Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Data waiving (study scientifically not necessary / other information available): According to column 2 of REACH Annex VIII, the study does not need to be conducted if a pre-natal developmental toxicity study is available.

No studies regarding fertility of the substance are available, but for analogue substance no effects on reproductive organs were observed. Hence, there is currently no suspicion of Cytidine 3'-(dihydrogen phosphate) affecting fertility.

Link to relevant study records
Reference
Endpoint:
one-generation reproductive toxicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because a pre-natal developmental toxicity study is available
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
Study scientifically not necessary / other information available: In accordance with the Column 2 of REACH Annex VIII, the study does not need to be conducted because a pre-natal developmental toxicity study is available.
Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available

Effects on developmental toxicity

Description of key information

Based on the available data, the NOAEL of the test item is deemed to be 529 mg/kg bw/day:

- Read-across from supporting substance (structural analogue or surrogate). Source: Key study. The analogue substance Citicoline was found to have a NOAEL for maternal and developmental toxicity in rabbits of 800 mg/kg bw/day . Based on the read-across approach, the target substance has a NOAEL of 529 mg/kg bw/day for both maternal and developmental toxicity.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1995
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Principles of method if other than guideline:
- Principle of test: To provide general information concerning the effects of prenatal exposure on the pregnant test animal and on the developing organism.
- Short description of test conditions: Albino rabbits were administered orally at a dose of 800 mg/kg during the organogenesis phase (from 7th to 18th day of gestation). On day 29th, the animals were sacrificed and mothers and foetuses were examined.
- Parameters analysed / observed: Any signs of both maternotoxicity or embryotoxicity.
GLP compliance:
not specified
Limit test:
yes
Species:
rabbit
Strain:
not specified
Details on test animals or test system and environmental conditions:
Albino rabbits.
Route of administration:
not specified
Vehicle:
not specified
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
From 7th to 18th day of gestation
Frequency of treatment:
Daily
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
800 mg/kg bw/day (nominal)
No. of animals per sex per dose:
Not reported
Control animals:
yes, concurrent vehicle
Maternal examinations:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: No data

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 29, and the foetuses were removed for examination.
- Organs examined: No data

Fetal examinations:
Foetuses were removed for examination.
Clinical signs:
no effects observed
Description (incidence and severity):
No toxicity signs were observed on maternal animals.
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
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 specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
not specified
Number of abortions:
not specified
Pre- and post-implantation loss:
not specified
Total litter losses by resorption:
not specified
Early or late resorptions:
not specified
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not specified
Changes in number of pregnant:
not specified
Other effects:
not specified
Details on maternal toxic effects:
No signs of maternal toxicity were observed.
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 800 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
dead fetuses
gross pathology
mortality
necropsy findings
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
not specified
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
effects observed, treatment-related
Description (incidence and severity):
A slight delay in cranial osteogenesis was observed in 10% of treated fetuses.
Details on embryotoxic / teratogenic effects:
No signs of embriofoetal toxicity were observed.
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 800 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
reduction in number of live offspring
external malformations
skeletal malformations
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no
Conclusions:
Citicoline at 800 mg/kg bw did not exhibit neither maternal or foetal toxicity in rabbits. Therefore, the NOAEL for both maternal and developmental toxicity in rabbits is 800 mg/kg bw.
Executive summary:

A study was conducted to assess the potential teratogenic effects of citicoline. Albino rabbits were administered 0 (control) or 800 mg citicoline/kg bw per day on gestation days 7 to 18. The animals were killed on gestation day 29, and the foetuses were removed for examination. No signs of maternal or foetal toxicity were reported. Approximately 10% of the foetuses exposed to citicoline were reported to display a slight delay in cranial osteogenesis. However, this difference was not considered by the authors to represent an adverse effect of citicoline on organogenesis. Therefore, the NOAEL for both maternal and developmental toxicity in rabbits is 800 mg/kg bw.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
529 mg/kg bw/day
Study duration:
subacute
Species:
rabbit
Quality of whole database:
The study has a Klimisch score of 2.
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

Based on the available data, the NOAEL of the test item is deemed to be 529 mg/kg bw/day for developmental toxicity:

- Read-across from supporting substance (structural analogue or surrogate): Source: Key study. A developmental toxicity study was conducted to assess the potential teratogenic effects of citicoline. Albino rabbits were administered orally 0 (control) or 800 mg citicoline/kg bw per day on gestation days 7 to 18. The animals were killed on gestation day 29, and the foetuses were removed for examination. No signs of maternal or fetal toxicity were reported. Approximately 10% of the foetuses exposed to citicoline were reported to display a slight delay in cranial osteogenesis. However, this difference was not considered by the authors to represent an adverse effect of citicoline on organogenesis. Therefore, the NOAEL for both maternal and developmental toxicity in rabbits is 800 mg/kg bw/day. Based on the available information for the read-across approach, the target substance has a NOAEL of 529 mg/kg bw/day in rabbits.

Justification for classification or non-classification

Based on the available information (NOAEL estimated to be 529 mg/kg bw in rabbits), the substance is not classified for toxicity to reproduction in accordance with CLP Regulation (EC) No. 1272/2008.

Additional information