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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:
2007-01-18 till 2007-02-14
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2007
Report date:
2007

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
2001
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Undec-10-enoic acid
EC Number:
203-965-8
EC Name:
Undec-10-enoic acid
Cas Number:
112-38-9
Molecular formula:
C11H20O2
IUPAC Name:
undec-10-enoic acid
Details on test material:
- Name of test material (as cited in study report): Undecylenic Acid / Acide Undecylenique
- Physical state: white solid
- Analytical purity: 98.75
- Lot/batch No.: 0607007 filling 0022/06
- Expiration date of the lot/batch: 2007-12-22
- Storage condition of test material: at RT, protected from light
- Purity test date: 06/04/2006

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS (Caesarian-obtained, barrier-sustaines, virus-antibody free pregnant animals)
- Source: Charles River, L`Arbresle, France
- Age at study initiation: 11 weeks
- Weight at study initiation: 212-312 g
- Fasting period before study:
- Housing: barrier rodent unit, housed individually in suspended wire-mesh cages
- Diet (e.g. ad libitum): ad lib. access to pelleted standard diet
- Water (e.g. ad libitum): ad lib. access to 0.22 um-filtered tap water
- Acclimation period:3,4, or 5 days (delivered as mated females from supplier)
-individual identification by ear tattoo


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22+/-2
- Humidity (%): 50+/-20
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: To:

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
-mixing: magnetic stirrer
-Rate of preparation of solution (frequency): for up to 4 / 9 days
- Storage temperature of solution: 4°C


VEHICLE
- Justification for use and choice of vehicle (if other than water): not soluble in water
- Concentration in vehicle: 30,90,150 mg/mL
- Amount of vehicle (if gavage): 5 ml/kg BW/day
- Lot/batch no. (if required): batch No. 015K0115 (Sigma)
- Purity:98.79 %
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
by HPLC-UV;
deviations from nominal value: 3-9%;
compound in vehicle stable over 9 days at 4°C;
Details on mating procedure:
- Impregnation procedure: purchased timed pregnant
- Proof of pregnancy: vaginal plug referred to as day 0 post coitum
Duration of treatment / exposure:
from day 6 to day 20 post coitum
Frequency of treatment:
once daily
Duration of test:
15 days
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
150 mg/kg bw/day (nominal)
Dose / conc.:
450 mg/kg bw/day (nominal)
Dose / conc.:
750 mg/kg bw/day (nominal)
No. of animals per sex per dose:
24 animals/group
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: preliminary study

Examinations

Maternal examinations:
MORBIDITY/MORTALITY/CLINICAL SIGNS: Yes
- Time schedule: once to twice a day during treatment, afterwards once a day

BODY WEIGHT: Yes
- Time schedule for examinations: days 2,4,6,9,12,15,18,21 post coitum

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

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 21 (high-dose group between day 8 and 16 p.c.)
- macroscopic examination of the principal thoracic and abdominal organs

OTHER: fixation and collection of macroscopic lesions
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Number and ditribution of dead/life fetuses: Yes
- Number and distribution of uterine scars: Yes
- Other: gross evaluation of placentas, macroscopic lesions fixec and collected
Fetal examinations:
- External examinations/fetal weights/sex: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter
Statistics:
Mean values: one-way ANOVA with Dunnett`s test
Percentage Values: Fisher exact probability test
Indices:
body weight change, net body weight (chnage), total number of resorptions, total number of dead fetuses, % of dead fetuses/litter, total number of live fetuses, % of live fetuses/litter, % of pre-implantation loss, % of post-implantation loss, average fetal body weight, %of pre-implantation loss relative to number of corpora lutea
Historical control data:
no

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Signs of hypersalivation were noted in 24/24 and 15/24 females given 450 and 150 mg/kg/day,
from weeks 1 and 2, respectively
Mortality:
mortality observed, treatment-related
Description (incidence):
Among the 24 mated females given 750 mg/kg/day, 8 were found dead on GD 6, 7, 8, 10, 11 or 13
without ante-mortem signs of toxicity, and decision was taken to prematurely sacrifice the
survivors. No unscheduled deaths occurred at 450 or 150 mg/kg/day.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The body weight gain and net weight change of females given
450 mg/kg/day were statistically lower than controls (-11%, p<0.05 and -32%, p<0.001,
respectively). This effect on body weight was correlated with statistically significantly lower food
consumption between GD 9 and 15 (GD 9-12: -8%, p<0.05, GD 12-15: -12%, p<0.01).
At 150 mg/kg/day, the net body weight change was lower than controls but was not statistically
significant.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
The food intake was unaffected when given 150 mg/kg/day.
Food consumption of treated females at 450 mg/kg/day was lower than controls over the whole
dosing period, being statistically significant between GD 9 and GD 15 (ranging from -8% to
-12%).
At the low dose-level, the food consumption was considered to be unaffected by the test item
treatment
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
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no remarkable necropsy findings in any animals.
Neuropathological findings:
not examined

Maternal developmental toxicity

Number of abortions:
no effects observed
Description (incidence and severity):
The mean number of resorptions was not affected by the test treatment.
There were no dead fetuses in any group treated with the test item.
The sex ratio was similar in the control and the treated groups.
The mean fetal body weight recorded in the test item-treated groups was similar to that of the
control group.
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
All mated animals from the control group and the groups treated at 150 and 450 mg/kg/day were
pregnant with live fetuses at term.
Details on maternal toxic effects:
Maternal toxic effects:yes

At 750 mg/kg/day, a total of eight pregnant females were found dead on GD (gestation days)
6, 7 (three females), 8, 10, 11 and 13 without ante-mortem signs of toxicity. Only signs of
hypersalivation were observed among three of them on the days preceding the death. Neither
body weight nor food consumption were affected. Female N24231 died accidentally on GD 11
because of a gavage error (the trachea was perforated). In female N24238, which was found dead
on GD 8, enlarged spleen with whitish focus was observed at necropsy. No necropsy findings
were observed in the six other animals.
Although no signs of toxicity were recorded before the death and in spite of the absence of
necropsy findings, these seven deaths were considered to be test item treatment-related.
A statistically lower body weight gain was recorded in females given 450 mg/kg/day over the
whole treatment period (-11%, p<0.05). This effect was mainly due to frank but transient decrease
in body weight gain of many females between GD 6-9. The terminal body weight was comparable
between groups, but the net weight change was statistically lower than controls (see below).
The body weight gain and body weight were unaffected by the treatment at 150 mg/kg/day.
Food consumption of treated females at 450 mg/kg/day was lower than controls over the whole
dosing period, being statistically significant between GD 9 and GD 15 (ranging from -8% to
-12%).
At the low dose-level, the food consumption was considered to be unaffected by the test item
treatment.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
150 mg/kg bw/day (actual dose received)
Basis for effect level:
other: maternal toxicity decrease in body weight gain and food consumption
Dose descriptor:
LOAEL
Effect level:
450 mg/kg bw/day (actual dose received)
Basis for effect level:
other: maternal toxicity

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
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
none of the parameters investigated was affected
(one fetus in the low dose group with several malformations was not considered relevant but of spontaneous origin)

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
450 mg/kg bw/day (actual dose received)
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Any other information on results incl. tables

Table 1: Maternal Body Weight Gain (±SD)

 

 

Interval

Dose in mg/kg bw/day (24 of Dams)

Control (N)

LDT (150)

MDT (450)

HDT (750)

Treatment:

Days 6 -12 

 40

37 

32**

 -

Treatment:

Days 6 -15 

63 

 57

 52**

 -

Treatment:

Days 6 -21 

 151

137 

135* 

 -

*  Significantly different (p 0.05) from the control

** Significantly different (p 0.01) from the control

 

Applicant's summary and conclusion

Conclusions:
No hints for developmental toxic effects of undecylenic acid were identified, not even in animals with clear maternal toxicity.
Executive summary:

The potential of the test substance undecylenic acid to induce developmental toxicity was evaluated in the rat according to OECD guideline 414. Pregnant Sprague-Dawley rats were treated daily with the test substance by oral gavage between days 6 and 21 post coitum. The dams were observed during the treatement for signs of toxicity. The animals were sacrificed on day 21 post coitum and fetuses as well as maternal animals were investigated for signs of toxicity.

Unexpectedly high mortality in the high dose group led to the decision to terminate the treatment of this group. All animals of the intermediate dose group exhibited hypersalivation, and a significantly reduced body weight gain compared to control. In the low dose group, no relevant effects were observed. Hypersalivation in half of the animals was not considered as a relevant sign of toxicity.

No effects or uncommon findings were observed in the fetuses of the animals (malformations observed in a single fetus of the low dose group was considered incidental).

Consequently, the NOAEL for maternal toxicity was set to 150 mg/kg bw/day, while the LOAEL for this parameter was 450 mg/kg bw/day based on body weight and clinical signs. No signs of teratogenicity/developmental toxicity were observed in the study, and the NOAEL was set to the highest dose level, 450 mg/kg bw/day (750 mg/kg bw/day was discontinued before end of study). A LOAEL for teratogenicity was not observed.

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