Registration Dossier

Diss Factsheets

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

The extended one generation reproductive toxicity study (EOGRTS) is waived in accordance with Annex XI, section 3.2(a) of the REACH Regulation. The study is waived on the following basis:

i) An exposure assessment covering all relevant exposures throughout the life cycle of the substance demonstrates the absence of or no significant exposure in all scenarios of the manufacture and all identified uses as referred to in Annex VI section 3.5 (see CSR)

ii) A DNEL has been derived from a recently conducted, reliable 90 day sub-chronic study (Envigo study number 41501041). It should be noted that the 90 day study did not demonstrate any adverse effects on reproductive organs or tissues or reveal other concerns in relation with reproductive toxicity.

iii) A comparison of the DNEL with the predicted exposures demonstrates that exposures are always well below the derived DNEL (see CSR).

Link to relevant study records
Reference
Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Data waiving:
exposure considerations
Justification for data waiving:
the study does not need to be conducted because relevant human exposure can be excluded as demonstrated in the relevant exposure assessment
Reproductive effects observed:
not specified
Effect on fertility: via oral route
Endpoint conclusion:
no study available
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 subchronic toxicity study the test material was administered to 10 Wistar rats/sex/dose by oral gavage at dose levels of 0, 100, 300 or 1000 mg/kg bw/day. There were no compound-related effects on mortality, clinical signs, body weight, food consumption, hematology, clinical chemistry, organ weights or gross or histopathology. The NOAEL is reported to be 1000 mg/kg bw/day, the highest dose tested. It should be noted that the 90 day study did not demonstrate any adverse effects on reproductive organs or tissues or reveal other concerns in relation with reproductive toxicity.

Effects on developmental toxicity

Description of key information

In a developmental study the test material was administered to Sprage-Dawley rats 24/sex/dose by gavage at dose levels of 0, 100, 300 or 1000 mg/kg bw/day. There were no compound related effects in the dams or the offspring for the parameters monitored.The NOEL is 1000 mg/kg bw/day (the highest dose employed).

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
23rd October 2015 to 11th November 2015
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
The Study Plan target range for relative humidity (RH) was 50 ± 20%. This target range was exceeded for one short period during the study, with a maximum humidity of 74% RH being reached.
Qualifier:
according to guideline
Guideline:
EU Method B.31 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Species:
rat
Strain:
Sprague-Dawley
Remarks:
Crl:CD® (SD) IGS BR
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Limited
- Weight at study initiation: 179g to 301g
- Housing: Solid-floor polypropylene cages with stainless steel mesh lids furnished with softwood flakes
- Diet: ad libitum
- Water: ad libitum

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

IN-LIFE DATES: From: To: 23 October 2015 (first day of treatment) and 11 November 2015 (final day of necropsy)
Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Details on exposure:
Polyethylene glycol (PEG 400) was successfully used as the vehicle in the preliminary study, it was also used for this main pre-natal study, utilizing a dosage volume of 4 ml/kg body weight.
Duration of treatment / exposure:
Day 3 (pre-implantation) to Day 19 of gestation, inclusive.
Frequency of treatment:
Daily.
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Control - animals were treated in an identical manner with the vehicle alone
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
24 animals per dose.
Control animals:
yes, concurrent vehicle
Maternal examinations:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Following arrival, all animals were examined for overt signs of toxicity, ill-health or behavioral changes once daily during the gestation period. Additionally, during the dosing period, observations were performed immediately before and soon after dosing and one hour post dosing.

BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights were recorded on Day 3 (before the start of treatment) and on Days 5, 6, 7, 8, 11, 14 and 17 of gestation. Body weights were also recorded for animals at terminal kill (Day 20).

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: The ovaries and uteri of pregnant females were removed, examined and the following data recorded:
i) Number of corpora lutea
ii) Number, position and type of intrauterine implantation
iii) Fetal sex
iv) External fetal appearance
v) Fetal weight
vi) Placental weight
vii) Gravid uterus weight
Ovaries and uterine content:
i) Number of corpora lutea
ii) Number, position and type of intrauterine implantation
iii) Fetal sex
iv) External fetal appearance
v) Fetal weight
vi) Placental weight
vii) Gravid uterus weight
Fetal examinations:
Skeletal alterations and soft tissue alterations, visceral anomalies and skeletal development and anomalies.
Statistics:
Body weight and body weight change (including adjustment for the contribution of the gravid uterus), food consumption, gravid uterus weight, litter data and fetal, litter and placental weights and external, visceral and skeletal observations were statitically analysed.

Data were first analysed using Shapiro Wilk normality test and Bartlett’s test for homogeneity of variance. Where there was no significance, parametric methodology was applied using one way analysis of variance and, if significant, Dunnett’s multiple comparison test. Where statistical significance was observed, non parametric methodology was applied using Kruskal-Wallis nonparametric analysis of variance; and, if significant, pairwise analysis of control values against treated values using the Mann-Whitney ‘U’ test. Due to the non-normal distribution of the data, externa , visceral and skeletal observations were generally analyzed using non-parametric methodology.

Probability values (p) are presented as follows:
p<0.01 **
p<0.05 *
p≥0.05 (not significant)
Indices:
Percentage pre- and post-implantation loss and sex ratio (% male fetuses).
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food efficiency:
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):
Other than generalized fur loss for one female receiving 300 mg/kg bw/day, no macroscopic abnormalities were apparent for females at Day 20 of gestation.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not specified
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
One animal in each of control group and top dose group was found to be non- pregnant.
Key result
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
clinical signs
dead fetuses
food consumption and compound intake
mortality
necropsy findings
number of abortions
pre and post implantation loss
total litter losses by resorption
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): 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:
effects observed, non-treatment-related
Description (incidence and severity):
At all dosages the incidence of fetuses with costal cartilage not fused to sternebra was higher than control with statistical significance being reached at 100 and 1000 mg/kg bw/day. However there was no dosage-relationship and this isolated finding was considered to be incidental and unrelated to maternal treatment.
Visceral malformations:
effects observed, treatment-related
Description (incidence and severity):
At 1000 mg/kg bw/day the overall incidence of fetuses showing visceral findings was slightly higher than control but there was no statistically significant increase in any fetal parameter that indicated any clear effect of maternal treatment. This increased incidence was considered most likely to be incidental and unrelated to maternal treatment.
Key result
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
changes in sex ratio
fetal/pup body weight changes
external malformations
visceral malformations
Remarks on result:
not determinable due to absence of adverse toxic effects
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
The administration off the test material to pregnant rats did not result in any adverse effects on the dams or on the survival, growth and development of the offspring. Therefore the NOEL is considered to be 1000 mg/kg bw/day (highest dose tested).
Executive summary:

In a developmental study the substance was administered to Sprage-Dawley rats 24/sex/dose by gavage at dose levels of 0, 100, 300 or 1000 mg/kg bw/day. Clinical symptoms, body weight and food consumption were recorded, and the uterus of females (number of corpora lutea, number, position and type of intrauterine implantation, placental weight, gravid uterus weight) and fetuses (total number, sex, weight and external, visceral-one-half and skeletal-one-half defects) were examined.There were no compound related effects in the dams or the offspring for the parameters monitored. The NOEL is 1000 mg/kg bw/day (the highest dose employed).

Effect on developmental toxicity: 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:
Sufficent to address requirements
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Toxicity to reproduction: other studies

Additional information

The constituents of Small Vinyl Ester do not contain sub-structures that are correlated to teratogenic potential in the MultiCASE human teratogenicity model (bisGMA, dihydroxy-monoGMA and polymeric reaction products) or are outside the model's domain (epoxy-monoGMA). However, the PASS system developed for drugs indicates potential of the constituents for teratogenicity and embryotoxicity. The residual monomer methacrylic acid is assessed by the EU not to be toxic to reproduction.

Justification for classification or non-classification

Based on the findings of the available reproductive toxicity data, classification of the substance is not justified.

Additional information