Registration Dossier

Diss Factsheets

Toxicological information

Toxicity to reproduction

Currently viewing:

Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2021-2022
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Report date:
2022

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Pentane-1,5-diol
EC Number:
203-854-4
EC Name:
Pentane-1,5-diol
Cas Number:
111-29-5
Molecular formula:
C5H12O2
IUPAC Name:
pentane-1,5-diol
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source (i.e. manufacturer or supplier) and lot/batch number of test material: (B 2024 v. 23.09.2020) (date of filling)
- Purity.: 97.8 area-%

Test animals

Species:
rat
Strain:
Wistar
Remarks:
Crl:WI(Han)
Details on species / strain selection:
The rat was chosen as the test species because it is accepted by regulatory agencies. The Han Wistar [RccHan®:WIST] strain was used because of the historical control data available at this laboratory
Sex:
male/female
Details on test animals or test system and environmental conditions:
Strain/Species:RccHan®:WIST rat.
Supplier:Envigo RMS Limited.
Number of animals ordered:44 males and 48 females. Spare animals were removed from the study room after treatment commenced.
Duration of acclimatization:
Males: Six days before commencement of treatment.
Females: 20 days before commencement of treatment.
Age of the animals at the start of treatment: Males 84 to 90 days old. Females 98 to 104 days old.
Weight range of the animals at the start of treatment: Males 311 to 352 g. Females 207 to 244 g.
Allocation:On arrival and non-selective allocation to cages. Estrous cycles were evaluated pre-treatment. After 14 days evaluation, animals that failed to exhibit typical 4-5 day cycles were not
allocated to the reproductive phase of the study. On Day 1 of study all animals were weighed, and body weights were reviewed by Study Management. Body weight of animals did not exceed 20% of the mean for each sex.
Identification of animals:Each adult animal was assigned a number and identified uniquely within the study by a microchip before Day 1 of treatment. The offspring were numbered individually within each litter on Day 1 of age, using a toe tattoo.
Identification of cages:Each cage label was color-coded according to group and was numbered uniquely with cage and study number, as well as the identity of the occupant(s).

Environmental Conditions:
Light: 12 hours daily, from 6.00 a.m. to 6.00 p.m.
Temperature: 20 - 24.0 ℃
Relative humidity: 40-70%

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Method of preparation :The required amount of test item was weighed and approximately 80% of the final volume of vehicle was added. This was magnetically stirred until uniformly mixed and made up to the required volume with the vehicle, followed by further magnetic stirring until homogeneous. A series of formulations at the required concentrations were prepared by dilution of individual weighings of the test item.
Frequency of preparation: Weekly.
Storage of formulation: Refrigerated (2 to 8°C).
Test item accounting: Detailed records of compound usage were maintained. The amount of test item necessary to prepare the formulations and the amount actually used were determined on each occasion. The difference between these amounts was checked before the formulations were dispensed.
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:
- 14 days premating
- up to 14 days mating
The exposure duration was at least five weeks

Females:
- 14 days premating
- up to 14 days mating
- gestation about 20 days
-sacrifice minimum 4 days after littering
The exposure duration was at least Day 13 of lactation.
Frequency of treatment:
once a daily
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:
10
Control animals:
yes, concurrent vehicle
Details on study design:
The dose levels for this study were based on the results of Labcorp Study Number 8460361, where doses of 300 or 1000 mg/kg/day were well-tolerated by Han Wistar rats during the 14 day administration period with no treatment-related clinical observations or deaths during the study.

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
Animals were inspected visually at least twice daily for evidence of ill-health or reaction to treatment. Cages were inspected daily for evidence of animal ill-health amongst the occupant(s). Any deviation from normal was recorded at the time in respect of nature and severity, date and time of onset, duration and progress of the observed condition, as appropriate.During the acclimatization period, observations of the animals and their cages were recorded at least once per day.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Clinical observations are presented for each animal, providing detail of type of sign, day of occurrence and information on the duration of the sign applicable.

BODY WEIGHT: Yes
The weight of animals was recorded as follows:
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. Days 1, 4, 7, 11 and 13 of lactation. On the day of necropsy.

FOOD CONSUMPTION AND COMPOUND INTAKE : Yes
The weight of food supplied to each cage, that remaining and an estimate of any spilled was recorded as follows: F0 animals: Weekly, from the day that treatment commenced. Food consumption was not recorded for males and females during the period when paired for mating (Week 3), but recommenced for males in Week 4. For females after mating food consumption was performed to match the body weight recording: Days 0-6, 7-13 and 14-19 after mating Days 1-3, 4-6 and 7-12 of lactation. From these records the mean weekly or daily consumption per animal (g/animal/week or g/animal/day) was calculated for each phase.
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
Sperm parameters (parental animals):
Qualitative evaluation of seminiferous tubules was performed with respect to their stage in the spermatogenic cycle and the integrity of various cell types present within the different stages. No stage or cell specific abnormalities were noted.
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: [yes]
Offspring: up to two females per litter (where possible; male pups wer reserved for nipple retention evaluation): one for T4 (serum)# one for TSH (serum)# Priority given to T4 sample.No offspring were allocated to these procedures on Day 4 of age if:
• the resultant live litter size would fall below eight offspring
• the resultant number of female pups would fall below three offspring
• If only four female offspring were available within a litter but the overall litter size was eight, one female was selected with priority given to the T4 sample.

GROSS EXAMINATION OF DEAD PUPS: YES
Externally normal offspring discarded without examination. Externally abnormal offspring identified on despatch to necropsy; examined externally, and retained pending possible future examination.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Female No. 132, administered 100 mg/kg/day, was found dead on Gestation Day 2, with no signs recorded ante mortem. The macroscopic examination revealed no findings. Microscopic findings consisted of focal vaginal changes comprising slight epithelial desquamation, moderate hemorrhage and slight inflammation. These findings may have contributed to the animal’s death.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Overall body weight gain (Day 1-35) was slightly lower than control in males receiving 1000 mg/kg/day (9% reduction) but statistical significance was not attained. Females receiving 100, 300 or 1000 mg/kg/day gained more body weight than the controls during gestation (19, 7 and 14% increases, respectively) and females receiving 300 or 1000 mg/kg/day gained more weight than the controls during lactation (22 and 19% increases, respectively). In each case there was no dose-response and statistical significance was not attained.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
Duration lactation, food intake was slightly higher than control in females receiving 100, 300 or 1000 mg/kg/day but there was no dose-response and statistical significance was not attained.
Food efficiency:
not examined
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):
All intergroup differences from control were minor, confined to one sex or lacked dose-response. Such differences included the slightly lower activated partial thromboplastin time in males receiving 1000 mg/kg/day, where the difference from control was slight and statistical significance was not attained.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
All intergroup differences from control were minor, confined to one sex or lacked dose-response. Such differences included the statistically significantly higher bilirubin concentration in males receiving 100, 300 or 1000 mg/kg/day, where the individual values were similar to control.
Endocrine findings:
no effects observed
Description (incidence and severity):
Thyroid stimulating hormone (TSH) concentration was unaffected by treatment . As there was considered no effect of treatment upon serum T4 and TSH concentration, no analysis of samples from F0 females and offspring on Day 4 of age samples was required.
Urinalysis findings:
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
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 Han Wistar rats of this age. Therefore, they were considered not test article related. Qualitative evaluation of seminiferous tubules was performed with respect to their stage in the spermatogenic cycle and the integrity of various cell types present within the different stages. No stage or cell specific abnormalities were noted. Qualitative evaluation of the ovaries was performed, and no abnormalities were observed.
Other effects:
no effects observed
Description (incidence and severity):
All macroscopic findings were considered spontaneous and/or incidental because they occurred at a low incidence, were randomly distributed across groups (including concurrent controls), and/or were as expected for Han Wistar rat of this age. Therefore, they were considered not test article-related.

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
Estrous cycles, pre-coital interval, mating performance, fertility and gestation length and index were unaffected by treatment. All females were in diestrus at scheduled termination.

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Remarks:
(systemic toxicity)
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other:
Remarks on result:
not determinable due to absence of adverse toxic effects
Dose descriptor:
NOAEL
Remarks:
( reproductive toxicity)
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive performance

Target system / organ toxicity (P0)

Key result
Critical effects observed:
no

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Anogenital distance (AGD):
no effects observed

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Remarks:
(developmental toxicity)
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:
not determinable due to absence of adverse toxic effects

Target system / organ toxicity (F1)

Key result
Critical effects observed:
no

Overall reproductive toxicity

Key result
Reproductive effects observed:
no

Applicant's summary and conclusion

Conclusions:
The no-observed-adverse-effect level (NOAEL) for reproductive/developmental toxicity was considered to be 1000 mg/kg/day.
Executive summary:

The oral administration of 1, 5 Pentanediol to Han Wistar rats at doses of 100, 300 or 1000 mg/kg/day was well tolerated, with no treatment-related premature deaths, clinical signs or adverse effects upon motor activity, sensory reactivity, grip strength or food intake. There was no adverse effect on body weight gain, though overall gain (Day 1-35) was 9% lower than control in males receiving 1000 mg/kg/day but without statistical significance. This study included a screen for reproductive/developmental effects and the results obtained were unremarkable.  Estrous cycles, pre-coital interval, gestation length and index, mating performance, fertility, litter size, offspring survival to Day 13 of age, sex ratio and offspring body weight gain were not adversely affected by treatment and there were no treatment-related clinical or macroscopic findings in the offspring. There was no evidence that 1, 5 Pentanediol had any effect on endocrine disruptor relevant endpoints, since circulating levels of T4 and TSH were similar to control in offspring on Day 13 of age and in adult males, there were no changes to organ weights or microscopic findings in endocrine-sensitive organs in adults and in offspring on Day 13 of age there were no effects on nipple development in males or on anogenital distance in either sex. There were no findings at the hematological or biochemical examination of the blood, and there were no treatment-related macroscopic or microscopic findings or changes to organ weights at the end of the treatment period.