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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
10 June to 29 September 2015
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2015
Report date:
2015

Materials and methods

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

Test material

Constituent 1
Chemical structure
Reference substance name:
Pentaerythritol
EC Number:
204-104-9
EC Name:
Pentaerythritol
Cas Number:
115-77-5
Molecular formula:
C5H12O4
IUPAC Name:
2,2-bis(hydroxymethyl)propane-1,3-diol
Test material form:
solid: crystalline
Details on test material:
- Name of test material (as cited in study report): Pentaerythritol
- Physical state: crystalline solid
- Analytical purity: 98.8%
- Lot/batch No.: 4410102701
- Expiration date of the lot/batch: 18 December 2016
- Storage condition of test material: ambient
Specific details on test material used for the study:
- Name of test material (as cited in study report): Pentaerythritol
- Physical state: crystalline solid
- Analytical purity: 98.8%
- Lot/batch No.: 4410102701
- Expiration date of the lot/batch: 18 December 2016
- Storage condition of test material: ambient

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River UK Limited, Margate, Kent, UK
- Strain: Crl:CD(SD) Sprague-Dawleys
- Age at study initiation: 9-10 weeks
- Weight at study initiation: 211 - 325 g
- Housing: Animals were housed up to 2 per cage in appropriately sized suspended polycarbonate/polypropylene cages with stainless steel grid tops and solid bottoms. Bedding material was sterilised white wood shavings which was provided with a certificate of analysis for significant contaminants. An analytical certificate for each batch of bedding used are retained at Charles River, Edinburgh. For psychological/environmental enrichment, animals were provided with items such as a device for hiding in and an object for chewing (certificates of analysis are retained at the test facility).
- Diet: SDS VRF-1 breeder diet ad libitum
- Water: Water from the public supply ad libitum
- Acclimation period: up to 4 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-25°C (target 19-23°C)
- Humidity (%): 39% - 78% (target 40% to 70%)
- Air changes (per hr): at least 10/hour (100% fresh air)
- Photoperiod (hrs dark / hrs light): 12 h cycle

IN-LIFE DATES: From: 19 June 2015 To: 16 July 2015

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The control item, corn oil, was prepared weekly, stored in a refrigerator set to maintain 4°C and dispensed daily for administration to Group 1 control animals. The control item was removed from the refrigerator and stirred for at least 30 minutes before dosing. The control item was also stirred continuously during dosing. Test item dosing formulations were prepared based on a method established at the Test Facility at appropriate concentrations to meet dosage level requirements. The dosing formulations were prepared weekly, stored in a refrigerator set to maintain 4°C, and dispensed daily. The dosing formulations were removed from the refrigerator and stirred for at least 30 minutes before dosing. The dosing formulations were also stirred continuously during dosing. Any residual volumes were discarded.

- Concentration in vehicle: 0, 25, 75 and 250 mg/mL
- Dose volume: 4 mL/kg bw
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples were collected from all groups for analysis of concentration on Day 1 and and Week 2. Samples were collected from the test substance groups for analysis of homogeneity of Day 1 and Week 2. Samples were analysed by gas chromatography with flame ionisation using a validated method. Stability analyses were performed for a previous study conducted at the test facility - stability in the vehicle was demonstrated.
Details on mating procedure:
Time-mated females were delivered to the test facility.
Duration of treatment / exposure:
Days 6-19 of gestation
Frequency of treatment:
Once daily
Duration of test:
15 days (treatment on Days 6-19 gestation; scheduled euthanasia on Day 20 of gestation)
Doses / concentrationsopen allclose all
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 females per group
Control animals:
yes, concurrent vehicle
Details on study design:
The oral gavage route of administration was selected for this study as this is a regulatory requirement. Dose levels were selected in agreement with the Sponsor following review of all available toxicological data where dose levels up to 1000 mg/kg/day were well tolerated with only minimal effects of toxicity.

Examinations

Maternal examinations:
Animals were observed for general health/mortality and moribundity twice daily, once in the morning and once as late as possible each day. Detailed clinical observations were made daily from the start of dosing. Prior to dosing and regularly throughout the day, all animals were examined for reaction to treatment. The onset, intensity and duration of these signs were recorded (if appropriate), particular attention being paid to the animals during and for the first hour after dosing. Body weights were recorded once during pretreatment (Day 5 of gestation) and daily (Day 6 - 20 of gestation) during the dosing period. Food consumption was quantitatively measured daily from Day 6 of gestation. Scheduled euthanasia took place on Day 20 of gestation. All adult animals were subjected to a complete necropsy examination, which included evaluation of the carcass and musculoskeletal system; all external surfaces and orifices; cranial cavity and external surfaces of the brain; and thoracic, abdominal, and pelvic cavities with their associated organs and tissues. Representative samples of abnormal tissues were collected and preserved in 10% neutral buffered formalin or other appropriate fixative.
Ovaries and uterine content:
The reproductive tract was dissected from the abdominal cavity. The gravid uterus was weighed. The uterus was opened and the contents were examined. The fetuses were removed from the uterus. The ovaries and uterus were examined for number and distribution of Corpora Lutea, Implantation Sites, Placentae (size, colour or shape) any abnormalities were recorded, Live and Dead Fetuses and Early and Late Embryonic Deaths.
Fetal examinations:
Fetuses were examined for external abnormalities. Late resorptions and dead fetuses were examined for external abnormalities to the extent possible. Each implant was classified as being live, or a dead fetus (dead full term fetus that shows no sign of maceration), or a late embryonic death (macerated tissue identifiable as an embryo fetus, with recognisable external features such as tail, limbs, mouth and nares present; attached to distinct identifiable placentae), or an early embryonic death (discrete, formless, discoloured tissue mass attached to the internal uterine wall; may be of varying size). The body weight of each fetus was recorded. Fetuses were individually identified within litters.

Visceral examination: Half of the viable fetuses from each uterus were fixed in methylated ethyl alcohol, examined internally for sex and eviscerated following initial fixation, the viscera was not examined from fetuses prior to disposal. The remaining half of viable fetuses from each uterus were fixed in Bouin's fluid.

The fetuses fixed in Bouin's fluid were examined for soft tissue abnormalities and sex using a freehand sectioning technique derived from that of Wilson.

Skeletal examination: The eviscerated carcasses were then macerated in potassium hydroxide, the skeletons stained with Alizarin Red S, and then the fetuses cleared with aqueous glycerol solutions. These preparations were examined for the presence of skeletal abnormalities and for the extent of ossification.
Statistics:
Means and standard deviations were calculated for body weight, food consumption and pregnancy data. To assist interpretations, tests were applied to determine the statistical significance of observed differences between Control and groups receiving test item. Unless otherwise stated, all statistical tests were two-sided and performed at the 5% significance level using in house software. Pairwise comparisons were only performed against the control group. Body weight and food consumption, data were analysed for homogeneity of variance using the ‘F-Max' test. If the group variances appeared homogeneous, a parametric ANOVA was used and pairwise comparisons were made using Fisher’s F protected LSD method via Student's t test ie pairwise comparisons were made only if the overall F-test was significant. If the variances were heterogeneous, log or square root transformations were used in an attempt to stabilise the variances. If the variances remained heterogeneous, then a Kruskal-Wallis non-parametric ANOVA was used and pairwise comparisons were made using chi squared protection (via z tests, the non-parametric equivalent of Student's t test).
Indices:
Not applicable.
Historical control data:
Not reported.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
There were no mortalities and no clinical signs of toxicity. There were no treatment-related effects on body weight or body weight gain. Food consumption was unaffected by treatment. No abnormalities were detected at necropsy.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
At dose levels up to and including 1000 mg/kg/day there was no effect on pregnancy frequency, gravid uterine weight, mean fetal weight, number of corpora lutea, number of implants or embryofetal survival including pre-implantation loss. The type and distribution of all fetal abnormalities and variations, including those indicating the extent of skeletal ossification were similar in all groups and did not indicate any association with test item administration.

Effect levels (fetuses)

Dose descriptor:
NOEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Remarks on result:
not determinable due to adverse toxic effects at highest dose / concentration tested

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Dose formulation analyses

All study samples analyzed had mean concentrations within the acceptance criteria of ± 10% of their theoretical concentrations, except for Day 1, Group 2 (-16.0%); therefore, as part of the investigation, the backup samples were analyzed in triplicate, and the results (-8.4%) were within the acceptance criteria. The investigation demonstrated that Day 1, Group 2 was likely to have been within specification. For homogeneity, the RSD of concentrations for all samples in each group was within the acceptance criteria of ≤ 10%, except for Week 2, Group 2 (12.7%); therefore as part of the investigation, the backup samples were analyzed in triplicate, and the result (6.2%) was within the acceptance criteria. The investigation demonstrated that Week 2, Group 2 was likely to have been within specification. The dose formulations were within specification. Homogeneity testing showed that the formulation technique used produced homogeneous preparations.

Applicant's summary and conclusion

Conclusions:
Under the conditions of this study, the maternal and embryofetal no observed effect levels (NOEL) were considered to be 1000 mg/kg/day.
Executive summary:

The potential toxicity of pentaerythritol when administered orally during the period of organogenesis and foetal period to pregnant rats was investigated according to OECD 414. Four groups of 24 females Sprague-Dawley rats were dosed orally by gavage on Days 6-19

of gestation (where Day 0 was the day of detection of mating), at dose levels of 0, 100, 300 or 1000 mg/kg bw/day in corn oil.

The following parameters and end points were evaluated: clinical signs, body weights, food consumption, gross necropsy findings, gravid uterine weight, and examination of pregnancies and fetal examinations (external abnormalities, fetal weights, visceral and

skeletal evaluations). Animals were killed on Day 20 of gestation. At dose levels up to and including 1000 mg/kg/day were no test item-related effects on clinical observations, body weight gain, food consumption, gross pathology findings, pregnancy performance parameters, embryofetal survival or fetal weights, fetal abnormalities and variants. In conclusion, under the conditions of this study, the maternal and embryofetal no observed effect levels (NOEL) were considered to be 1000 mg/kg/day.