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Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

Reaction mass of 2-Propenoic acid, 2-methyl-, 2-dodecylhexadecyl ester and 2-Propenoic acid, 2-methyl-, 2-tetradecyloctadecyl ester was tested in a Combined Repeated Dose Toxicity Study and Reproductive/Developmental Toxicity Screening Study with rats. No adverse treatment-related effects on reproduction/developmental toxicity were observed with the test substance at doses up to 1000 mg/kg bw/day. Based on the results, the NOAEL for reproduction is considered to be 1000 mg/kg bw/day (highest dose tested).

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
FROM 29 DEC 2020 to 28 JUL 2021
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose for cross-reference:
reference to same study
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Version / remarks:
adopted July 2016
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source (i.e. manufacturer or supplier): Sponsor.
- Lot/batch number of test material: F1-0S002C
- Purity, including information on contaminants, isomers, etc.: 93.3 % w/w

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At ambient temperature (15 to 25°C) in the dark.

FORM AS APPLIED IN THE TEST
- Pale yellow liquid
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd
- Females (if applicable) nulliparous and non-pregnant: not specified
- Age at study initiation: Males 71 to 77 days old; Females 84 to 97 days old.
- Weight at study initiation: Males 341 to 394 g; Females 254 to 314 g.
- Housing: Cages comprised of a polycarbonate body with a stainless steel mesh lid; changed at appropriate intervals
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: Males: Seven days before commencement of treatment. Females: 21 days before commencement of treatment

DETAILS OF FOOD AND WATER QUALITY:
The diet contained no added antibiotic or other chemotherapeutic or prophylactic agent.
Potable water from the public supply via polycarbonate bottles with sipper tubes. Bottles were changed at appropriate intervals.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 40-70%
- Air changes (per hr): Filtered fresh air which was passed to atmosphere and not recirculated
- Photoperiod (hrs dark / hrs light): Artificial lighting, 12 hours light: 12 hours dark
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
VEHICLE
- Amount of vehicle (if gavage): 5 mL/kgy:
Details on mating procedure:
- Pairing commenced: After a minimum of two weeks of treatment.
- Male/female ratio: 1:1 from within the same treatment groups.
- Duration of pairing: Up to two weeks.
- Daily checks for evidence of mating: Ejected copulation plugs in cage tray and sperm in the vaginal smear.
- Day 0 of gestation: When positive evidence of mating was detected.
- Male/female separation: Day when mating evidence was detected.
- Pre-coital interval: Calculated for each female as the time between first pairing and evidence of mating.

Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
Males: Two weeks before pairing up to necropsy after minimum of five weeks.
Females: Two weeks before pairing, then throughout pairing and gestation until Day 12 of lactation.
Animals of the F1 generation were not dosed.
Frequency of treatment:
Daily
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Control
Dose / conc.:
100 mg/kg bw/day (nominal)
Remarks:
low dose
Dose / conc.:
300 mg/kg bw/day (nominal)
Remarks:
mid dose
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Remarks:
high dose
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Positive control:
no
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Cages were inspected daily for evidence of animal ill-health amongst the occupants. During the acclimatization period, observations of the animals and their cages were recorded at least once per day.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Animals were inspected visually at least twice daily for evidence of ill-health or reaction to treatment

BODY WEIGHT: Yes
- Time schedule for examinations:
F0 males: Before dosing on the day that treatment commenced (Week 0) and weekly thereafter.
On the day of necropsy.
F0 females: Before dosing on the day that treatment commenced (Week 0) and weekly before pairing. Days 0, 7, 14 and 20 after mating. Day 1, 4, 7, 11 and 13 of lactation. On the day of necropsy

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

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

OTHER
* HAEMATOLOGY: Yes
- Time schedule for collection of blood: at necropsy
- Anaesthetic used for blood collection: Yes ( isoflurane)
- Animals fasted: Not specified
- How many animals: 5 lowest numbered surviving males per group. The first 5 lactating females with a surviving litter per group.
- Parameters examined:
Hematocrit (Hct)
Hemoglobin concentration (Hb)
Erythrocyte count (RBC)
Absolute reticulocyte count (Retic)
Mean cell hemoglobin (MCH)
Mean cell hemoglobin concentration (MCHC)
Mean cell volume (MCV)
Red cell distribution width (RDW)
Total leucocyte count (WBC)
Differential leucocyte count: Neutrophils (N), Lymphocytes (L), Eosinophils (E), Basophils (B), Monocytes (M), Large unstained cells (LUC)
Platelet count (Plt)

* CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at necropsy
- Animals fasted: Not specified
- How many animals: 5 lowest numbered surviving males per group. The first 5 lactating females with a surviving litter per group.
- Parameters examined:
Alkaline phosphatase (ALP)
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Total bilirubin (Bili)
Bile acids (BiAc)
Urea
Creatinine (Creat)
Glucose (Gluc)
Total cholesterol (Chol)
Triglycerides (Trig)
Sodium (Na)
Potassium (K)
Chloride (Cl)
Calcium (Ca)
Inorganic phosphorus (Phos)
Total protein (Total Prot)
Albumin (Alb

* SERUM HORMONES (Thyroid Hormone Analysis): Yes
- Time of blood sample collection: F0: at necropsy, F1 at day 4 and day 13 of age
- Animals fasted: Not specified
- How many animals:
All surviving F0 males and females.
At day 4 of age, offspring: up to two females per litter (where possible; male pups were reserved for nipple retention evaluation): one for T4 (serum), one for TSH (serum)
At day 13 of age, F1 offspring, two males and two females per litter (where possible) two for T4 (serum); where possible one male and one female, two for TSH (serum); where possible one male and one female

* NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: For males during Week 5, for females day 7-9 of lactation
- Dose groups that were examined: 5 lowest numbered surviving males in each group during Week 5 of treatment and on the first five lactating females in each group at Day 7-9 of lactation.
- Battery of functions tested: sensory activity / grip strength / motor activity
Oestrous cyclicity (parental animals):
The incidence and percentage females showing the following classifications of estrous cycles before treatment commenced are presented:
Regular: All observed cycles of 4 or 5 days
Irregular: At least one cycle of 2, 3 or 6 to 10 days
Acyclic: At least 10 days without estrus

Vaginal smearing prior to termination is presented in terms of numbers of females that showed estrus during this period and the cycle stage at termination.

Sperm parameters (parental animals):
Parameters examined in P male parental generations:
Qualitative evaluation of spermatogenesis was performed
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in F1offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities, anogenital distance (AGD), presence of nipples/areolae in male pups.

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

ASSESSMENT OF DEVELOPMENTAL NEUROTOXICITY: No

ASSESSMENT OF DEVELOPMENTAL IMMUNOTOXICITY: No
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals after Week 5 investigations completed.
- Maternal animals: All surviving animals at Day 13 of lactation

GROSS PATHOLOGY: Yes (see tables 1 and 2)

HISTOPATHOLOGY: Yes (see tables 1 and 2)
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring were sacrificed at 13 days of age.
- These animals were subjected to postmortem examinations macroscopic and/or microscopic examination as follows:
Premature deaths: Where possible, a fresh macroscopic examination (external and internal) with an assessment of stomach for milk content was performed.
All animals were subject to an external macroscopic examination; particular attention was paid to the external genitalia.
Thyroid glands were preserved from one male and one female in each litter, where possible.
Statistics:
Statistical analyses were performed on the majority of data presented and results of these tests, whether significant or non-significant, are presented on the relevant tables. For some parameters, including estrous cycles before treatment, estrous cycles during treatment, pre-coital interval, mating performance, gestation length and index and stage of estrous cycle at termination, the similarity of the data was such that analyses were not considered to be necessary.

All statistical analyses were carried out separately for males and females. Data relating to food consumption (except during gestation and lactation) were analyzed on a cage basis. For all other adult parameters, the analyses were carried out using the individual animal as the basic experimental unit. For litter/fetal findings the litter was taken as the treated unit and the basis for statistical analysis and biological significance was assessed with relevance to the severity of the anomaly and the incidence of the finding within the background control population.

Significant differences between the groups compared were expressed at the 5% (p<0.05) or 1% (p<0.01) level. The stastical methods used are given below

Pre-treatment comparison of all groups using Analysis of variance followed by pairwise t-tests.

Comparison of all groups using Chi-square test

For grip strength, motor activity, body weight, food consumption, corpora lutea, implantations, pre/post implantation loss, live young, sex ratio - percentage male, placental, litter and fetal weights, ano-genital distance, organ weight and clinical pathology data:
Treated groups compared with Control using Dunnett’s test
Treated groups compared with Control using Shirley’s test
Treated groups compared with Control using Williams’ test
Treated groups compared with Control using Fisher’s exact test
Reproductive indices:
Mating Performance and Fertility:
- Percentage mating (%) = (Number of animals mating/Animals paired)x 100
- Conception rate (%) = (Number of animals achieving pregnancy/Animals mated) x 100
- Fertility index (%) = (Number of animals achieving pregnancy/ Animals paired) x 100

Gestation Length and Index:
- Gestation index (%) = (Number of live litters born/Number pregnant) x 100

Survival Indices:
- Post-implantation survival index (%) = (Total number of offspring born/Total number of uterine implantation sites) x 100
Post-implantation survival index was expressed as 100% where the number of offspring exceeded the number of implantation sites recorded.
- Live birth index (%) = (Number of live offspring on Day 1 after littering/Total number of offspring born) x 100




Offspring viability indices:
- Viability index (%) = (Number of live offspring on Day 4 (before blood sampling)/Number live offspring on Day 1 after littering) x 100
- Lactation index (%) = (Number of live offspring on Day 13 after littering/Number of live offspring on Day 4 (after blood sampling))x 100









Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No treatment-related clinical signs were observed for either sex pre- or post-pairing or during gestation and lactation for females. One male receiving 1000 mg/kg bw/day was observed with dry rales following dose administration on Day 20. There were no signs seen in females post-dose administration throughout the study.

All other signs observed were considered incidental and not related to treatment.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One control female (No. 127) was found dead on Day 7 of gestation during the morning cage side checks. On Day 6 of gestation this female was showing signs of irregular breathing, piloerection, hunched posture and chromodacryorrhea. Macroscopic findings included yellow abnormal contents in the duodenum and jejunum, abnormal contents in the thoracic cavity (pale caseous material, clear fluid, food material and clear oily material), pale fibrous adhesions affecting multiple organs and a perforated oesophagus. The female was pregnant with 16 implantations. Histopathological evaluation revealed inflammation and presence of foreign material in the thoracic cavity and inflammation of the heart. The thoracic cavity and heart lesions are indicative of dosing trauma, which was considered responsible for the animal’s death.

One female that received 1000 mg/kg bwday (No. 114) was euthanized for welfare reasons on Day 1 of lactation. The animal had decreased activity, irregular breathing, piloerection, vaginal bleeding, dull eyes, and whole-body pallor. Macroscopic findings included dark fluid present in the cecum, jejunum, rectum, thoracic cavity and vagina, an enlarged lumbar lymph node, edematous thymus and a pale area on the left ventricle of the heart and many pale organs. Histopathological findings included inflammation of the heart, extramedullary hemopoiesis of the spleen and liver, edematous thymus and increased generalized cellularity of the lumbar lymph node. The heart and thymus lesions were indicative of dosing trauma, despite no findings in the esophagus, which was considered to be responsible for the terminal condition of the animal.

One female that received 100 mg/kg bw/day (No. 109) was dispatched to necropsy for welfare reasons on Day 2 of lactation due to general poor clinical condition and a swollen area on the upper ventral surface. This female had 17 offspring (8 male and 9 female) and on Day 2 of lactation two male offspring were found dead, one female offspring was missing, and the remaining pups were abnormally cold to touch with little or no milk present in their stomachs. Macroscopic findings at necropsy revealed hair loss of the fore and hind limbs. No histopathological evaluation was done for this animal in accordance with the study plan. Given the single incidence in the low-dose group, this premature death was not considered to be related to treatment.


Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Effect on body weight performance comprising low body weight gain prior to pairing (Weeks 1-2) was observed for males receiving 300 or 1000 mg/kg bw/day, which was not associated with reduced food intake. Body weight gains were slightly high for females receiving 1000 mg/kg bw/day from the second week of gestation onwards, corresponding with higher food intake, and from Days 7 to 11 of lactation with no associated increase in food consumption. Since there was no effect of treatment on the clinical condition of the F0 males and females, no effect on offspring survival or development and in the absence of any dose-relationship the extent of these body weight differences was of no toxicological importance.
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
The hematological examination of peripheral blood performed in males in Week 5, when compared with controls, revealed low reticulocyte and high basophil counts at all dose levels although no dose relationship was observed. Mean cell hemoglobin content and concentration was also high at 300 or 1000 mg/kg bw/day, but again, no dose relationship was apparent. These differences from control were considered not treatment related due to the lack of any dose relationship.

The hematological examination of peripheral blood performed in females on Day 13 of lactation, when compared with controls, revealed high hemoglobin concentrations at 1000 mg/kg bw/day. Total leucocyte counts and total lymphocyte count were high for males that received 100 or 300 mg/kg/day. However, these are considered to be incidental and not an effect of treatment as values at 1000 mg/kg/day were similar to controls. All other differences from controls were minor and were therefore attributed to normal biological variation.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
The biochemical examination of the blood plasma performed in males after 5 weeks of treatment, when compared with controls, revealed low glucose and phosphorus concentrations at 1000 mg/kg bw/day. The biochemical examination of the blood plasma performed in females on Day 13 of lactation, when compared with controls, revealed high chloride and phosphorus concentrations at 1000 mg/kg bw/day. All other differences from controls were minor and were therefore attributed to normal biological variation.
Endocrine findings:
effects observed, treatment-related
Description (incidence and severity):
The serum T4 concentrations show a dose dependent increase in F0 males with concentrations, relative to control, increased by +15% (at 100 mg/kg bw/day), +20% (at 300 mg/kg bw/day) and +24% (at 1000 mg/kg bw/day). Statistical significance was obtained for rats tested at 300 mg/kg bw/day and rats tested at 1000 mg/kg bw/day only. However, there were no microscopic and macroscopic findings in the thyroid or liver, no organ weight changes and no increased body weight gain in the treated F0 males (for further details see 'Any information on results' section. ). There were no other statistically significant differences observed between the treated groups the control.
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
No test item-related finding was observed after at least 4 weeks of oral gavage administration of the test substance o Sprague Dawley rats.

All microscopic findings were considered spontaneous and/or incidental because they occurred at a low incidence, were randomly distributed across groups (including concurrent controls), and/or their severity was as expected for Sprague Dawley rats of this age. Therefore, they were considered not test item-related.
Histopathological findings: neoplastic:
no effects observed
Other effects:
not examined
Reproductive function: oestrous cycle:
effects observed, non-treatment-related
Description (incidence and severity):
Before treatment commenced, all allocated females showed normal four or five day estrous cycles.
During the two-week pre-mating period, one female receiving 100 mg/kg bw/day showed an irregular estrous cycle.
All females surviving to the scheduled termination on Day 13 of lactation were in di-estrus; therefore, as expected, estrus cycles ceased during lactation.
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
A qualitative evaluation of spermatogenesis was performed. The testes revealed normal progression of the spermatogenic cycle, and the expected cell associations and proportions in the various stages of spermatogenesis were present.
Reproductive performance:
effects observed, non-treatment-related
Description (incidence and severity):
There was no effect of treatment on pre-coital interval, gestation length, mating performance, conception rate or fertility index.
One female at each dose level at 100 mg/kg bw/day or 300 mg/kg bw/day had pre-coital intervals that were extended to 13 or 14 days, respectively. Both females showed normal four-day estrous cycles before treatment or before pairing but were acyclic (at least ten days without estrus) during pairing. In the absence of any similar occurrence for females receiving 1000 mg/kg bw/day, these isolated findings were considered to be incidental and not related to treatment
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other:
Remarks on result:
other: no adverse treatment-related effects on the estrous cycle, sperm count and reproductive performance
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other:
Remarks on result:
other: absence of adverse treatment-related effects observed
Dose descriptor:
LOEL
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: serum/plasma hormone analyses
Remarks on result:
other: Dose-dependent increase in T4 concentration in F0 males without microscopic findings in thyroid and liver, without changes in organ weights and without increase in body weight gain in treated F0 males.
Key result
Critical effects observed:
no
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality / viability:
mortality observed, non-treatment-related
Description (incidence and severity):
The number of implantations, post implantation survival index (%), post-natal litter size, viability index (%) on Day 4 and the sex ratio (% males) were all considered to be unaffected by maternal treatment.
Live birth index (%) was slightly, but not statistically significantly, lower than Control at 1000 mg/kg/day mainly due to one female euthanised for welfare reasons on Day 1 of lactation with its litter.
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
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
Sexual maturation:
not specified
Anogenital distance (AGD):
no effects observed
Nipple retention in male pups:
no effects observed
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Increase in T4 concentration in F1 male and female offspring at day 13 of age without statistical significance.
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other:
Remarks on result:
other: No adverse treatment-related effects were observed with respect to viability, sexual maturation, body weight, clinical signs and gross pathology
Key result
Critical effects observed:
no
Key result
Reproductive effects observed:
no

Table 3: Mean serum T4 concentration (pg/mL) in offsprings and F0 males

























































































































































































Group



Treatment



Dose


 


(mg/kg/day)



Parameters



F1 offspring on Day 13 of age 


(Male)



F1 offspring on Day 13 of age 


(Female)



1



 


Control 


(Vehicle) a



0



Mean



59300



51700



SD



11000



16800



CV%



18.5



32.5



N



9



9



2







Reaction mass of 2-Propenoic acid, 2-methyl-, 2- dodecylhexadecyl ester and 2-Propenoic acid, 2-methyl-, 2-tetradecyloctadecyl ester



 


100



Mean



59500



62700



SD



13500



26200



CV%



22.7



41.8



N



9



9



3



 


300



Mean



61800



61700



SD



14200



13000



CV%



23.0



21.1



N



10



10



4



 


1000



Mean



58600



60400



SD



8080



11900



CV%



13.8



19.7



N



9



9



Group



Treatment



Dose


 


(mg/kg/day)



Parameters



F0 Adult Terminal Male



1



 


Control 


(Vehicle) a



 


0



Mean



49100



SD



7990



CV%



16.3



N



10



2







Reaction mass of 2-Propenoic acid, 2-methyl-, 2- dodecylhexadecyl ester and 2-Propenoic acid, 2-methyl-, 2-tetradecyloctadecyl ester



 


100



Mean



56700



SD



12300



CV%



21.7



N



10



3



 


300



Mean



58800*



SD



7830



CV%



13.3



N



10



4



 


1000



Mean



60700*



SD



11100



CV%



18.3



N



10



a – Corn oil


* - Statistically significant difference observed (p value < 0.05) between treatment and control group (Group 1) using a Williams’ test (two tailed).


Table 4: Serum concentrations of T4 in individual F0 adult male animals at termination after receiving the vehicle (corn oil) by daily oral gavage administration













































































































DoseAnimal number
Concentration (pg/mL) 
Control21222324252627282930
47200493005700040200576005200044700612004510036200
100 mg/kg bw/day11023456789
494006230057100598005220086600-46600533004120058600
300 mg/kg bw/day31323334353637383940
51200631005070061500573004650063900586006140073500-
1000 mg/kg bw/day11121314151617181920
51500593005890086000-515006410065300-457005830066800-

-individual outliners above the historical control data range


Table 5: Historical control data (HCD) for F0 males (presented as percentiles)











































































































































































































































































































































































































































































































StudyStart DateAnimalT4 Concentration (pg/mL)
122-Jul-201139100
  1244900
  1342600
  1451300
  1554000
  1645700
  1746700
  1841100
  1937000
  2059300
    
204-Sep-191128500
  1242800
  1344400
  1439100
  1549500
  1660900
  1764700
  1841900
  1924200
  2038700
    
312-Jul-19134800
  249300
  336300
  462200
  559200
  648700
  742900
  843200
  953000
  1052200
    
413-Mar-191653700
  1754100
  1852000
  1953100
  2048600
    
521-Oct-18149000
  240700
  353200
  431500
  644100
  754400
  859100
  954000
  1054000
    
610-Oct-18140300
  250400
  356300
  445900
  549200
  658700
  744800
  865000
  960100
  1048500
    
718-Jun-181637000
  1743200
  1839800
  1938800
  2060500
    
810-May-181641000
  1752800
  1831700
  1944000
  2046600
    
  n64
  0.01026909.000
  0.05032165.000
  0.50047600.000
  0.95060840.000
  0.99064811.000
  mean47410.938
  sd8944.4869

 


 


 


 


 

Conclusions:
Under the given conditions of this combined repeated dose toxicity study and reproductive/developmental toxicity screening study in male and female rats, the NOAEL was determined to be 1000 mg/kg bw/day for reproductive/developmental toxicity based on the absence of adverse treatment-related effects observed.
Executive summary:

In a Combined Repeated Dose Toxicity Study and Reproductive/Developmental Toxicity Screening Study (according to OECD TG 422) Reaction mass of 2-Propenoic acid, 2-methyl-, 2-dodecylhexadecyl ester and 2-Propenoic acid, 2-methyl-, 2-tetradecyloctadecyl ester was administered to 10 Sprague-Dawley rats/sex/dose by oral gavage at dose levels of 0, 100, 300 or 1000 mg/kg bw/day.


Treatment at dose levels up to 1000 mg/kg bw/day was well tolerated. There were no treatment-related premature deaths, no treatment-related signs were observed post-dose, no treatment-related changes in clinical condition of the F0 males or females or their offspring and no findings at macroscopic examination of the F0 adults or their offspring considered to be treatment related. Sensory reactivity, grip strength and motor activity investigations were unaffected by treatment. In addition, there was no adverse effect of parental treatment on offspring survival or development up to Day 13 of age at any dose level investigated.


Effect on body weight performance comprising low body weight gain prior to pairing (Weeks 1-2) was observed for F0 males receiving 300 or 1000 mg/kg bw/day, which was not associated with reduced food intake. Body weight gains were slightly high for F0 females receiving 1000 mg/kg bw/day from the second week of gestation onwards, corresponding with higher food intake, and from Days 7 to 11 of lactation with no associated increase in food consumption. Since there was no effect of treatment on the clinical condition of the F0 males and females, no effect on offspring survival or development, and in the absence of any dose-relationship the extent of these body weight differences was of no toxicological importance.


The estrous cycle investigations, during the pre-mating period and at the end of the treatment period was unaffected by treatment and all animals with litters were in di-estrus at termination, indicating that estrous cycles had ceased during lactation. Pre-coital interval, mating performance, gestation length, and gestation index were unaffected by treatment. However, the pre-coital interval for two females (one at 100 and one at 300 mg/kg bw/day) was extended to 13 or 14 days as these females were acyclic during pairing despite showing normal four-day estrus cycles before treatment or pairing. However, this was considered not related to treatment as there were no similar findings in females receiving 1000 mg/kg bw/day.


Findings in the blood of F0 animals were the result of secondary consequences of the effects of treatment or attributable to stress. Such findings in males included the low reticulocyte counts at all dose levels and high mean cell hemoglobin content and concentrations at 300 or 1000 mg/kg/day and high hemoglobin concentrations in females given 1000 mg/kg/day. These changes were considered non-adverse. For animals receiving 1000 mg/kg bw/day there were no macroscopic or microscopic associations for the low glucose and phosphorus concentrations observed in males and high chloride and phosphorus concentrations observed in females. These changes were therefore considered non-adverse and of uncertain relationship to treatment. The serum T4 concentrations showed a dose-dependent increase in F0 males with concentrations, relative to control, increased by +15% (at 100 mg/kg bw/day), +20% (at 300 mg/kg bw/day) and +24% (at 1000 mg/kg bw/day). Statistical significance was obtained only for rats tested at 300 mg/kg bw/day and for rats tested at 1000 mg/kg bw/day. However, no microscopic or macroscopic observations of the thyroid or liver, no changes in organ weights and no increase in body weight gain were observed in treated F0 males. These changes were therefore also considered non-adverse and of uncertain relationship to treatment


No test item-related finding was observed in F0 animals after at least 4 weeks of oral gavage administration of the test substance at histopathology examination. All microscopic findings were considered spontaneous and/or incidental because they occurred at a low incidence, were randomly distributed across groups (including concurrent controls), and/or their severity was as expected for Sprague Dawley rats of this age. Therefore, they were considered not test item-related.


A qualitative evaluation of spermatogenesis was performed. The testes revealed normal progression of the spermatogenic cycle, and the expected cell associations and proportions in the various stages of spermatogenesis were present.


Furthermore, no adverse treatment-related effects were observed with respect to viability, sexual maturation, body weight, clinical signs and gross pathology in male and female offsprings.


 The NOAEL for general systemic toxicity and for reproductive/developmental toxicity was determined to be 1000 mg/kg bw/day based on the absence of adverse treatment-related effects observed.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Guideline study
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 a Combined Repeated Dose Toxicity Study and Reproductive/Developmental Toxicity Screening Study (according to OECD TG 422) Reaction mass of 2-Propenoic acid, 2-methyl-, 2-dodecylhexadecyl ester and 2-Propenoic acid, 2-methyl-, 2-tetradecyloctadecyl ester was administered to 10 Sprague-Dawley rats/sex/dose by oral gavage at dose levels of 0, 100, 300 or 1000 mg/kg bw/day.


Treatment at dose levels up to 1000 mg/kg bw/day was well tolerated. There were no treatment-related premature deaths, no treatment-related signs were observed post-dose, no treatment-related changes in clinical condition of the F0 males or females or their offspring and no findings at macroscopic examination of the F0 adults or their offspring considered to be treatment related. Sensory reactivity, grip strength and motor activity investigations were unaffected by treatment. In addition, there was no adverse effect of parental treatment on offspring survival or development up to Day 13 of age at any dose level investigated.


Effect on body weight performance comprising low body weight gain prior to pairing (Weeks 1-2) was observed for F0 males receiving 300 or 1000 mg/kg bw/day, which was not associated with reduced food intake. Body weight gains were slightly high for F0 females receiving 1000 mg/kg bw/day from the second week of gestation onwards, corresponding with higher food intake, and from Days 7 to 11 of lactation with no associated increase in food consumption. Since there was no effect of treatment on the clinical condition of the F0 males and females, no effect on offspring survival or development, and in the absence of any dose-relationship the extent of these body weight differences was of no toxicological importance.


The estrous cycle investigations, during the pre-mating period and at the end of the treatment period was unaffected by treatment and all animals with litters were in di-estrus at termination, indicating that estrous cycles had ceased during lactation. Pre-coital interval, mating performance, gestation length, and gestation index were unaffected by treatment. However, the pre-coital interval for two females (one at 100 and one at 300 mg/kg bw/day) was extended to 13 or 14 days as these females were acyclic during pairing despite showing normal four-day estrus cycles before treatment or pairing. However, this was considered not related to treatment as there were no similar findings in females receiving 1000 mg/kg bw/day.


Findings in the blood of F0 animals were the result of secondary consequences of the effects of treatment or attributable to stress. Such findings in males included the low reticulocyte counts at all dose levels and high mean cell hemoglobin content and concentrations at 300 or 1000 mg/kg/day and high hemoglobin concentrations in females given 1000 mg/kg/day. These changes were considered non-adverse. For animals receiving 1000 mg/kg bw/day there were no macroscopic or microscopic associations for the low glucose and phosphorus concentrations observed in males and high chloride and phosphorus concentrations observed in females. These changes were therefore considered non-adverse and of uncertain relationship to treatment. The serum T4 concentrations showed a dose-dependent increase in F0 males with concentrations, relative to control, increased by +15% (at 100 mg/kg bw/day), +20% (at 300 mg/kg bw/day) and +24% (at 1000 mg/kg bw/day). Statistical significance was obtained only for rats tested at 300 mg/kg bw/day and for rats tested at 1000 mg/kg bw/day. However, no microscopic or macroscopic observations of the thyroid or liver, no changes in organ weights and no increase in body weight gain were observed in treated F0 males. These changes were therefore also considered non-adverse and of uncertain relationship to treatment


No test item-related finding was observed in F0 animals after at least 4 weeks of oral gavage administration of the test substance at histopathology examination. All microscopic findings were considered spontaneous and/or incidental because they occurred at a low incidence, were randomly distributed across groups (including concurrent controls), and/or their severity was as expected for Sprague Dawley rats of this age. Therefore, they were considered not test item-related.


A qualitative evaluation of spermatogenesis was performed. The testes revealed normal progression of the spermatogenic cycle, and the expected cell associations and proportions in the various stages of spermatogenesis were present.


Furthermore, no adverse treatment-related effects were observed with respect to viability, sexual maturation, body weight, clinical signs and gross pathology in male and female offsprings.


The NOAEL for general systemic toxicity and for reproductive/developmental toxicity was determined to be 1000 mg/kg bw/day based on the absence of adverse treatment-related effects observed.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
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

Based on the results, the test substance does not warrant classification for reproductive toxicity in accordance with CLP Regulation 1272/2008.

Additional information