Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Oral gavage administration of fatty acids, c18-unsatd., dimers, polymers with epichlorohydrin at doses of 50, 150, and 500 mg/kg/day for up to 35-63 days was associated with test item-related epithelial hyperplasia/hypertrophy in the uterus/cervix and/or vagina at ≥50 mg/kg/day, atrophy in the prostate at ≥50 mg/kg/day, and/or atrophy in the epididymis at 500 mg/kg/day.  Hepatocellular hypertrophy in the liver was present in males and females at ≥50 mg/kg/day.  

In females and males, the administration of ≥50 mg/kg/day fatty acids, c18-unsatd., dimers, polymers with epichlorohydrin was considered adverse due to microscopic findings of epithelial hyperplasia/hypertrophy in the uterus/cervix and vagina associated with failure to litter in females and prostatic atrophy in males at this dose. Centrilobular hypertrophy was considered non-adverse due to minimal severity and the lack of any correlating clinical pathology findings.

In conclusion, based on the findings at 50 mg/kg/day, a NOAEL could not be determined in the current study.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
04 October to 11 January 2019
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Justification for study design:
The purpose of this study was to assess possible effects of Fatty Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin on male and female reproductive performance, including a repeated dosing toxicity part (in accordance with Test Guideline 422) when the test item is administered by oral gavage. Based on the results of Study No. LX93VG, the dose levels for this study are 50, 150 and 500 mg/k/day.
Specific details on test material used for the study:
Identification: Fatty acids, C18-unsatd., dimers, polymers with epichlorohydrin
CAS Number: 68475-94-5
Physical state/Appearance: Clear liquid
Batch: 52611021
Purity: 100% (UVCB product)
Expiry Date: 1 Dec 2018
Storage Conditions: Room temperature in the dark
Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
CD (Sprague-Dawley derived) Crl:CD (SD) from reputable commercial supplier
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: Approximately 15 to 16 weeks
- Weight at study initiation: Males: 449 - 643 grams, Females: 233 - 328 grams
- Housing: Polycarbonate cages with a stainless steel mesh lid.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITION
- Temperature (°C): 20 to 26
- Humidity (%): 30 to 70
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Fatty Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin was prepared for administration by mixing appropriate amounts of the test item with the vehicle to achieve the desired concentrations. The test item was used as supplied when calculating quantities to be used during dose preparation. Fresh formulations were prepared once weekly and were stored frozen (-20 °C) when not in use. Detailed records of test item usage were maintained. The amount of test item necessary to prepare the formulations and the amount actually used were determined at each preparation.

VEHICLE
- Concentration in vehicle: 0, 10, 30, 100mg/mL
- Amount of vehicle (if gavage): 5 mL/kg
- Lot/batch no.: 2GH0193, 2GK0223
- Purity: Assume 100 %
Details on mating procedure:
- M/F ratio per cage: 1M:1F
- Length of cohabitation: until evidence of mating was seen or until 14 consecutive days of cohabitation had elapsed
- Proof of pregnancy: presence vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy
- After 14. days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: no In the absence of positive signs of mating during the second pairing, the morning of the last day of cohabitation was considered “presumed GD 0” for that female.
- After successful mating each pregnant female was caged (how): singly
- Any other deviations from standard protocol:
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Homogeneity:
Homogeneity of the dose formulation was demonstrated by taking two samples each (2.5 mL/sample) from the top, middle and bottom portion of the low and high concentrations prepared for use on the study.

Stability:
Stability under storage conditions used in this study (24 hours at room temperature; 8 days refrigerated [2 to 8°C] and up to 9 months frozen [-20°C ± 10ºC]); were performed. Five (5) grams of the test item and 200 mL of the vehicle were sent to the Test Site for stability assessment.

Dose Concentration:
Two samples (2.5 mL each) were taken from the middle region of each formulation (including control) for each week on the day of dose preparation. For the first and seventh dose formulations prepared, one sample was analyzed, in duplicate, for dose confirmation analysis and one sample was retained refrigerated (retained sample was discarded after valid analytical results were obtained).

Storage:
All dose formulation samples were stored frozen (-20°C ± 10ºC) until shipped to the Test Site for analysis.
Duration of treatment / exposure:
The duration of dosing for the main study F0 males was 2 weeks pre-cohabitation, during cohabitation (up to 3 weeks) and continuing during post-cohabitation until the day prior to termination [approximately 35 days].
The duration of dosing for the main study F0 females was 2 weeks pre-cohabitation, cohabitation (up to 3 weeks) and during gestation and lactation continuing until LD 13 (maximum of 60 days).
Frequency of treatment:
Rats were dosed once daily
Dose / conc.:
0 mg/kg bw/day
Dose / conc.:
50 mg/kg bw/day
Dose / conc.:
150 mg/kg bw/day
Dose / conc.:
500 mg/kg bw/day
No. of animals per sex per dose:
10 male and 10 female
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: In a previous 14-day oral dose study in rats at initial doses of 100 and 1000 mg/kg/day, there was an average decreased weight gain for the males and slight weight loss for the females dosed at 1000 mg/kg/day on Day 2. After 4 days of dosing at 1000 mg/kg/day, two of six animals (1 male and 1 female) were in poor condition that included decreased activity, irregular breathing and irregular gait, and were subsequently euthanized. The remaining 2 per sex dosed at 1000 mg/kg/day were in normal health and were given a “dose holiday”. Of the remaining 2 per sex that were dosed at 1000 mg/kg/day, 2 males and 1 female were considered in
good health and after 3 days of “dose holiday” resumed dosing for 7 days at 500 mg/kg/day. The animals dosed for 7 days at 500 mg/kg/day and the animals dosed for 14 days at 100 mg/kg/day were in good health at the end dosing. Based on the results of the previous study, the dose levels for this study are 50, 150 and 500 mg/k/day.
Parental animals: Observations and examinations:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly


OTHER:
- Estrous Cycling - Females were evaluated prior to treatment for estrous cyclicity so that animals that failed to exhibit a typical 4 to 5-day cycle could be excluded from the study. Normally cycling F0 females (demonstrating 4 to 5 days cyclicity) were selected for each dose group

- Cohabitation (Mating) - Within each treatment group, the F0 male and female rats were co-housed (1:1 in the male’s cage) until evidence of mating was seen or until 14 consecutive days of cohabitation had elapsed. Female rats were observed each morning for the presence of a vaginal plug or sperm in the
vaginal smear. If not mated, the stage of the estrous cycle was recorded. The day on which evidence of mating was observed was defined as Day 0 of presumed gestation (GD 0). Once mated, the female rat was removed from the mating cage and housed individually until delivery. Presumed pregnant dams that did not deliver litters were euthanized on presumed GD 25.
After 14 consecutive days of cohabitation with no positive signs of mating, the pairing (with identified male and female) was deemed “unsuccessful” upon review of the estrous cycle for that female. The female was placed with a second suitable co-group male that had already successfully mated. The female remained with this second male until positive evidence of mating was detected or for a maximum of 7 days.
In the absence of positive signs of mating during the second pairing, the morning of the last day of cohabitation was considered “presumed GD 0” for that female. If the presumed pregnant dam did not appear visibly/palpably pregnant, she was euthanized on presumed GD 25.

- Parturition and Lactation - On GD 18, several days prior to expected parturition, examination for signs of parturition was performed twice daily (morning and afternoon). Whenever possible a female that was in the process of delivery was not disturbed. Dosing and other activities (e.g., detailed physical observations and body weights) were not performed during parturition. The day on which parturition was observed as completed was defined as LD 1 (dams) and is equivalent to PND 1 (pups).
Oestrous cyclicity (parental animals):
Vaginal smears were obtained daily from each F0 female pretest (to determine suitability for study) and during the pre-cohabitation and cohabitation phases until mating was confirmed and the stage of estrous was determined.
Vaginal smears recorded for the F0 female rats prior to treatment are not reported.
Litter observations:
Litters were observed as soon as possible after completion of parturition for the number of live and dead pups, runts and pup abnormalities and the sex of each pup. Thereafter, litters were observed twice daily (morning and afternoon); all pups in the litter were uniquely identified by tattoo after parturition was completed. Because the litters were not culled, the full number of pups remained in each litter. The presence of dead pups was recorded and these were removed from the litter as found and necropsied.
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: Necropsy was performed on 10 F0 males/group after males had been treated for 5 weeks.
- Maternal animals: Necropsy was performed on up to 10 F0 females in Groups 1 and 2 on LD 14.

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations. Special attention was paid to the organs of the reproductive system.

HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table 1 were prepared for microscopic examination and weighed, respectively.
Postmortem examinations (offspring):
GROSS NECROPSY
- Macroscopic post-mortem examinations (external only) were performed on all surviving F1 pups on PND 13. Particular attention was paid to the external reproductive genitals which were examined for signs of altered development. Unusual observations, including gross abnormalities were noted and then the carcasses were discarded. F1 pups that died during the study were given a macroscopic postmortem examination. Particular attention was paid to the external reproductive genitals which were examined for signs of altered development. Unusual observations and the absence of milk in the stomach (up to PND 2), including gross abnormalities were noted.

HISTOPATHOLOGY / ORGAN WEIGTHS
- The thyroid gland from one randomly selected male and female F1 pup per litter for all groups that littered was removed, fixed, weighed and stored in 10% neutral buffered formalin and processed for histopathology.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
There were test item-related clinical observations during postmating for males and gestation for females at 500 mg/kg/day Fatty Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin.
Similar clinical signs (abnormal gait and flattened posture) were noted for both sexes. However, these signs presented earlier in the majority of the males (Postmating Days 6 - 8) compared to the females (Gestation Days 23 – 25).
There were no test item-related clinical observations during the following phases: precohabitation (both sexes), cohabitation (both sexes), and lactation (females only).
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
There were test item-related decreases in body weight changes in males and females at 500 mg/kg/day and 150 mg/kg/day Fatty Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin, respectively.
In the males, the decrease in body weight change (-0.44% of the respective control). was noted during the mating phase from Days 7 - 14. In the females, the maximal decrease of -78% of the respective control value was noted during the gestation phase for the GD 14 – 20 interval.
There were no test item-related decreases in body weight or body weight change at 50 mg/kg/day (both sexes) or 150 mg/kg/day (males) or 500 mg/kg/day (females).
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
There were test item-related effects on male food consumption during the postmating phase in the 500 mg/kg/day Fatty Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin group and on female food consumption during lactation in the 50 mg/kg/day Fatty Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin group (the highest dose group that delivered).
Male food consumption was reduced (87.5% of the control group value) during the postmating phase in the 500 mg/kg/day Fatty Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin group.
Food consumption during the gestation phase in the 150 mg/kg/day female group were slightly but not adversely reduced when compared with control group values. Food consumption during the lactation phase in the 50 mg/kg/day female group were significantly reduced on LDs 1 to 7 and LDs 7 to 14 when compared with control group values. The 150 and 500 mg/kg/day Fatty Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin female group food consumption could not be evaluated during the lactation phases due to none of the females having delivered.
Food consumption in the 50, 150 and 500 Fatty Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin male and female groups were comparable with control group values during Precohabitation.
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
Grip Strength:
Males: There were test item-related statistically significant reductions in hindlimb grip strength (68% ofthe control group value) in the male (Week 5) 500 mg/kg/day Fatty Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin group. There were non-adverse reductions in hindlimb grip strength in the male 50 and 100 mg/kg/day Fatty Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin groups. The reductions were 74.9% and 72.6% in the respective groups. Due to limited number of animals and the inherent variability in this parameter, the statistically significant value was considered non-adverse.
There was a non-adverse reduction in forelimb grip strength (89.8% of the control group value) in the male (Week 5) 500 mg/kg/day Fatty Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin group. There were slight non-adverse increases in hindlimb grip strength in the male 50 and 100 mg/kg/day Fatty Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin groups.
Females: There were no test item-related effect in forelimb grip strength in the female (LD 8) 50 mg/kg/day Fatty Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin group. There was a non-adverse reduction in hindlimb grip strength (88.0% of the control group value) in the female

Motor Activity:
There were no treatment relate effects on horizontal or vertical motor activity in the males (Week 5) at ≤ 500 mg/kg/day Fatty Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin and in females (LD8) at 50 mg/kg/day Fatty Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Microscopic findings related to fatty acids, c18-unsatd., dimers, polymers with epichlorohydrin were observed in the uterus/cervix, and vagina at ≥50 mg/kg/day, prostate gland at ≥50 mg/kg/day, epididymides at 500 mg/kg/day, and liver at ≥50 mg/kg/day.
Female reproductive tract
Epithelial hyperplasia/hypertrophy (minimal) of the vagina and/or uterus/cervix was observed in female rats at ≥50 mg/kg/day. Epithelial hyperplasia/hypertrophy was characterized by increased numbers of luminal and glandular (uterus) cell layers. Epithelial hyperplasia/hypertrophy in the vagina sometimes occurred with mucification, in which epithelial cells were enlarged with mucin-filled vacuoles, and extracellular mucous within the vaginal lumen.
Male reproductive tract
Atrophy (minimal to slight) of the prostate was observed in male rats at 500 mg/kg/day. Atrophy was characterized by reduced acinar/vesicle lumina with decreased acinar secretory material and crowding of intra-acinar/vesicle epithelial folds. Atrophy of the epididymides was observed in male rats at 500 mg/kg/day. Epidydimal atrophy was characterized by smaller ductal lumina containing reduced sperm content and germ cells and/or cellular debris.
Reproductive function: oestrous cycle:
effects observed, treatment-related
Description (incidence and severity):
There were test item-related alterations of Estrous Cyclicity at 150 and 500 mg/kg/day Fatty
Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin.
The number of animals with irregular cycles (cycles ≤ 2 days or ≥ 6 days duration) during
precohabitation were increased in the 150 and 500 mg/kg/day of Fatty Acids, C18-Unsatd.,
Dimers, Polymers with Epichlorohydrin groups and the 500 mg/kg/day of Fatty Acids, C18-
Unsatd., Dimers, Polymers with Epichlorohydrin group had extended estrous and a female that
was acyclic.
The number of cycles were slightly reduced and the cycle durations were slightly increased in
the 50, 150 and 500 mg/kg/day of Fatty Acids, C18-Unsatd., Dimers, Polymers with
Epichlorohydrin groups, however these were considered non-adverse.
Reproductive performance:
effects observed, treatment-related
Description (incidence and severity):
There were test item-related reductions in the pregnancies and in the resultant male and female
fertility indices in the 150 and 500 mg/kg/day of Fatty Acids, C18-Unsatd., Dimers, Polymers
with Epichlorohydrin groups as well as reduced number of pregnant females. There were no
pregnant animals in the 150 or 500 mg/kg/day of Fatty Acids, C18-Unsatd., Dimers, Polymers
with Epichlorohydrin groups.
There were 10 females paired with 10 males in each group. Of these, 10, 10 10 and 9 females
mated in the 0 (corn oil), 50, 150 and 500 mg/kg/day of Fatty Acids, C18-Unsatd., Dimers,
Polymers with Epichlorohydrin groups. Of those that females that mated, 10, 7, 2 and 0 females
in the respective groups were presumed pregnant. However there were 3, 10 and 10 females that
failed to litter in the 50, 150 and 500 mg/kg/day of Fatty Acids, C18-Unsatd., Dimers, Polymers
with Epichlorohydrin groups. Of those females that were pregnant, 10 and 7 females delivered
live pups in the 0 (corn oil) and 50 mg/kg/day of Fatty Acids, C18-Unsatd., Dimers, Polymers
with Epichlorohydrin groups. The male and female mating indices were 100, 100, 100 and 90%
in the respective groups. The male and female fertility indices were 100, 70, 20 and 0% in the
respective groups.
Key result
Dose descriptor:
LOAEL
Effect level:
50 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
organ weights and organ / body weight ratios
reproductive function (oestrous cycle)
reproductive performance
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
50 mg/kg bw/day (actual dose received)
System:
female reproductive system
Organ:
cervix
uterus
vagina
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
50 mg/kg bw/day (actual dose received)
System:
male reproductive system
Organ:
dorsolateral prostate gland
ventral prostate gland
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
Anogenital distance values for male pups was slightly but not statistically significantly decreased (94% of the control group value) in the 50 mg/kg/day of Fatty Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin group. Anogenital distance for female pups were comparable with the control group in the 50 mg/kg/day of Fatty Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin group. All male pups were examined for nipple retention, no male pups retained nipples
Mortality / viability:
mortality observed, treatment-related
Description (incidence and severity):
There were test item-related reductions in the litter viability at 50 mg/kg/day of Fatty Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin. (the highest dose that had litters). The number of implantation sites, pre-implantation losses and total live pups for the 50 mg/kg/day of Fatty Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin group were significantly reduced when compared with the concurrent control values while the post-implantation losses were reduced. The total of pups alive per litter on PND 1, 4, 7, 11 and 13 were significantly reduced in the 50 mg/kg/day of Fatty Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin group.
Body weight and weight changes:
no effects observed
Key result
Dose descriptor:
LOAEL
Generation:
F1
Effect level:
50 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
Key result
Reproductive effects observed:
yes
Lowest effective dose / conc.:
50 mg/kg bw/day (actual dose received)
Treatment related:
yes
Relation to other toxic effects:
reproductive effects in the absence of other toxic effects
Dose response relationship:
yes
Relevant for humans:
not specified
Conclusions:
There were test item-related clinical observations during postmating for males and gestation for females at 500 mg/kg/day Fatty Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin. Similar clinical signs (abnormal gait and flattened posture) were noted for both sexes. However, these signs presented earlier in the majority of the males (Postmating Days 6 - 8) compared to the females (Gestation Days 23 – 25).
There were test item-related decreases in body weight changes in males and females at 500 mg/kg/day and 150 mg/kg/day Fatty Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin, respectively. In the males, the decrease in body weight change (-0.44% of the respective control). was noted during the mating phase from Days 7 - 14. In the females, the maximal decrease of -78% of the respective control value was noted during the gestation phase for the GD 14 – 20 interval.
There were test item-related effects on male food consumption during the postmating phase in the 500 mg/kg/day Fatty Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin group and on female food consumption during lactation in the 50 mg/kg/day Fatty Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin group (the highest dose group that delivered). Male food consumption was reduced (87.5% of the control group value) during the postmating phase in the 500 mg/kg/day Fatty Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin group.
Food consumption during the lactation phase in the 50 mg/kg/day female group were significantly reduced on LDs 1 to 7 and LDs 7 to 14 when compared with control group values. The 150 and 500 mg/kg/day Fatty Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin female group food consumption could not be evaluated during the lactation phases due to none of the females having delivered.
There were test item-related alterations of Estrous Cyclicity at 150 and 500 mg/kg/day Fatty Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin.
The number of animals with irregular cycles (cycles ≤ 2 days or ≥ 6 days duration) during precohabitation were increased in the 150 and 500 mg/kg/day of Fatty Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin groups and the 500 mg/kg/day of Fatty Acids, C18- Unsatd., Dimers, Polymers with Epichlorohydrin group had extended estrous and a female that was acyclic.

There were test item-related reductions in the pregnancies and in the resultant male and female fertility indices in the 150 and 500 mg/kg/day of Fatty Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin groups as well as reduced number of pregnant females. There were no pregnant animals in the 150 or 500 mg/kg/day of Fatty Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin groups. There were 10 females paired with 10 males in each group. Of these, 10, 10 10 and 9 females mated in the 0 (corn oil), 50, 150 and 500 mg/kg/day of Fatty Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin groups. Of those that females that mated, 10, 7, 2 and 0 females in the respective groups were presumed pregnant. However there were 3, 10 and 10 females that failed to litter in the 50, 150 and 500 mg/kg/day of Fatty Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin groups. Of those females that were
pregnant, 10 and 7 females delivered live pups in the 0 (corn oil) and 50 mg/kg/day of Fatty Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin groups. The male and female mating indices were 100, 100, 100 and 90% in the respective groups. The male and female fertility indices were 100, 70, 20 and 0% in the respective groups.

There were test item-related reductions in the litter viability at 50 mg/kg/day of Fatty Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin. (the highest dose that had litters). The number of implantation sites, pre-implantation losses and total live pups for the 50 mg/kg/day of Fatty Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin group were significantly reduced when compared with the concurrent control values while the post-implantation losses were reduced. The total of pups alive per litter on PND 1, 4, 7, 11 and 13 were significantly reduced in the 50 mg/kg/day of Fatty Acids, C18-Unsatd., Dimers, Polymers with Epichlorohydrin group.

Oral gavage administration of fatty acids, c18-unsatd., dimers, polymers with epichlorohydrin at doses of 50, 150, and 500 mg/kg/day for up to 35-63 days was associated with test item-related epithelial hyperplasia/hypertrophy in the uterus/cervix and/or vagina at ≥50 mg/kg/day, atrophy in the prostate at ≥50 mg/kg/day, and/or atrophy in the epididymis at 500 mg/kg/day. Hepatocellular hypertrophy in the liver was present in males and females at ≥50 mg/kg/day.
In females and males, the administration of ≥50 mg/kg/day fatty acids, c18-unsatd., dimers, polymers with epichlorohydrin was considered adverse due to microscopic findings of epithelial hyperplasia/hypertrophy in the uterus/cervix and vagina associated with failure to litter in females and prostatic atrophy in males at this dose. Centrilobular hypertrophy was considered non-adverse due to minimal severity and the lack of any correlating clinical pathology findings.
In conclusion, based on the findings at 50 mg/kg/day, a NOAEL could not be determined in the current study.
Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
50 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Good

Justification for classification or non-classification

An NOAEL could not be determined as adverse effects were seen in reproductive organs at all dose levels. Due to the adverse effects noted the test substance is classified for reproductive toxicity. As human data is not available the test item is classified as category 1B according to CLP criteria.

Additional information