Registration Dossier

Diss Factsheets

Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Wistar rats, strain: Hsd:HanWIST with appropriate range of bodyweight at study start.
- Source: Advinus Therapeutics Ltd. in-house random bred (conventionally bred)
- Age at treatment start: 11-12 weeks old, both sexes
- Weight at treatment start: 241-294 g for males, 185-210 g for females
- Housing in polysulfone cages with stainless steel top grill
during pre-pairing dosing period: In groups of 2 by sex
during pairing: 1 male+1 female/cage
males after pairing: In groups of 2 by sex
females during gestation and lactation: Females housed individually (+litter).
- Bedding material (in polysulfone cages): steam sterilised clean corn cob
- Diet (ad libitum): Teklad certified Global 14% protein Rodent maintenance diet - pellets, Harlan, 5800 AN Venray, The Netherlands
- Water (ad libitum): Deep bore-well water passed through activated charcoal filter and UV irradiated, regular quality control
- Acclimation period: 5 days before treatment start, after examination for health and suitability.

ENVIRONMENTAL CONDITIONS
The animal room was maintained at (target ranges for temperature and relative humidity):
- Temperature (°C): 19 - 24°C
- Relative Humidity (%): 57 - 67 %
- Photoperiod (artificial lighting): 12 hrs day / 12 hrs night
- Ventilation: 12-15 times/h
Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Remarks:
PEG 300
Details on exposure:
- Concentration in vehicle: The concentration of the test material in vehicle varied between dose groups thus allowing constant dosage volume in terms of mL/kg bw/day. Concentrations amounted to 15, 30, and 100 mg/ml vehicle, accordingly.
- Amount (dose volume by gavage): 10 mL/kg bw/day.
Actual dose volumes were calculated at about weekly or shorter intervals accounting for the latest bodyweight.

- Frequency of preparation of dose formulations: Once a week

Treatment of parental animals by oral gavage administration. Test substance was not directly administered to F1 animals, as these pups were sacrificed on Day 4 post partum, i.e. Day 4 of lactation.
Details on mating procedure:
- Male/female ratio per cage: 1/1
- Length of cohabitation: At the most 14 days, until proof of pregnancy was confirmed. 
- Proof of pregnancy: Formation of vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
For analysis of the test substance in the vehicle GC / FID was used with a DB-35 column (30 m long, 0.53 mm i.d., 0.5 μm film thickness). The analytical method was validated. The mean contents of the test substance in dose formulations were found to be well within the acceptance limit (within +/- 15%) of dose theoretical concentration; the relative standard deviation was equal to or less than 10%.
Duration of treatment / exposure:
- Treatment period, parental males: 42 days (14 days before mating and 28 days including up to 14 days for mating)
- Treatment period, parental females (dams): approx. 40-45 days (from 14 days prior to mating to Lactation Day 4)
- Pups were not treated directly (possibly via milk): until Lactation Day 4.
Frequency of treatment:
Daily
Dose / conc.:
150 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
Positive control:
Not included in the study.
Parental animals: Observations and examinations:
Clinical observations performed and frequency:
- Clinical signs: Daily (covering external appearance, motor activity & morbidity in each animal)
- Body weight, Males: Weekly from Treatment Day 0 to 42 (i.e. from the first treatment day until the day before necropsy).
Body weight, Females: Weekly for pre-pairing & pairing period, Gestation Days 0, 7, 14, 20 & Lactation Days 0 (i.e. the day post partum) & 4
- Food consumption, Males: Weekly for pre-pairing period
Food consumption, Females: Weekly for pre-pairing period (Days 0-7 & 7-14) and for Gestation (Days 0-7, 7-14, 14-20) & Lactation (Days 0-4, i.e. the day post partum until the day of necropsy).
Oestrous cyclicity (parental animals):
not observed
Sperm parameters (parental animals):
Parameters examined in male parental animals: testis weight, epididymis weight, histopathology with special emphasis on stages of spermatogenesis in male gonads and of interstitial testicular cell structure
Litter observations:
LITTER PARAMETERS EXAMINED
- Delivery or post-implantation survival index (Total no. of pups born / Total no. of implantation sites) x 100
- Total no. of pups (alive and dead), sex
- Body weight of live pups (on Lactation Days 1 and 4)
- No. of pups alive, dead or cannibalised on Lactation Days 1, 2, 3, 4
- Live birth index (No. of live pups on Lactation Day 1 / Total no. of pups born) x 100
- Viability index (No. of live pups on Lactation Day 4 / No. of live pups on Lactation Day 1) x 100
- Sex ratio  (Nos. of male pups and Nos. of female pups)
- Clinical signs, on each day after birth



Postmortem examinations (parental animals):
GROSS PATHOLOGY: Yes, see below
WEIGHING OF ORGANS: Yes, see below
HISTOPATHOLOGY: Yes, see below

Terminal sacrifice
- Males: Killed on the day after the 42-day treatment period.
- Terminal sacrifice, Females (dams): Killed on Lactation Day 4
- Terminal sacrifice, unmated Female: 1 mid dose female (300 mg/kg/day) which had failed to mate was killed on the day after 26 daily doses

Gross pathology: Necropsy with tissue collection.
The number of implantation sites and corpora lutea was recorded for all dams

Organs Weights: The following organs were weighed at necropsy and their ratios to terminal bodyweight determined:
testes, epididymides.

Histopathology: The following organs were microscopically observed for the control and 1000 mg/kg bw/day groups:
testes, epididymides, prostate, seminal vesicles and coagulating glands, ovaries.
Postmortem examinations (offspring):
On Lactation Day 4 external macroscopic examination of all survivors for gross abnormalities.
Statistics:
The statistical analysis of the experimental data was carried out using the validated package in Excel and also using licensed copies of SYSTAT Statistical package ver.12.0. All quantitative variables like body weight, food consumption, organ weights and organ weight ratios were tested for normality (Shapiro-Wilk test) and homogeneity of variances (Levene’s test) within the group before performing a one-factor ANOVA modeling by treatment groups. Non-optimal (non-normal or heteroschedastic) data were transformed, before using ANOVA. Means between treatment and control groups were compared using Dunnett’s test if the overall ‘F’ test was found to be significant.
Pre-implantation loss (%), post implantation loss (%), no. of corpora lutea, implantations, pre-coital interval and gestation length (days) were analyzed after suitable transformation (√ x + ½) of the data. One-way analysis of variance (ANOVA) was carried out for the transformed data. Dunnett’s pairwise comparison of the treated means with the control mean was done for the significant group differences.
Z test was performed for testing the differences in proportions for mating and fertility indices.
All analyses and comparisons were evaluated at the 5% (P≤0.05) level.
Reproductive indices:
- Pre-coital interval (pairing days until detection of mating)
- No. of animals mating (evidence of successful copulation, i.e. at least one copulation plug or a sperm positive vaginal smear)
- No. of animals achieving pregnancy
- Percentage mating or copulation index (No. of animals mating/No. of animals paired) x 100
- Conception rate or fertility index (No. of animals achieving pregnancy/No. of animals mated) x 100
- Gestation length (time elapsing from detection of mating until the day prior to confirmation of parturition)
- No. of pregnant animals
- No. of pregnant animals with parturition
- Gestation Index (No. of animals achieving pregnancy with parturition/No. of animals achieving pregnancy) x 100
- No. of corpora lutea
- No. of implantation sites
- Implantation index (No. of implantation sites/No. of corpora lutea) x 100
Offspring viability indices:
- Mean litter size per group (number of implantations - number of live fetuses / number of implantations) x 100
- Day 4 survival index (No. of live pups on Lactation Day 4 / No. of live pups born) x 100.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
semi-solid feces in 2/10 males at 1000 mg/kg/day from Day 5 to 9.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
one dam from the 1000 mg/kg/d group was found dead on treatment day 37 (GD21); attributed to spontaneous dystocia thus not related to treatment.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Significantly lower mean body weight was observed in males at 1000 mg/kg Bwt/day on Day 43; mean body weight gain was lower in males between Days 1-8, 36-43 and 1-43. Reduced body weight gain in females at 1000 mg/kg/day between Day 1-8 and 11-15. See attached Tables in "Attached background material".
Food consumption and compound intake (if feeding study):
no effects observed
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:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
only reproduction organs were examined
Other effects:
not examined
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
represented by testes & epididymis weights and absence of histopathological findings.
Reproductive performance:
no effects observed
Description (incidence and severity):
See attached Tables in "Attached background material".
Key result
Dose descriptor:
NOAEL
Remarks:
reproductive toxicity
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Key result
Dose descriptor:
NOAEL
Remarks:
parental toxicity
Effect level:
> 300 - < 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
body weight and weight gain
other: with regard to parental toxicity the NOAEL was derived at the dose level of 300 mg/kg/d based on reduction in body weight gain primarily in males of the high dose group
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
1 000 mg/kg bw/day (actual dose received)
System:
other: body weight gain
Organ:
other: body weight gain
Treatment related:
yes
Clinical signs:
no effects observed
Mortality / viability:
mortality observed, treatment-related
Description (incidence and severity):
See attached Table on survival data of pups in "Attached background material".
Body weight and weight changes:
no effects observed
Description (incidence and severity):
See attached Table on body weight of pups in "Attached background material".
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
Day 4 survival index was significantly lower at 300 and 1000 mg/kg Bwt/day when compared to the control group. This finding was mainly due to the loss of an entire litter from a single dam (Animal No. Ro2741) at 300 mg/kg Bwt/day and also due to litter losses in two dams (Animals No. Ro2751 and Ro2754) at 1000 mg/kg Bwt/day during the lactation period. A similar incidence of total litter loss was spontaneously observed in a previous OECD 421 study performed in-house. The observed low Day 4 survival index in both 300 and 1000 mg/kg Bwt/day groups was therefore considered to bear no relationship to treatment with test item.
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: NOAEL = highest dose tested.
Key result
Critical effects observed:
no
Key result
Reproductive effects observed:
no
Conclusions:
In this screening study there were no treatment related effects on reproduction or developmental toxicology parameters. The no-observed-adverse- effect-levels (NOAEL) for parental toxicity regarding reprotoxic endpoints and for foetal toxicity are 1000 mg/kg bw/day. The NOAEL for general parental toxicity was derived at 300 mg/kg bw/day based on reduction of weight gain at the highest dose.
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
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Short description of key information:

In the reproduction / developmental toxicity screening study by oral gavage no effects were observed on reproductive endpoints up to and including the highest dose of 1000 mg/kg body weight/day. The NOAEL for parental toxicity was derived at 300 mg/kg bw/day based on reduction of body weight gain at the highest dose.

In the 90 -day oral toxicity study no effects on reproductive tissues were observed up to and including the highest dose of 1000 mg/kg body weight/day.

Effects on developmental toxicity

Description of key information

From the oral gavage study with octane-1,2-diol being adminstered to pregnant rats during gestation days 5 to 19 the following NOAELs were derived: 150 mg/kg bw/day for maternal toxicity, 300 mg/kg bw/day for developmental toxicity and of 1000 mg/kg bw/day for teratogenicity.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
of 2001
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Species, Strain & Condition: Female Wistar rats, HsdHan: WIST rats
Day 0 pregnant rats, body weight 219 - 248 g
- Source: Advinus Therapeutics Ltd, in-house random bred (conventionally bred)
- Assignment to dose groups: At animal arrival bodyweight stratified randomization to ensure similar group mean bodyweights
- Housing:
Upon arrival: Mated females were housed individually in polysulfone cages with stainless steel grid
- Bedding material: steam sterilised corn cob
- Diet (ad libitum): Teklad Certified Global 14% protein rodent maintenance diet, pellets. Harlan 5800 AN Venray, The netherlands
- Water (ad libitum): Deep bore-well water passed through activated charcoal filter and exposed to UV rays

ENVIRONMENTAL CONDITIONS
The animals were housed in a single air-conditioned room maintained at (target ranges for temperature and relative humidity):
- Temperature (°C): 20-23°C
- Relative Humidity (%): 57-66%
- Photoperiod: 12 h day / 12 h night
- Rate of air exchange: 12 - 15 changes/h
Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Remarks:
PEG 300
Details on exposure:
- Dosing formulations (test material / vehicle mixtures) were prepared fresh every 3 to 4 days.

- Concentration in vehicle: The concentration of the test material in vehicle varied between dose groups thus allowing constant dosage volume in terms of mL/kg bw/day. Concentrations were 15, 30, 100 mg/ml vehicle.

- Amount (dose volume by gavage): 10 mL/kg bw/day.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
For analysis of the test substance in the vehicle GC / FID was used with a DB-35 column (30 m long, 0.53 mm i.d., 0.5 μm film thickness). The analytical method was validated. The mean contents of the test substance in dose formulations were found to be well within the acceptance limit (within +/- 15%) of dose theoretical concentration; the relative standard deviation was equal to or less than 10%.
Details on mating procedure:
Females were received within several days at Gestation Day 0, i.e. the day positive evidence of mating was observed, and allocated to the treatment by body weight stratification.

Duration of treatment / exposure:
- Duration of treatment: Gestation Day 5 to 19 (to cover the period of organogenesis)
- Caesarian section and necropsy: On Gestation Day 20
Frequency of treatment:
Once daily
Duration of test:
20 days
Dose / conc.:
150 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:
24
Control animals:
yes, concurrent vehicle
Details on study design:
Dose selection was based on the result of the 28 day study.
Maternal examinations:
Clinical observations of dams: Twice daily during the normal working week, once daily at weekends
Body weight of dams: On Days 3, 5, 8, 11, 14, 17 and 20 of gestation
Food consumption of individual dams: For Days 0-3, 3-5, 5-8, 8-11, 11-14, 14-17 and 17-20 of gestation
Caesarean section and necropsy of dams: On Gestation Day 20, external observation and macroscopic examination of visceral organs
Ovaries and uterine content:
The ovaries and the gravid uterus were excised and immediately examined on Gestation Day 20.
Examinations included:
- Pregnancy status
- uterine weight
- Number of corpora lutea
- number of implantation sites
- number of early resorptions
- number of late resorptions
Fetal examinations:
- Number of fetuses, no. of viable fetuses, no. of non-viable fetuses
- Individual external examination of fetuses for gross abnormalities
- Individual fetus' examination of sex and weight (weight only of live fetuses)
- Examination of visceral malformations by modified Wilson's Razor Blade Sectioning Technique *
- Examination of skeletal malformations and bone development**, other half of each litter.

* after fixation in in 70% alcohol
** after fixation in 70% alcohol, evisceration, etc.and processing to 100% glycerol and staining with alizarin red S in Mall's solution.

Statistics:
The data on maternal body weight, body weight change, maternal food consumption, gravid uterus weight, number of corpora lutea, number of implantations, litter size, litter weight, male and female fetus number and fetal body weight were analyzed using ANOVA model, after testing for homogeneity for intra group variance using Levene’s test. When the intra group variances were heterogeneous, ANOVA was performed after suitable transformation of data. Dunnett’s pairwise comparison of the treated group means with the control group mean was performed if the group differences were found significant.
Incidence of pre-implantation loss, post implantation loss, number of early, late and total resorptions were analyzed using Kruskal Wallis.
Overall percentage of minor external, visceral and skeletal malformations, Sex ratio and number of dams with any resorptions were analyzed using 2 X 2 Contingency Table.
Indices:
- Mean number of corpora lutea (CL)/group: [Total no. of CL / Total no. of pregnant animals]
- Mean number of implantations/group: [Total no. of implantations / Total no. of pregnant animals]
- Percentage of early resorptions per group: [(No. of early resorptions / No. of implantations) x 100]
- Percentage of late resorptions per group: [(No. of late resorptions / No. of implantations) x 100]
- Pre-implantation loss (%): [(number of corpora lutea - number of implantations) / number of corpora lutea] x 100
- Post-implantation loss (%): [No. of (early + late) resorptions / number of implantations] x 100
- Sex ratio: [number of male foetuses : number of female foetuses]
Historical control data:
Included in the study report.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
mean maternal body weight and body weight gains were unaffected by the administration of the test substance. Mean corrected body weight gains were statistically significantly higher at all dose levels when compared to the control (61%, 57%, and 74% at 150, 300, and 1000 mg/kg bw/d, respectively). See attached Table on body weight in "Attached background material".
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
See attached Table on food intake in "Attached background material".
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:
not examined
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Other effects:
no effects observed
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
See attached table on maternal developmental data in "Attached background material".
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
See attached table on maternal developmental data in "Attached background material".
Early or late resorptions:
no effects observed
Description (incidence and severity):
See attached table on maternal developmental data in "Attached background material".
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
no effects observed
Details on maternal toxic effects:
Details on maternal toxic effects:
Body weight gain and food intake were unaffected by treatment. Mean corrected body weight gains were significantly higher at all dose levels compared to control animals. Mean gravid uterine weights were significantly reduced at 300 and 1000 mg/kg bw/day.
All other maternal parameters (mean number of corpora lutea, implantations, early and late resorptions, pre and post-implantation loss, number of dams with resorptions) remained unaffected in all treatment groups.
Key result
Dose descriptor:
NOAEL
Effect level:
> 150 - < 300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Key result
Dose descriptor:
NOAEL
Effect level:
> 300 - < 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
See attached table with summary of litter data in "Attached background material".
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
See attached table with summary of litter data in "Attached background material".
Changes in sex ratio:
no effects observed
Description (incidence and severity):
See attached table with summary of litter data in "Attached background material".
Changes in litter size and weights:
effects observed, treatment-related
Description (incidence and severity):
no effects on litter size but on foetus weights, see attached table with summary of litter data in "Attached background material".
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Skeletal malformations:
effects observed, treatment-related
Description (incidence and severity):
See attached table with skeletal observation data in "Attached background material".
Visceral malformations:
no effects observed
Other effects:
no effects observed
Details on embryotoxic / teratogenic effects:
Details on embryotoxic / teratogenic effects:
Mean fetus weights (both male and female) were significantly lower at all dose levels when compared to the vehicle control group. These values were within the historical control range at 150 and 300 mg/kg bw/day, but below the historical control range at 1000 mg/kg bw/day. Thus, this effect was considered treatment-related at 1000 mg/kg bw/day. The significantly increased incidence of a 14th accessory rib in fetuses at 1000 mg/kg bw/day was considered as sign of fetotoxicity due to the significant reduction of fetal weights at the same dose level. Teratogenic effects were not observed.
All other litter parameters (mean litter size, number of live fetuses, total number of fetuses and sex ratio) were comparable to the vehicle control group at all dose levels.
Key result
Dose descriptor:
NOAEL
Effect level:
> 300 - < 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
changes in litter size and weights
Key result
Abnormalities:
effects observed, treatment-related
Localisation:
skeletal: supernumerary rib
other: reduced body weight, delayed development
Key result
Developmental effects observed:
yes
Lowest effective dose / conc.:
1 000 mg/kg bw/day (actual dose received)
Treatment related:
yes
Relation to maternal toxicity:
developmental effects as a secondary non-specific consequence of maternal toxicity effects
Conclusions:
Oral gavage administration of octane-1,2-diol to pregnant Wistar rats during gestation days 5 to 19 resulted in lower gravid uterine weight at doses of 300 and 1000 mg/kg bw/day. Fetuses at 1000 mg/kg bw/day had significantly lower body weights and a significantly increased incidence of a 14th accessory rib. These observations led to NOAELs of 150 mg/kg bw/day for maternal toxicity, of 300 mg/kg bw/day for developmental toxicity and of 1000 mg/kg bw/day for teratogenicity as no such potential was observed. As detailed in the discussion in the endpoint summary "Toxicity to reproduction" classification of octane-1,2-diol as reproductive toxicant is not considered appropriate.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
300 mg/kg bw/day
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Repeated oral administration (gavage) of octane-1,2-diol to rats did not result in systemic toxic effects to organs, blood parameters and neurobehaviour. However, reduced body weight gain was observed (already starting in the first week) at 300 and 1000 mg/kg body weight/day in males and females of the 90-day study as well as in the parental animals of the reproduction / developmental toxicity screening study (42 days dosing). Reduced body weight gain was observed not continuously but sporadically and led to reduced body weights at the end of the test periods.

Based on the antimicrobial activity of octane-1,2-diol it is very likely that at the high dose levels applied by gavage the test substance caused disruption of the animal’s gut microbiota. In consequence of this gut microbiota disruption imbalanced nutrition or malnutrition of the animal may result.

In the developmental toxicity study with 14 days gavage dosing of the dams no body weight reduction of dams was observed but dosed dams had increased net body weight gain at study termination compared to control animals. However, mean gravid uterine weights of dosed dams were significantly reduced at 300 and 1000 mg/kg bw/day and mean foetus weights (both male and female) were significantly lower at all dose levels when compared to the control group.

A similar effect on body weight increase of dosed females was observed in the reproduction / developmental toxicity screening study. Maternal body weight was significantly increased after the gestation phase in dosed dams compared to control dams. This imbalance between increased maternal body weight on the one hand and decreased foetus weights on the other hand in dams dosed with octane-1,2-diol is considered strong evidence of imbalanced nutrition of dosed animals due to disruption of the gut microbiota.

Imbalanced nutrition of dams and further effects on developing foetuses is considered a secondary effect and not a primary toxic effect of the substance on the animal.

In the absence of effects other than reduced foetus weights in the developmental toxicity study and in view of absence of any effects on offspring up to the highest dose of 1000 mg/kg bw/day in the reproduction / developmental toxicity screening study it is rather likely that octane-1,2-diol is not a developmental toxicant but that reduced foetus weights are a secondary non-specific consequence of maternal malnutrition. (Detailed information on the hypothesis of the secondary effect is provided in the “Review of reported effects on developmental parameters” attached to the endpoint study record of the developmental toxicity study in Section 7.8.2 of the IUCLID dataset.). In the developmental toxicity study performed with hexane-1,2 -diol no developmental effects were observed up to and including the highest dose of 300 mg/kg body weight/day

Justification for classification or non-classification

In the developmental toxicity study at the high dose level of 1000 mg/kg body weight/day reduced foetus weights were observed. However, at this dose level in repeat dose studies significant effects on body weight gain of adult rats were observed that might be due to disruption of the gut microbiota by the antimicrobial activity of octane-1,2 -diol leading to imbalanced nutrition. Thus, the effect observed in the developmental toxicity study very likely is a secondary non-specific consequence of maternal malnutrition.

With regard to classification of octane-1,2 -diol the situation is considered inconclusive.

Additional information