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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information
 No study on reproduction is available on Tricyclodecanemonomethylol acrylate ; however data are available on an analogue substance.
    
    

 In the screening study on reproduction, Tricyclodecane dimethanol diacrylate was administered daily by oral gavage to male and female Sprague Dawley rats, for 2 weeks before pairing, during pairing, gestation and until day 5 p.p., at dose-levels of 100, 300 or 1000 mg/kg/day. No adverse effect was observed in this study at any doses. Therefore, based on the experimental conditions of this study: the NOAEL for parental toxicity, the NOAEL for reproductive performance (mating and fertility) and the NOAEL for toxic effects on progeny were 1000 mg/kg/day.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
14 May 2014 -- 30 August 2014
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: breeder: Charles River Laboratories Italia, Calco, Italy.
- Age/Mean body weight at study initiation: on the first day of treatment, the males were approximately 10 weeks old and had a mean body weight of 372 g (range: 347 g to 399 g) and the females were approximately 9 weeks old and had a mean body weight of 216 g (range: 195 g to 245 g).
- Housing: polycarbonate cages; individual housing
- Diet: SSNIFF R/M-H pelleted diet (free access)
- Water: tap water filtered with a 0.22 µm filter (free access)
- Acclimation period: 7 days before the beginning of the treatment period.

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

IN-LIFE DATES: 15 July 2014 to 30 August 2014
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The test item was administered as a solution in the vehicle. The test item was mixed with the required quantity of vehicle. No correction factor was applied.
Test item dose formulations were prepared on a weekly basis. They were stored at room temperature protected from light and delivered to the study room at room temperature and protected from light.

VEHICLE
- Justification for use and choice of vehicle: test item soluble in the vehicle and corn oil is commonly used for this type of study
- Concentration in vehicle: 20, 60, and 200 mg/mL
- Amount of vehicle (if gavage): 5 mL/kg/day.
Details on mating procedure:
- M/F ratio per cage: 1/1
- Length of cohabitation (mating period): until mating occurred (within one week)
- Proof of pregnancy: vaginal plug or sperm in the morning vaginal lavage. Day of confirmed mating referred to as day 0 post-coitum
- After successful mating each pregnant female was caged individually
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Type of method: GC-FID
Test item concentrations: the test item concentrations in the administered dose formulations in Weeks 1 and 4 were within the acceptable range of -0.8% to +3.1% when compared to the nominal values (± 10% of the nominal concentrations accepted).
No test item was observed in the control dose formulation.
Homogeneity: not assessed, dose formulation is a solution
Stability: stable for 10 days at room temperature and protected from light.
Duration of treatment / exposure:
In the males:
- 2 weeks before mating,
- during the mating period,
- until sacrifice (at least 5 weeks in total).


In the females:
- 2 weeks before mating,
- during the mating period,
- during gestation,
- during lactation until Day 4 post-partum inclusive,
- until sacrifice for females with no delivery.
Frequency of treatment:
Daily
Details on study schedule:
- No F1 parents (only one generation mated)
- Age at mating of the mated animals in the study: 11-12 weeks
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
The dose-levels were selected in agreement with the Sponsor based on the results of a 4 week toxicity study in which five Sprague-Dawley males and five females per group received the test item at 0, 100, 300 or 1000 mg/kg/day as solutions in corn oil. There were no premature mortality in this study, no relevant clinical signs and no relevant effects on mean body weight, mean food consumption and Functional Observation Battery data. The most relevant findings, but not considered as adverse, observed at 1000 mg/kg/day when compared with controls were higher mean liver weight and mean cholesterol and glucose levels in females. The results of the microscopic examination were not available at that time.

Therefore, 1000 mg/kg/day was selected as the high-dose level. The low-dose and mid dose were selected using a ratio representing approximately a 3-fold interval.

- Rationale for animal assignment: computerized stratification procedure
Positive control:
no (not required)
Parental animals: Observations and examinations:
MORTALITY/MORBIDITY:
- Time schedule: once a day before the treatment period and at least twice a day during the treatment period.

CLINICAL OBSERVATIONS:
- Time schedule: once a day.

BODY WEIGHT:
- Time schedule: Males: on the first day of treatment (Day 1), then once a week until sacrifice. Females: on the first day of treatment (Day 1), then once a week until mating, on Days 0, 7, 14 and 20 post-coitum (p.c.) and days 1 and 5 post-partum (p.p.) or until sacrifice for females with no delivery.

FOOD CONSUMPTION:
- Time schedule: Males: once a week, over a 7 day period, from the first day of treatment until the start of the mating period. Females: once a week, over a 7 day period, from the first day of treatment until the start of the mating period, during gestation for the intervals Days 0-7, 7 14 and 14-20 p.c. and during lactation for the interval Days 1 5 p.p.

REPRODUCTION (apart from indices):
- Pre-coital time and duration of gestation were recorded
Oestrous cyclicity (parental animals):
fresh vaginal lavage (stained with methylene blue), each morning during the pairing period, until females were mated.
Sperm parameters (parental animals):
Parameters examined in males of parental generation:
- testis weight (all groups) + microscopic evaluation (control and high-dose groups)
- epididymis weight (all groups) + microscopic evaluation (control and high-dose groups)
- special emphasis during microscopic evaluation on stages of the spermatogenic cycle and testicular interstitial cells (control and high-dose groups)
Litter observations:
STANDARDISATION OF LITTERS: No

PARAMETERS EXAMINED:
- number and sex of pups,
- number of live, dead and cannibalized pups,
- presence of gross anomalies, weight gain, clinical signs

GROSS EXAMINATION OF DEAD AND SURVIVING PUPS:
- external and internal abnormalities
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: all surviving animals after the end of the mating period (at least 5 weeks of treatment in total)
- Female animals: all surviving animals: on Day 5 p.p., female which did not deliver: on Day 26 p.c..

GROSS NECROPSY
Macroscopic post-mortem examination of principal thoracic and abdomnal organs.

HISTOPATHOLOGY
A microscopic examination was performed on:
- ovaries (with oviducts), uterus, epididymides, and testes from all animals of the control and high-dose groups (groups 1 and 4) sacrificed at the end of the treatment period (at the end of the mating period for males or on Day 5 p.p. for females),
- all macroscopic lesions of all groups.


ORGAN WEIGHTS: ovaries (with oviducts), uterus, epididymides, and testes.
Postmortem examinations (offspring):
SACRIFICE: on Day 5 post-partum

GROSS NECROPSY: on all pups (surviving and found dead)

HISTOPATHOLOGY: No

ORGAN WEIGTHS: No
Statistics:
Reproductive, body weight and food consumption data were compared by one-way analysis of variances and Dunnett test (mean values being considered as normally distributed, variances being considered as homogenous) or by Fischer exact probability test (proportions).

PathData software was used to perform the statistical analysis of organ weight data (level of significance: 0.05 or 0.01).
Reproductive indices:
Pre-implantation loss = 100 * (Number of corpora lutea - Number of implantation sites) / Number of corpora lutea
Post-implantation loss = 100 * (Number of implantation sites - Number of live pups) / Number of implantation sites
Mating index = 100 * (Number of mated animals / Number of paired animals)
Fertility index = 100 * (Number of pregnant female partners / Number of mated pairs)
Gestation index = 100 * (Number of females with live born pups / Number of pregnant females)
Offspring viability indices:
Live birth index = 100 * (Number of live born pups / Number of delivered pups)
Viability index on Day 4 p.p. = 100 * (Number of surviving pups on Day 4 p.p. / Number of live born pups)
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
The only clinical sign ascribed to the test item treatment was ptyalism which was recorded in several animals treated at 300 mg/kg/day (7 males, 5 females) and all animals treated at 1000 mg/kg/day. This finding was considered to be of minor toxicological relevance.
Incidental clinical signs noted in test item-treated animals were piloerection, reflux at dosing, half-closed eyes, area of hair loss on forelimb, scabs and cutaneous lesions. They are commonly seen in Sprague Dawley rats and were not related to the administration of the test item.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
There were no unscheduled deaths of males in any groups and of females in groups treated at 0, 100 or 1000 mg/kg/day.
At 300 mg/kg/day, there was one female prematurely sacrificed for ethical reasons (pallor of extremities, piloerection, hard abdomen, plus brownish vaginal discharge for several days). At necropsy, one uterine horn still contained seven dead fetuses while the other was empty. These findings were considered to be related to difficulties of delivery. The relationship to test item treatment was considered to be unlikely in view of the single occurrence of this finding and in absence of a dose relationship.
One female treated with 300 mg/kg/day was sacrificed on Day 26 p.c. in absence of delivery. This female was not pregnant.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
There were no test item treatment-related effects on mean body weight and mean body weight change.
The higher mean body weight gains noted in both sexes were considered to be fortuitous because of the absence of statistical significance for nearly all of them and because of the absence of dose-relationship. In particular, there was no dose-relationship for the statistically significant higher mean body weight gain in females at 1000 mg/kg/day in the first week of treatment, which was transient.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
There were no effects on mean food consumption.
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:
effects observed, non-treatment-related
Description (incidence and severity):
No test item-related organ weight differences were observed.
The slightly higher mean absolute and relative-to-body uterus weights (without statistical difference) when compared to controls were considered to be of no toxicological importance in view of the absence of dose-relationship and of the low magnitude of these differences.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Unscheduled death: One female treated at 300 mg/kg/day was sacrificed on Day 46 had seven dead fetuses in the uterus at necropsy. The vagina contained red and thick content (not seen at microscopic examination) and the liver was tan (which correlated with minimal hepatocellular periportal vacuolation). The relationship to test item of these findings was considered to be unlikely.
Terminal sacrifice: There were no test item-related gross findings. The few gross findings (scabs), although seen in test item-treated males only, correlated with common background findings and thus were considered not to be related to test item administration.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Unscheduled death: For the female treated at 300 mg/kg/day sacrificed on Day 46 with seven dead fetuses in the uterus at necropsy, there were no test item-related findings at microscopic examination.

Terminal sacrifice: There were no test item-related microscopic findings.
The few microscopic findings were considered to be unrelated to test item since they were seen with similar incidence in control animals.
The few ulcers associated with sero-cellular crusts seen in test item-treated males only were considered to be unrelated to test item administration since these lesions are commonly seen in untreated rats and since the incidences were not dose-related and of low magnitude (1 or 2 out of 10 animals).

A detailed examination of the testes was performed, using a thorough understanding of tubule development through the different stages of the spermatogenic cycle. No test item-related findings were observed.
Histopathological findings: neoplastic:
no effects observed
Other effects:
not examined
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
effects observed, non-treatment-related
Description (incidence and severity):
There were no effects on mating and fertility data.
The slightly higher mean pre-coital time (mean number of days taken to mate) at 1000 mg/kg/day was due to one pair which mated in 6 days vs. up to 4 among all groups.
One female treated at 300 mg/kg/day was non-pregnant (no corpora lutea).
There were no effects on mean duration of gestation, mean number of corpora lutea, mean number of implantations, mean percentage of pre-implantation loss and mean number of pups delivered at any dose levels.
At 1000 mg/kg/day there was a trend towards a slightly higher mean percentage of post-implantation loss with 2/10 females having lost five implants (26.3% and 71.4% of post-implantation loss). This finding was considered to be test item treatment-related but non-adverse because no effects on the mean number of pups per litter were observed.
At 300 mg/kg/day one female (and its litter) was not included in the reported group mean data on mean post-implantation loss, lactation, delivery and litter data. Indeed, the female delivered nine pups from one uterine horn (the day recorded for their delivery was considered to be uncertain) but not from the second uterine horn (seven fetuses found inside at necropsy). This event was not ascribed to the test item treatment in view of the single occurrence and in absence of dose-relationship.
Key result
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Critical effects observed:
no
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
There were no effects on pup survival by Day 5 p.p..
At 1000 mg/kg/day, there was one entire litter with blackish abdomen (clinical sign also recorded in three fetuses of another litter from the same group), hypoactivity, cold to the touch and dehydration until Day 3 p.p.. A relationship of these clinical signs with the test item treatment was considered to be doubtful.
At 300 mg/kg/day, all the pups of one litter were recorded with no milk in the stomach. At 100 mg/kg/day, there was one pup with absence of tail. The clinical signs noted in these litters were considered to be fortuitous.
Dermal irritation (if dermal study):
not examined
Mortality / viability:
no mortality observed
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
The slightly lower mean body weights recorded at 1000 mg/kg/day was particularly due to one litter for which low body weights and clinical signs were noted in all pups. This was not considered to be toxicologically significant.
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 examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no test item treatment-related macroscopic findings at pup necropsy.
Histopathological findings:
not examined
Other effects:
not examined
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effect observed on reproduction parameters or on foetal developmental at this dose.
Reproductive effects observed:
no
Conclusions:
Under the experimental conditions of this study:
- the No Observed Adverse Effect Level (NOAEL) for parental systemic toxicity and reproductive performance was considered to be 1000 mg/kg/day, based on the absence of adverse effects at all dose-levels,
- the NOAEL for toxic effects on progeny was considered to be 1000 mg/kg/day, based on the absence of adverse effects in pups at all dose-levels.
Executive summary:

The objective of this study was to evaluate the potential toxic effects of Tricyclodecane dimethanol diacrylate

following daily oral administration (gavage) to male and female rats from before mating, through mating and, for females, through gestation until Day 4 post-partum (p.p.).

This study provides initial information on male and female reproductive performance, such as gonadal function, mating behavior, conception, development of the conceptus and parturition.

Methods

 

Three groups of ten male and ten female Sprague-Dawley rats received the test item daily by oral (gavage) administration before mating, through mating and, for the females, through gestation until Day 4 p.p.. The test item was administered as a solution in the vehicle, corn oil, at dose-levels of 100, 300 or 1000 mg/kg/day.

Another group of ten males and ten females received the vehicle alone, under the same experimental conditions and acted as a control group. A constant dose-volume of 5 mL/kg/day was used.

The concentrations of the dose formulations were checked in study Weeks 1, 3 and 6.

The animals were checked twice daily for mortality and morbidity and once daily for clinical signs during the treatment period. Body weight and food consumption were recorded once a week during pre-mating and mating periods (food consumption not during mating), and during gestation on Days 0, 7, 14 and 20 post-coitum (p.c.) and lactation on Days 1 and 5 p.p..

The animals were paired for mating after 2 weeks of treatment and the dams were allowed to litter and rear their progeny until Day 5 p.p.. The total litter sizes and numbers of pups of each sex were recorded after birth. Pups were observed daily for clinical signs, abnormal behavior and external abnormalities and weighed on Days 1 and 5 p.p..

Males were sacrificed after at least 5 weeks of treatment and dams on Day 5 p.p.. Final body weights and selected organs weights (ovaries (with oviducts), uterus, epididymides, testes) were recorded and a macroscopic post-mortem examination of the principal thoracic and abdominal organs was performed, with particular attention paid to the reproductive organs. A microscopic examination was performed on ovaries (with oviducts), uterus, epididymides and testes from all males sacrificed at the end of the treatment period and all females sacrificed on Day 5 p.p. in the control and high-dose groups and on all macroscopic lesions.

Pups were sacrificed on Day 5 p.p. and submitted for a macroscopic post-mortem examination of the principal thoracic and abdominal organs.

Results

 

Chemical analyses

The test item concentrations in the administered dose formulations analyzed in Weeks 1, 3 and 6 were within the acceptable range of variation when compared to the nominal values (target concentration ± 10%).

Parental animals

There were no unscheduled deaths ascribed to test item treatment. Test item-related clinical signs were limited to ptyalism which was noted in several animals given 300 mg/kg/day and in all animals given 1000 mg/kg/day and was considered to be of minor toxicological relevance. There were no test item treatment-related effects on mean body weight, mean food consumption, mean organ weights and at macroscopic and microscopic examinations.

 

There were no test item treatment-related effects on mating and fertility data, mean duration of gestation, mean number of corpora lutea, mean number of implantations, mean percentage of pre-implantation loss and mean number of pups delivered. At 1000 mg/kg/day, there was a trend towards a slightly high mean percentage of post-implantation loss (14.6% vs. 6.9% in controls) due to 2/10 females; this effect was considered to be non-adverse because no effects on the mean number of pups per litter were observed.

Pups

There were no toxicologically significant effects on pup data (viability, mean body weight, sex ratio, macroscopic findings). A relationship of the clinical signs noted in one litter mainly (blackish abdomen, hypoactivity, cold to the touch and dehydration) with the test item treatment was considered to be doubtful.

Conclusion

 

Under the experimental conditions of this study:

- the No Observed Adverse Effect Level (NOAEL) for parental systemic toxicity and reproductive performance was considered to be 1000 mg/kg/day, based on the absence of adverse effects at all dose-levels,

- the NOAEL for toxic effects on progeny was considered to be 1000 mg/kg/day, based on the absence of adverse effects in pups at all dose-levels.

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:
This screening test is considered to be reliable: study was performed according to guideline study and has a klimisch score of 1.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Screening reproduction study (Bentz 2015, OECD 421) / read-across :

The objective of this study was to evaluate the potential toxic effects of Tricyclodecane dimethanol diacrylate following daily oral administration (gavage) to male and female rats from before mating, through mating and, for females, through gestation until Day 4 post-partum (p.p.). This study provides initial information on male and female reproductive performance, such as gonadal function, mating behavior, conception, development of the conceptus and parturition.

Three groups of ten male and ten female Sprague-Dawley rats received the test item daily by oral (gavage) administration before mating, through mating and, for the females, through gestation until Day 4p.p.. The test item was administered as a solution in the vehicle, corn oil, at dose-levels of 100, 300 or 1000 mg/kg/day. Another group of ten males and ten females received the vehicle alone, under the same experimental conditions and acted as a control group. A constant dose-volume of 5 mL/kg/day was used.

Parental animals:There were no unscheduled deaths ascribed to test item treatment. Test item-related clinical signs were limited to ptyalism which was noted in several animals given 300 mg/kg/day and in all animals given 1000 mg/kg/day and was considered to be of minor toxicological relevance. There were no test item treatment-related effects on mean body weight, mean food consumption, mean organ weights and at macroscopic and microscopic examinations.

Reproduction parameters:There were no test item treatment-related effects on mating and fertility data, mean duration of gestation, mean number of corpora lutea, mean number of implantations, mean percentage of pre-implantation loss and mean number of pups delivered. At 1000 mg/kg/day, there was a trend towards a slightly high mean percentage of post-implantation loss (14.6%vs.6.9% in controls) due to 2/10 females; this effect was considered to be non-adverse because no effects on the mean number of pups per litter were observed.

Pups:There were no toxicologically significant effects on pup data (viability, mean body weight, sex ratio, macroscopic findings). A relationship of the clinical signs noted in one litter mainly (blackish abdomen, hypoactivity, cold to the touch and dehydration) with the test item treatment was considered to be doubtful.

Under the experimental conditions of this study:

- the No Observed Adverse Effect Level (NOAEL) for parental systemic toxicity and reproductive performance was considered to be 1000 mg/kg/day, based on the absence of adverse effects at all dose-levels,

- the NOAEL for toxic effects on progeny was considered to be 1000 mg/kg/day, based on the absence of adverse effects in pups at all dose-levels.

 

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 available on Tricyclodecane dimethanol diacrylate (no effect on reproductive organs in male and female rats in the 28 -day repeated study, and no effects on the reproduction in the screening study), no classification for Tricyclodecanemonomethylol acrylate, the registered substance, is required for reprotoxicity according to the Regulation EC n°1272/2008.