Undec-10-enoic acid

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Description of key information

One test in rats is available according to the OECD 421 guideline (CIT 2009). Based on the results of this study, the dose-level of 150 mg/kg/day was considered to be the No Observed Adverse Effect Level (NOAEL) for parental toxicity, and the dose-level of 450 mg/kg/day was the NOEL for reproductive performance. There is no need for classification of test item undecylenic acid as to its reprotoxic properties.

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2007-06-11 till 2009-07-01

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

Version / remarks:

1995

Deviations:

yes

Remarks:

Some relatively minor deviations are discussed in the study report. These deviations were not considered to have compromised the validity or integrity of the study.

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories France, L’Arbresle, France
- Age at study initiation: (P) 11 wks
- Weight at study initiation: (P) Males: mean body weight of 441 g (range: 386 g to 506 g); females: mean body weight 251 g (range: 223 g to 280 g)
- Fasting period before study: no data
- Housing: The animals were individually housed (except during mating) in suspended wire-mesh cages (43.0 x 21.5 x 18.0 cm). A metal tray, containing autoclaved sawdust (SICSA, Alfortville, France), was placed under each cage. Shortly before parturition, the females were moved to polycarbonate cages (43.0 x 21.5 x 20.0 cm) with wood shavings as nesting material.
- Diet (e.g. ad libitum): The animals had free access to SsniffR/M-H pelleted maintenance diet, batch Nos. 6557303 and 9557111 (SSNIFF Spezialdiäten GmbH, Soest, Germany) which was distributed weekly.
- Water (e.g. ad libitum): The animals had free access to bottles containing tap water (filtered with a 0.22 µm filter).
- Acclimation period: 14 days before the beginning of the treatment period


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2°C
- Humidity (%): 50 ± 20%
- Air changes (per hr): about 12 cycles/hour of filtered, non-recycled air
- Photoperiod (hrs dark / hrs light): 12h/12h (7:00 - 19:00)


IN-LIFE DATES: From: 2007-06-12 To: 2007-08-21

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): Diet distributed weekly. Each batch of diet was analyzed by the supplier for composition and contaminant levels
- Storage temperature of food: no data

VEHICLE
- Justification for use and choice of vehicle (if other than water): no justification given
- Concentration in vehicle: 10, 30 and 90 mg/mL
- Amount of vehicle (if gavage): 5 mL/kg bw / day
- Lot/batch no. (if required): batch No. 065K0077, supplied by Sigma
- Purity: no data

Details on mating procedure:

- M/F ratio per cage: one female was placed with one male
- Length of cohabitation: Each female was placed with the same male until mating occurs or 14 days have elapsed.
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 post coitum
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): Shortly before parturition, the females were moved to polycarbonate cages (43.0 x 21.5 x 20.0 cm) with wood shavings as nesting material.
- Any other deviations from standard protocol: none reported

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The test item concentration of samples taken from each dosage form (including the control) prepared for use in weeks 1, 2 and 4 (all groups) or week 8 (group 2, see § Study plan adherence) was determined. On 27th June 2007, the control dosage form was re-sampled and analyzed in duplicate further to abnormal values obtained during the first analysis. Only replicated data was reported. The analytical procedure used is presented in the study report.
Acceptance criterion: actual concentration: nominal value ± 10%.

Duration of treatment / exposure:

Males: 2 weeks before mating, during the mating period (2 weeks), until sacrifice (i.e. at least 4 weeks in total)
Females: 2 weeks before mating, during the mating period (2 weeks), during pregnancy, during lactation until day 4 post-partum inclusive (until sacrifice).

Frequency of treatment:

once a day, 7 days per week

Details on study schedule:

- F1 parental animals not mated until [...] weeks after selected from the F1 litters. not applicable
- Selection of parents from F1 generation when pups were [...] days of age. not applicable
- Age at mating of the mated animals in the study: 11 weeks

Dose / conc.:

50 mg/kg bw/day

Dose / conc.:

150 mg/kg bw/day

Dose / conc.:

450 mg/kg bw/day

No. of animals per sex per dose:

10 males, 10 females

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The dose-levels were selected in agreement with the Sponsor, following the results of a previously conducted prenatal toxicity study (CIT/Study No. 31486 RSR) in which the test item, UNDECYLENIC ACID (batch No. 0607007), was administered daily by gavage to pregnant
Sprague-Dawley rats from day 6 to day 20 p.c. at the dose-levels of 150 or 450 mg/kg/day. At 750 mg/kg/day, the death of eight animals occurred before mid gestation and the surviving females were prematurely sacrificed. Therefore, the dose-level of 450 mg/kg/day is anticipated to produce minor signs of toxicity (750 mg/kg/day exceeded the MTD), and the two other dose-levels were selected using a factor of 3 between each dose.
- Rationale for animal assignment (if not random): Allocation to groups: during the pre-treatment period, the required number of animals (40 males
and 40 females) were selected according to body weight (recorded twice for planning reasons, see § Study plan adherence) and clinical condition and allocated to groups (by sex), according to a computerized stratification procedure (these data were not presented in the report), so that the average body weight of each group was similar.
- Other:

Positive control:

not applicable

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Each animal was checked at least twice a day for mortality and signs of morbidity. The pups were observed daily for clinical signs.
- Cage side observations checked in Appendices 4 to 7 of the original study report were included.


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Each animal was checked at least twice a day for mortality and signs of morbidity. The pups were observed daily for clinical signs.


BODY WEIGHT: Yes
- Time schedule for examinations: Males: days 1, 8, 15, 29; Females: days 1, 8, 15 premating period; days 0, 7, 14, 20 pregnancy period; days 1, 4 post partum; days 1 - 4 of lactation


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): not applicable


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): not applicable
- Time schedule for examinations:


OTHER:

Oestrous cyclicity (parental animals):

no data

Sperm parameters (parental animals):

no data

Litter observations:

STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no
- If yes, maximum of [...] pups/litter ([...]/sex/litter as nearly as possible); excess pups were killed and discarded.


PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities


GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was not determined for pups born or found dead

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals after the end of the mating period
- Maternal animals: All surviving animals from day 5 post-partum


GROSS NECROPSY
- A macroscopic post-mortem examination of the principal thoracic and abdominal organs (with special attention paid to the reproductive organs) was performed on all parent animals including any that died during the study. In all females, the number of implantation sites was recorded.


HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in the following table were prepared for microscopic examination and weighed, respectively.
The macroscopic lesions and the following tissues from all parent animals were preserved in 10% buffered formalin (except for testes and epididymides which were fixed in Davidson’s fixative):
. epididymides,
. ovaries,
. prostate,
. seminal vesicles,
. testes,
. uterus (horns and cervix),
. vagina.

Postmortem examinations (offspring):

SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at 5 days of age.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows:
A gross external examination was performed on all pups including those that died during lactation or were sacrificed moribund. There was no preservation of tissues.

GROSS NECROPSY: not conducted


HISTOPATHOLOGY / ORGAN WEIGTHS: not applicable

Statistics:

Data other than organ weights
Mean values were compared by one-way variance analysis and Dunnett's test, (mean values being considered as normally distributed, variances being considered as homogeneous). Percentage values were compared by Fisher's exact probability test.

Organ weights
PathData software (version 6.2b5) was used for the statistical analysis of organ weight data (level of significance: 0.05 or 0.01).

Reproductive indices:

Data are expressed as group mean values ± standard deviation (body weight, food consumption, corpora lutea, implantations, fetuses, resorptions, pups, gestation length) or as proportions (pre-implantation loss, post-implantation loss, fetal observations, gestation index, live birth index, viability index). Whenever necessary, the experimental unit of comparison was the litter.
The calculations were performed for each group as follows:
Pre-implantation loss: ((Number of corpora lutea - Number of implantation sites) / (Number of corpora lutea)) x 100
Post-implantation loss: ((Number of implantation sites - Number of live concepti) / (Number of implantations)) x 100
Mating index: (Number of mated animals - Number of paired animals) / x 100
Fertility index: (Number of pregnant female partners / Number of mated pairs) x 100
Gestation index: (Number of females with live born pups / Number of pregnant females) x 100
Live birth index: (Number of live born pups / Number of delivered pups) x 100

Offspring viability indices:

Viability index on day 4 post-partum:
(Number of surviving pups on day 4 post-partum / Number of live born pups) x 100

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Description (incidence):

Two males given 450 mg/kg/day were found dead on day 3 (P23036, body weight on day 1:
457 g) or 35 (P23040, body weight on day 29: 565 g, food consumption days 8-15: 25 g). Only
sign of hypersalivation was observed prior to the death of the animal that died on day 35. There
were no necropsy findings and no evident cause of death could be identified. However, a
relationship to the test item treatment could not be excluded.
In this group, two females were sacrificed because no evidence of mating was detected in
female No. P23114 (but was pregnant), or fem ale No. P23115 (was not pregnant).
Except for these two findings, there were no unscheduled deaths in the group given
450 mg/kg/day.

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

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):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

Microscopic examination of the ovaries, testes and epididymides were performed in males and
females of the control and high-dose groups.
Qualitative testes staging did not indicate any abnormalities in the integrity of the various cell
types present within the different stages of the spermatogenic cycle. No treatment-related findings
were noted in the epididymides of males treated with UNDECYLENIC ACID at 50, 150 or
450 mg/kg/day.
No treatment-related findings were noted in the ovaries of females treated with
UNDECYLENIC ACID at 50, 150 or 450 mg/kg/day.
The few microscopic findings were those commonly recorded in the rat of this strain and age and
consequently none were considered to be toxicologically relevant.

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)
At 450 mg/kg/day, two males died on days 3 and 35 without ante-mortem clinical signs of toxicity and no evident cause of death were diagnosed at macroscopic examination.
At 150 mg/kg/day group, hypersalivation was observed in males and females and one male had loud breathing transiently.
At 50 mg/kg/day, hypersalivation was the single effect, but observed to a lower extent than in previous treated groups.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS) no effects


TEST SUBSTANCE INTAKE (PARENTAL ANIMALS) no effects


REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS) not examined


REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS) not examined


REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS) no effects


ORGAN WEIGHTS (PARENTAL ANIMALS) no effects


GROSS PATHOLOGY (PARENTAL ANIMALS) no effects


HISTOPATHOLOGY (PARENTAL ANIMALS) no effects


OTHER FINDINGS (PARENTAL ANIMALS) no effects

Dose descriptor:

NOAEL

Remarks:

reproductive performance

Effect level:

450 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Dose descriptor:

NOAEL

Remarks:

parental toxicity

Effect level:

150 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: mortality: At 450 mg/kg/day, two males died on days 3 and 35 without ante-mortem clinical signs of toxicity and no evident cause of death were diagnosed at macroscopic examination.

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

no effects observed

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings:

not examined

as indicated above

VIABILITY (OFFSPRING)


CLINICAL SIGNS (OFFSPRING)


BODY WEIGHT (OFFSPRING)


SEXUAL MATURATION (OFFSPRING)


ORGAN WEIGHTS (OFFSPRING)


GROSS PATHOLOGY (OFFSPRING)


HISTOPATHOLOGY (OFFSPRING)


OTHER FINDINGS (OFFSPRING)

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

450 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effect

Reproductive effects observed:

not specified

Tab. 2: Summary of relevant clinical signs

Sex	Male				Female
Dose level (mg/kg/d)	0	50	150	450	0	50	150	450
Male
Ptyalism	0	4	10	9	n.a.	n.a.	n.a.	n.a.
Loud breathing	0	0	1	4	n.a.	n.a.	n.a.	n.a.
Dyspnea	0	0	0	0	n.a.	n.a.	n.a.	n.a.
Female
Ptyalism	n.a.	n.a.	n.a.	n.a.	0	4	6	10
Loud breathing	n.a.	n.a.	n.a.	n.a.	0	4	7	9
Dyspnea	n.a.	n.a.	n.a.	n.a.	0	2	7	8

n.a.: not applicable

Hypersalivation was observed from week 1 of dosing in general and continued throughout the study, with dose-related increase in terms of onset, incidence and duration. This clinical sign was considered not to be adverse as it likely represents a reaction to the dosing procedure and not a direct effect of UNDECYLENIC ACID. Loud breathing was observed in a single male given 150 mg/kg/day and in four males given 450 mg/kg/day. One out of these four males experienced dyspnea. These signs of respiratory discomfort were transiently observed.

In all other observations made (body weight, body weight gain, mating data, female fertility, delivery data, observations on the pups, and pathology) no significant deviations of the dose groups compared to the control group were being noted.

Conclusions:

Based on the results of this study, the dose-level of 150 mg/kg/day was considered to be the No Observed Adverse Effect Level (NOAEL) for parental toxicity, and the dose-level of 450 mg/kg/day was the NOEL for reproductive performance. There is no need for classification of test item undecylenic acid as to its reprotoxic properties.

Executive summary:

The objective of this study was to evaluate the potential toxic effects of the test item, UNDECYLENIC ACID, following daily oral administration (gavage) to male and female rats from before mating, through mating and gestation until the end of the parturition period. This study should provide initial information on possible toxicological effects likely to arise from repeated exposure over a relatively limited period of time and on male and female reproductive performance, such as gonadal function, mating behavior, conception, development of the conceptus and parturition. The rat was chosen because it is a rodent species commonly accepted by regulatory authorities for this type of study and the Sprague-Dawley strain was selected since background data from previous studies are available at CIT. The oral route was selected since it is a route of administration which is requested by the regulatory authorities for this type of test item. The dose-levels were selected in agreement with the Sponsor, following the results of a previously conducted prenatal toxicity study (CIT/Study No. 31486 RSR).

The test item, UNDECYLENIC ACID (CAS RN 112-38-9) batch No. 0607007 was administered to male and female Sprague-Dawley rats by oral route (gavage), under the above detailed experimental conditions, at the dose-levels of 50, 150 or 450 mg/kg/day. At 450 mg/kg/day, two males died on days 3 and 35 without ante-mortem clinical signs of toxicity and no evident cause of death were diagnosed at macroscopic examination. Hypersalivation was observed in males and females, and respiratory difficulties (loud breathing and dyspnea) were noted transiently in males. At 150 mg/kg/day group, hypersalivation was observed in males and females and one male had loud breathing transiently. At 50 mg/kg/day, hypersalivation was the single effect, but observed to a lower extent than in previous treated groups. There were no substance-induced effects on the male and female reproductive performance, or on the progeny at any dose-level. No treatment-related effects were noted on testes or epididymides weights, at necropsy or on microscopic examination of the testes, epididymides or ovaries in treated rats. Based on the results of this study, the dose-level of 150 mg/kg/day was considered to be the No Observed Adverse Effect Level (NOAEL) for parental toxicity, and the dose-level of 450 mg/kg/day was the NOEL for reproductive performance. There is no need for classification of test item undecylenic acid as to its reprotoxic properties.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

450 mg/kg bw/day

Study duration:

subacute

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

In the GLP reproduction screening test performed according to OECD 421 guideline the following results were observed:

At 450 mg/kg/day, two males died on days 3 and 35 without ante-mortem clinical signs of toxicity and no evident cause of death were diagnosed at macroscopic examination. Hypersalivation was observed in males and females, and respiratory difficulties (loud breathing and dyspnea) were noted transiently in males.

There were no substance-induced effects on the male and female reproductive performance, or on the progeny at any dose-level. No treatment-related effects were noted on testes or epididymides weights, at necropsy or on microscopic examination of the testes, epididymides or ovaries in treated rats. Based on the results of this study, the dose-level of 150 mg/kg/day was considered to be the No Observed Adverse Effect Level (NOAEL) for parental toxicity, and the dose-level of 450 mg/kg/day was the NOEL for reproductive performance.

Effects on developmental toxicity

Description of key information

One test with rats is availble according to the OECD 414 guideline (Chevalier, 2007). 
  
    
    
    

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.






    
    
    



In the developmental reproduction study in rats performed according to OECD 414, 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).











    





In the developmental reproduction study in rats performed according to OECD 414, 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).

Link to relevant study records

Reference

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

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Version / remarks:

2001

Deviations:

no

GLP compliance:

yes

Limit test:

no

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:

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

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

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

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

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.

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

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)

Dose descriptor:

NOAEL

Effect level:

450 mg/kg bw/day (actual dose received)

Basis for effect level:

other: teratogenicity

Abnormalities:

no effects observed

Developmental effects observed:

no

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

 

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.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

450 mg/kg bw/day

Study duration:

subacute

Species:

rat

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

Since no signs of teratogenicity / developmental toxicity were consistently observed in the reported studies, there is no classification of undecylenic acid as to its reprotoxic properties according to EU regulation (EC) No 1272/2008 (CLP).