 mg/kg bw/day compared to controls (5.4 % and 11.6 % respectively, the latter being statistically significant).
- No significant reduction in gravid uterine weights was observed.
- Food consumption was significantly reduced in the 35 and 50 mg/kg bw/day dose group.
- A significant increase in mean liver weights was seen in the 35 and 50 mg/kg bw/day group

Dose descriptor:

LOAEL

Effect level:

10 mg/kg bw/day

Based on:

test mat.

Remarks:

allyl alcohol

Basis for effect level:

other: maternal toxicity

Dose descriptor:

NOAEL

Effect level:

10 mg/kg bw/day

Based on:

test mat.

Remarks:

allyl alcohol

Basis for effect level:

other: developmental toxicity

Dose descriptor:

LOAEL

Effect level:

27 mg/kg bw/day

Based on:

other: allyl hexanoate

Basis for effect level:

other: maternal toxicity

Dose descriptor:

NOAEL

Effect level:

27 mg/kg bw/day

Based on:

other: allyl hexanoate

Basis for effect level:

other: developmental toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
- Small numbers of malformations observed in the 10 and 35 mg/kg bw/day dose groups were considered spontaneous in origin (none seen at 50 mg/kg bw/day).
- There were no soft-tissue malformations or developmental variations which were related to test substance exposure.
- Dose-related increases in post-implantation loss were observed in females of the 35 and 50 mg/kg bw/day dose groups.

Abnormalities:

not specified

Developmental effects observed:

not specified

Conclusions:

No teratogenic effects were seen in this study. The maternal LOAEL is 10 mg/kg bw/day and the developmental NOAEL is 10 mg/kg bw/day.

Executive summary:

In a developmental toxicity study allyl alcohol was administered to 25 female rats (Crl:CD (SD)IGS BR) per dose by oral gavage at dose levels of 10, 35, 50 mg/kg bw/day from days 6 through 19 of gestation.

The maternal LOAEL was 10  mg/kg bw/day, based on mortalities, clinical signs, food consumption and body weight gain reduction plus macroscopic liver effects seen at higher dosages. The developmental NOAEL was 10 mg/kg bw/day, based on post-implantation losses seen at higher dosages.

The developmental toxicity study in the rat is classified acceptable and satisfies the guideline requirement for a developmental toxicity study (OECD 414) in rats (strain: Crl:CD (SD)IGS BR) 

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

27 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

This GLP-study is according to OECD TG 414 and reliable without deviations.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

In pre-natal developmental toxicity study OECD TG 414 with allyl alcohol (see read across statement, section 13), NOAEL for developmental effects was determined at 10 mg/kg bw/day (27 mg/kg bw/day allyl hexanoate), whereas LOAEL for maternal effects was 10 mg/kg bw/day (27 mg/kg bw/day allyl hexanoate). No teratogenic effects were seen in this study.

Justification for selection of Effect on developmental toxicity: via oral route:
There is one read across from allyl alcohol reliable study on developmental toxicity via oral route (see read across statement, section 13)

Justification for classification or non-classification

- Reproductive toxicity:

Based on the above stated assessment of the reproduction toxicity potential of Allyl hexanoate is deemed that the compound is not toxic to the reproduction and does not need to be classified according to Council Directive 2001/59/EC (28th ATP of Directive 67/548/EEC) and according to CLP (Regulation (EC) No 1272/2008 of the European Parliament and of the Council) as implementation of UN-GHS in the EU.

- Developmental toxicity

Based on the above stated assessment of the developmental toxicity potential of Allyl hexanoate is deemed that the compound is not teratogenic and does not need to be classified according to Council Directive 2001/59/EC (28th ATP of Directive 67/548/EEC) and according to CLP (Regulation (EC) No 1272/2008 of the European Parliament and of the Council) as implementation of UN-GHS in the EU.