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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Test material form:
liquid

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on mating procedure:
Mating will be performed using a ratio of 1:1 (male to female) (if possible). The vaginal smear of the females will be checked every morning after the start of the mating period to confirm the mating. If the vaginal smear of a particular female is not found to be sperm-positive, the actual stage of the estrus cycle on that day will be documented. The day of the vaginal plug and/or sperm will be considered as day 0 of gestation.
The cages will be arranged in such a way that possible effects due to cage placement are minimised. In case of unsuccessful mating, re-mating of females with proven males of the same group can be considered.
Duration of treatment / exposure:
7 days per week for a maximum period of 63 days, i.e. during 14 days of pre-mating and maximum 14 days of mating in both males and females. Then in females, treatment will be done during the gestation period and up to post-natal day 12. Males will be dosed after the mating period until the minimum total dosing period of 28 days is completed.
Frequency of treatment:
7 days per week
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day (nominal)
Remarks:
LD
Dose / conc.:
300 mg/kg bw/day (nominal)
Remarks:
MD
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Remarks:
HD
No. of animals per sex per dose:
Group 1 (C, control): 0 mg/kg bw/day. 10 males and 10 females.
Group 2 (LD, low dose): 100 mg/kg bw/day. 10 males and 10 females.
Group 3 (MD, medium dose): 300 mg/kg bw/day. 10 males and 10 females.
Group 4 (HD, high dose): 1000 mg/kg bw/day. 10 males and 10 females.
Control animals:
yes, concurrent no treatment

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
In this study there were no clinical findings related to a systemic effect of the test item.
During the weekly detailed clinical observation, no significant changes or differences between the groups were found.
Female number 55 of the LD group was observed with the clinical findings of pale skin, hypothermia, half eyelid closure, moderate piloerection, and slow movements on post-natal day 0. However, these signs were not assumed to be test item-related but to be result of the abortion of pregnancy.
The finding of wound in two males of the HD group (male number 37: wound on snout, male number 40 wound on the head) were not considered to be test item-related.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One female of the LD group (No. 55) was euthanized on post-natal day 0 due to animal welfare reasons
Body weight and weight changes:
no effects observed
Description (incidence and severity):
The test item had no effect on body weight development in this study. Body weights of male and female animals were in the normal range of variation throughout the treatment period of this study
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
The test item had no effect on food consumption in this study. Mean daily food intake of male and female animals was in the normal range of variation throughout the treatment period of this study.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
The test item had no toxicologically relevant effect on haematology and blood coagulation parameters analysed at the end of the treatment period of this study.
Besides, all haematological parameters were within the normal range of historical data variation. Differences between the animals are due to the natural occurring inter-individual variation and are not assumed to be biologic ally relevant.
Blood coagulation was not affected by the test item as the individual values were within the normal range of variation for this strain
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
The test item had no toxicologically relevant effect on parameters of clinical biochemistry analysed at the end of the treatment period of this study.
All parameters of clinical chemistry were within the normal range of variation for this strain and without biological relevance.
Urinalysis findings:
effects observed, non-treatment-related
Description (incidence and severity):
The test item had no significant or toxicologically relevant effect on urinary parameters analysed at the end of the treatment period of this study.
One female of the MD group (number 24) showed an elevated level of erythrocytes in the urine. This was considered to be blood contamination during urine sampling and not related to treatment with the test item.
Further, one male of the LD group (number 59) was observed with a high level of ketones and one male of the MD group (number 68) showed a high level of protein in the urine. Both findings were considered to be incidental and not to be test item-related.
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
The test item had no toxicologically relevant effect on organ weights determined at the end of the treatment period of this study.
Mean pituitary weight was slightly higher in test item-treated males compared to the control group (deviation of LD from control: 13 %, deviation of MD from control: 38 %, deviation of HD from control: 27 %). Mean pituitary weight however, was slightly lower in females treated with TEA Trioleate compared to the corresponding control (deviation of LD from control: -17 %, deviation of MD from control: -24 %, deviation of HD from control: -16 %). As the effect on mean pituitary weight shows no dose-dependency and consistency between males and females, it is not assumed to be toxicologically relevant.
Mean thyroid/parathyroid weight was slightly higher in females of the MD group (deviation from control: 24 %) compared to the corresponding control group. However, this effect is not considered test item-related as mean thyroid/parathyroid weight was not affected in all other test item-treated groups.
Mean ovary weight was slightly lower in females of the HD group compared to the control group (deviation from control: 15 %). This difference is not assumed to be toxicologically relevant as female reproductive organs undergo variable inter-individual changes depending on the stage of the estrous cycle.
Slightly higher mean thymus weight of males of the HD group (deviation from control: 14 %) and slightly higher mean thymus weight of females of the LD group (deviation from control: 16 %) were considered as incidental and not related to treatment with the test item as this effect does not follow a dose-dependency and consistency when compared with respective control groups of males and females.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
No specific gross pathological changes were recorded for male and female animals, except for a few females which were not considered to be treatment-related.
Single findings like kidney cyst (MD male number 24), a mass in the abdominal cavity (MD female number 25), a red spotted thymus (LD female number 58), an abnormally colored pancreas (red; HD female number 73), and an abnormally colored pancreas (red) and an abnormally shaped papillary process of the liver (MD female number 68) were incidental and are not assumed to be related to treatment with the test item.
Female number 55 which was euthanized on post-natal day 0 with clinical signs of abortion was observed with an abnormal content (dark) in stomach, duodenum, jejunum, ileum, and cecum. Further, the uterus was found containing a placenta indicating the birth process of this animal. However, the findings observed in this single female were not considered to be test item-related.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
not specified

Effect levels (P0)

Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects treatment-related observed
Remarks on result:
not determinable due to absence of adverse toxic effects

Target system / organ toxicity (P0)

Critical effects observed:
no

Results: P1 (second parental generation)

General toxicity (P1)

Clinical signs:
not examined
Dermal irritation (if dermal study):
not examined
Mortality:
not examined
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not examined
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 specified
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined

Reproductive function / performance (P1)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
not examined

Effect levels (P1)

Remarks on result:
not measured/tested

Target system / organ toxicity (P1)

Critical effects observed:
no

Results: F1 generation

General toxicity (F1)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not examined
Mortality / viability:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
not examined
Other effects:
not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not examined

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects treatment-related observed
Remarks on result:
not determinable due to absence of adverse toxic effects

Target system / organ toxicity (F1)

Critical effects observed:
no

Results: F2 generation

General toxicity (F2)

Clinical signs:
not examined
Dermal irritation (if dermal study):
not examined
Mortality / viability:
not examined
Body weight and weight changes:
not examined
Food consumption and compound intake (if feeding study):
not examined
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
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined
Other effects:
not examined

Developmental neurotoxicity (F2)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F2)

Developmental immunotoxicity:
not examined

Effect levels (F2)

Remarks on result:
not measured/tested

Target system / organ toxicity (F2)

Critical effects observed:
no

Overall reproductive toxicity

Reproductive effects observed:
no

Applicant's summary and conclusion

Conclusions:
No treatment related effects were observed up the maximum dose tested. NOAEL >= 1000 mg/kg bw/day