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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
21 April 2016 till 31 October 2016
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2017
Report date:
2017

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Qualifier:
according to guideline
Guideline:
other: Japanese Ministry of AgricultureForestry and Fisheries Testing guidelines for Toxicology studies, 12 NohSan No 8147
Version / remarks:
Japanese Ministry of Agriculture, Forestry and Fisheries Testing guidelines for
Toxicology studies, 12 NohSan No 8147
Qualifier:
according to guideline
Guideline:
other: Commission Regulation (EC) No 440/2008 of 30 May 2008 test methods pursuant to Regulations (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH)
Version / remarks:
Commission Regulation (EC) No 440/2008 of 30 May 2008 test methods pursuant to
Regulations (EC) No 1907/2006 of the European Parliament and of the Council on the
Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2,6,10-trimethyldodecane
EC Number:
622-542-2
Cas Number:
3891-98-3
Molecular formula:
C15H32
IUPAC Name:
2,6,10-trimethyldodecane
Test material form:
other: liquid
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL

- Source and lot/batch No.of test material: Distilled Farnesane w/no BHT Lot#: 15P0112023100001
- Expiration date of the lot/batch: 03 March 2017
- Purity test date: 99%

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature, in the dark
- Stability under test conditions: Formulations were prepared twice and stored at approximately +4 °C in the dark.
- Solubility and stability of the test substance in the solvent/vehicle: Stable for at least twenty-one days.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Remarks:
Crl:CD (SD) IGS BR
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: mated female Sprague-Dawley rats from Charles River (UK) Limited, Margate, Kent
- Age at study initiation: females prior to Day 3 of gestation
- Weight at study initiation: 232 to 271g (Gestation day 3)
- Fasting period before study: not applicable
- Housing: animals were housed individually in solid-floor polypropylene cages with stainless steel mesh lids furnished with softwood flakes (Datesand Ltd., Cheshire, UK)
- Diet (e.g. ad libitum): ad libitum, pelleted diet (Rodent 2018C Teklad Global Certified Diet, Envigo RMS (UK) Limited, Oxon, UK)
- Water (e.g. ad libitum): ad libitum, polycarbonate bottles attached to the cage
- Acclimation period: not applicable

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 ºC
- Humidity (%): 50 ± 20%
- Air changes (per hr): at least fifteen air changes per hour
- Photoperiod (hrs dark / hrs light): twelve hours continuous light and twelve hours darkness

IN-LIFE DATES: From: To: between 06 May 2016 (first day of treatment) and 25 May 2016 (final day of necropsy).

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on exposure:
VEHICLE - Arachis Oil
Treatment volume : 4 mL/kg


Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples were taken of each test item formulation and were analyzed for concentration of Farnesane at Envigo Analytical Laboratory, Shardlow. The prepared formulations were within ± 6% of the nominal concentration.
Details on mating procedure:
Proof of pregnancy: the day that positive evidence of mating was observed was designated Day 0 of gestation.
Duration of treatment / exposure:
from Day 3 to Day 19 of gestation
Frequency of treatment:
once daily
Duration of test:
Termination on gestation: day 20
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day
Dose / conc.:
300 mg/kg bw/day
Dose / conc.:
1 000 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 based on the previous toxicity data:
- Envigo Research Limited Study Number 41500675: Fourteen Day Repeated Dose Oral (Gavage) Range-Finding Toxicity Study in the Rat
- Envigo Research Limited Study Number 41500677: the Preliminary Oral (Gavage) Pre-Natal Development Toxicity Study in the Rat.

The latter study was designed to investigate the effects of the test item on embryonic and fetal development following repeated administration by gavage to the pregnant female during gestation including the period of organogenesis.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once daily during the gestation period. Additionally, during the dosing period, observations were recorded immediately before and up to thirty minutes after dosing and one hour after dosing. All observations were recorded.

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes
- Time schedule for examinations:Individual body weights were recorded on Day 3 (before the start of treatment) and on Days 4, 5, 8, 11, 14 and 17 of gestation. Body weights were also recorded for surviving animals at terminal kill (Day 20).

FOOD CONSUMPTION: Food consumption was recorded for each surviving individual animal at Day 3, 5, 8, 11, 14, 17 and 20 of gestation.

WATER CONSUMPTION: Water intake was observed daily by visual inspection of the water bottles for any overt changes.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: All animals were subjected to a full external and internal examination and any macroscopic abnormalities were recorded.

Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes / No / No data
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: sex ratio Yes
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
Statistics:
Female body weight change, food consumption and gravid uterus weight: Shapiro Wilk normality test and Bartlett’s test for homogeneity of variance and one way analysis of variance, followed by Dunnett’s multiple comparison test or, if unequal variances were observed, on alternative multiple comparison test.

All caesarean necropsy parameters and fetal parameters: Kruskal-Wallis non-parametric analysis of variance; and a subsequent pairwise analysis of control
values against treated values using the Mann-Whitney ‘U’ test, where significance was seen.

Fetal evaluation parameters, including skeletal or visceral findings: Kruskal-Wallis nonparametric analysis of variance and Mann-Whitney ‘U’ test.
Indices:
All data was summarized in tabular form, including reproductive indices.
Historical control data:
The rat was selected for this study as it is a readily available rodent species historically used in safety evaluation studies and is acceptable to appropriate regulatory authorities.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
No clinical signs of toxicity were evident in the surviving females.
Mortality:
no mortality observed
Description (incidence):
One female treated with 1000 mg/kg bw/day was killed in extremis on Day 13 of gestation. This female had hunched posture and was emaciated. At necropsy, a fibrous mass (approximately 12mm x 6mm) was found in the chest cavity. In the absence of any similar effects evident in the remaining females, this death was considered to be incidental and unrelated to treatment.

There were no further unscheduled deaths.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Body weight and body weight gain, including adjustment for the contribution of the gravid uterus, was unaffected by treatment at 100, 300 or 1000 mg/kg bw/day.
Statistical analysis of the data did not reveal any significant intergroup differences.
Food efficiency:
no effects observed
Description (incidence and severity):
Food consumption during gestation was unaffected by treatment at 100, 300 or 1000 mg/kg bw/day.
Statistical analysis of the data did not reveal any significant intergroup differences.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No abnormalities were detected during the macroscopic examination of the surviving pregnant females at termination on gestation Day 20.

Maternal developmental toxicity

Pre- and post-implantation loss:
effects observed, non-treatment-related
Description (incidence and severity):
Females treated with 100 mg/kg bw/day showed a statistically significant reduction in pre implantation loss. The group mean value was within historical control ranges and in the absence of a true dose-related effect the intergroup difference was considered not to be of toxicological importance.
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
Females treated with 1000 and 100 mg/kg bw/day showed a statistically significant reduction in the number of corpora lutea. Group mean values were within historical control ranges and in the absence of a true dose-related effect or subsequent effect on the number of implantations the intergroup differences were considered not to be of toxicological importance.
Details on maternal toxic effects:
No clinical signs of toxicity were evident in the surviving females. No treatment-related effects were detected in the uterine parameters examined.
Neither the type, incidence nor the distribution of findings observed during external examination of the fetuses at necropsy on gestation Day 20 and subsequent detailed visceral and skeletal examination indicated any adverse effect of maternal exposure on fetal development.

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:
Remarks on result:
other: no treatment-related effects observed

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
External malformations:
no effects observed
Description (incidence and severity):
No treatment-related effects were detected in fetal external findings.
Skeletal malformations:
no effects observed
Description (incidence and severity):
No treatment-related adverse effects on skeletal development were detected or in the type and incidence of visceral findings in fetuses from females treated with 100, 300 or 1000 mg/kg bw/day.

Visceral malformations:
no effects observed
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
A statistically significant reduction in the number of fetuses/litters showing incomplete ossification of the ischium was evident at 1000 and 300 mg/kg bw/day. Group mean values were within historical control ranges and the observation of one variant at a lower incidence compared with controls is not significant when evaluated in isolation.

A statistically significant increase in the number of fetuses/litters showing a mis-aligned sternebra was evident in all treatment groups. Group mean values were within historical control ranges and the observation of one variant at a higher incidence compared with controls is not significant when evaluated in isolation. In the absence of any particular pattern of abnormal skeletal development of skeletal structures affecting treated fetuses, the observation of two affected skeletal structures can be considered unlikely to represent true developmental abnormality. In addition, the observed findings are regularly seen in developmental studies amongst control group fetuses.
Details on embryotoxic / teratogenic effects:
No treatment-related adverse changes were detected in the offspring parameters measured or on embryofoetal development. The number of implantations, subsequent embryofetal survival and litter size, sex ratio and mean fetal, litter and placental weights on gestation Day 20 were unaffected by maternal treatment at 100, 300 or 1000 mg/kg bw/day.

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:
skeletal malformations
other: developmental toxicity
Remarks on result:
other: No treatment-related adverse changes observed

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
The administration of Farnesane to pregnant rats by oral gavage from gestation on days 3 to 19 at dose levels of 100, 300 or 1000 mg/Kg bw/day did not result in any treatment-related effects.

The ‘No Observed Effect Level’ (NOEL) for the pregnant female was considered to be 1000 mg/Kg bw/day. No treatment-related adverse changes were detected in the offspring parameters measured or on embryofoetal development. The ‘No Observed Effect Level’ (NOEL) for developmental toxicity was therefore considered to be 1000 mg/Kg bw/day.
Executive summary:

The test material Farnesane was administrated by oral gavage to 24 female Sprague-Dawley rats during gestation, including the period of organogenesis at dose levels of 100, 300 and 1000 mg/Kg/bw. The aim of the study was to investigate the effects of Farnesane on embryonic and fetal development.

There were no deaths of rats occurred in the study. One female treated with 1000 mg/Kg bw/day was killed in extremis on Day 13 of gestation. This death was considered to be incidental and unrelated to treatment.

All surviving females were terminated on Day 20 of gestation and subjected to gross necropsy including examination of the uterine contents. No treatment-related effects were detected in the uterine parameters examined, in fetal viability or in growth and development.

The oral administration of Farnesane to pregnant rats did not result in any treatment-related effects.  The ‘No Observed Effect Level’ (NOEL) for the pregnant female was considered to be 1000 mg/Kg bw/day.

No treatment-related adverse effects on skeletal development were detected or in the type and incidence of visceral findings in fetuses from females treated with 100, 300 or 1000 mg/Kg bw/day. The number of implantations, subsequent embryofetal survival and litter size, sex ratio and mean fetal, litter and placental weights on gestation Day 20 were unaffected by maternal treatment at 100, 300 or 1000 mg/Kg bw/day.

No treatment-related effects were detected in the offspring parameters measured or on embryofoetal development. The ‘No Observed Effect Level’ (NOEL) for developmental toxicity was therefore considered to be 1000 mg/Kg bw/day.