Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
fertility, other
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Data have been obtained by a secondary source (RTECS database) and it was not possible to assess the quality of the original source.
Qualifier:
no guideline available
Principles of method if other than guideline:
Not specified.
GLP compliance:
not specified
Species:
rat
Strain:
not specified
Sex:
male/female
Route of administration:
oral: unspecified
Type of inhalation exposure (if applicable):
other: not applicable
Vehicle:
not specified
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Males: 1 day pre-mating
Females: from day 15 to day 22 of pregnancy
Lacting females: 21 days post-birth
Frequency of treatment:
No data
Details on study schedule:
No data
No. of animals per sex per dose:
No data
TDLo: 100 mg/kg bw for parent males.
TDLo: 3480 mg/kg bw for parent females.
The numerical dose data is a cumulative amount over the duration of the study.
Dose descriptor:
other: TDLo
Effect level:
100 mg/kg bw (total dose)
Based on:
not specified
Sex:
not specified
Basis for effect level:
other: Fetal death. The total dose amount that was administered to the exposed parent (male for 1 day) is given.
Remarks on result:
other: Generation: fetus (migrated information)
Dose descriptor:
other: TDLo
Effect level:
3 480 mg/kg bw (total dose)
Based on:
not specified
Sex:
not specified
Basis for effect level:
other: Effects on Newborn: Growth statistics (e.g., reduced weight gain). The total dose amount that was administered to the exposed parent (female 15-22 days pregnancy and 21 days post-birth) is given.
Remarks on result:
other: Generation: newborn (migrated information)
Reproductive effects observed:
not specified
Conclusions:
The TDLo for fetol death of chenodeoxycholic acid is 100 mg/kg bw (total dose) for parent males and 3480 mg/kg bw (total dose) for parent females.
Executive summary:

After one oral administration of chenodeoxycholic acid to males per-mating, the TDLo for fetal death is 100 mg/bw (total dose) for parent males, while after oral administration to pregnant rats from day 9 to day 14 of pregnancy, and after 21 days post-birth, the TDLo for effects on newborn (growth statistics, like reduced weight gain) is 3480 mg/kg bw (total dose).

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
100 mg/kg bw/day
Species:
rat
Quality of whole database:
Not many studies are available regarding toxicity to fertility, however an increase in fetal death or in post-implantation mortality have been observed also in developmental studies.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Quality of whole database:
Exposure of humans via inhalation is unlikely and not significant. The substance is solid with very low vapor pressure and it is only
used at industrial sites by trained workers, under operative conditions not forming aerosols and dusts and under specific risk control
measures (as described in the Exposure Scenarios).
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Exposure of male rats to 100 mg/kg bw of chenodeoxycholic acid produced fetal death, while exposure of female rats to chenodeoxycholic acid from day 15 to day 22 of pregnancy and for 21 days of lactation affected growth statistics in newborns (eg. reduced weight gain, ...). The calculated LOAEL for females was estimated at 120 mg/kg bw/day. Results of the QSAR study confirmed the concern related to reproduction toxicity of chenodeoxycholic acid.


Justification for selection of Effect on fertility via oral route:
Although the original report is not availbale, the toxicological database reporting the information is well recognized.

Justification for selection of Effect on fertility via dermal route:
Exposure of humans via dermal route is unlikely and not significant. The substance is only used at industrial sites by trained
workers, wearing suitable protective gloves and clothes, under specific risk control measures (as described in the Exposure
Scenarios).

Effects on developmental toxicity

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Data have been obtained by a secondary source (RTECS database) and it was not possible to assess the quality of the original source.
Qualifier:
no guideline available
Principles of method if other than guideline:
No method reported.
GLP compliance:
not specified
Species:
rabbit
Strain:
not specified
Route of administration:
oral: unspecified
Type of inhalation exposure (if applicable):
other: not applicable
Vehicle:
not specified
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
Not available
Duration of treatment / exposure:
Females: fom day 6 to day 18 of pregnancy.
Frequency of treatment:
Not available
Duration of test:
Not available
No. of animals per sex per dose:
Not available
Details on maternal toxic effects:
Maternal toxic effects:no data
Dose descriptor:
other: TDLo
Effect level:
260 mg/kg bw (total dose)
Based on:
no data
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Specific Developmental Abnormalities. Musculoskeletal system.
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
The TDLo for developmental effects of chenodeoxycholic acid in rabbits isre 260 mg/kg bw (total dose).
Executive summary:

After oral administration of chenodeoxycholic acid to female rabbits from day 6 to day 18 of pregnancy, the TDLo for developmental effects is 260 mg/kg bw (total dose).

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
21 mg/kg bw/day
Species:
rabbit
Quality of whole database:
Although the reliability of the studies was not possible to assess, the studied are reported by a well recognized toxicological database and similar effects have been reported by differt authors in different studies.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Quality of whole database:
Exposure of humans via inhalation is unlikely and not significant. The substance is solid with very low vapor pressure and it is only
used at industrial sites by trained workers, under operative conditions not forming aerosols and dusts and under specific risk control
measures (as described in the Exposure Scenarios)..
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Quality of whole database:
Exposure of humans via dermal route is unlikely and not significant. The substance is only used at industrial sites by trained
workers, wearing suitable protective gloves and clothes, under specific risk control measures (as described in the Exposure
Scenarios).
Additional information

Developmental studies on rats, rabbits and monkeys are available. While in rats and rabbits developmental abnormalities in musculoskeletal system have been reported, in rats and mainly in monkeys specific developmental abnormalities in hepatobiliary (in both species), endocrine and urogenital systems (only in monkeys) have been observed. Al toxicity values (TDLo or lowest toxic dose) have been reported as cumulative doses, therefore the toxic doses per day have been estimated dividing the cumulative TDLo by the amont of days of exposure. In the absence of other information, the obtained values have been considered as LOAELs (Lowest Observed Adverse Effect Levels). Rabbits showed the lowest toxic dose (about 21 mg/kg bw/day), however the other toxicity values in rats ranged from 55 mg/kg bw/day to 137 mg/kg bw/day, while toxicity values in monkeys were all calculated to be about 60 mg/kg bw/day.


Justification for selection of Effect on developmental toxicity: via oral route:
The selected study reports the lowest TDLo per day available. Other studies however confirm the concern regarding developmental effects of chenodeoxycholic acid.

Toxicity to reproduction: other studies

Additional information

In conclusion, effects on fertility and development realted to chenodeoxycholic acid have been observed. The main effects were developmental abnormalities in hepatobiliary, endocrine and urogenital systems, although also musculoskeletal abnormalities have been observed. Although the effects have been unequivocally observed, there is a reasonable uncertainty on the doses causing these effects, because only total toxic doses were available and LOAELs were therefore estimated dividing the total dose by the number of exposure days. Moreover, chenodeoxycholic acid is an endogenous substance in humans, and therefore it is not expected to be a substance of concern.

Justification for classification or non-classification

Basing on the overall data, the uncertainty on the derived LOAELs and according to Regulation 1272/2008/EC, chenodeoxycholic acid was not classified.