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Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
toxicity to reproduction
Data waiving:
other justification
Justification for data waiving:
other:
Reproductive effects observed:
not specified
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
Additional information

This endpoint is waived due to the low toxicity potential of tributyl citrate.


Short description of key information:
This endpoint is waived due to the low toxicity potential of tributyl citrate.

Justification for selection of Effect on fertility via oral route:
Based on the available toxicity data for the substance and its structural analogues, adverse effects concerning toxicity to reproduction are not to be expected and therefore no further study is needed.

Justification for selection of Effect on fertility via inhalation route:
Inhalation is not a relevant route of exposure. Further, based on the available toxicity data for the substance and its structural analogues, adverse effects concerning toxicity to reproduction are not to be expected and therefore no further study is needed.

Justification for selection of Effect on fertility via dermal route:
Based on the available toxicity data for the substance and its structural analogues, adverse effects concerning toxicity to reproduction are not to be expected and therefore no further study is needed.

Effects on developmental toxicity

Description of key information
1) From a 12-months oral study with cross over mating after 9 months in rats NOEL values for maternal toxicity and developmental toxicity were given with 50 and 250 mg/kg, respectively (Larionov AG & Cherkasova TE, 1977). [Read-across data from tributyl-O-acetylcitrate (CAS 77-90-7)]
2) From a 12-months oral study with cross over mating after 9 months in mice NOEL values for maternal toxicity and developmental toxicity were given with 50 and 250 mg/kg, respectively (Larionov AG & Cherkasova TE, 1977). [Read-across data from tributyl-O-acetylcitrate (CAS 77-90-7)]
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Data are reliable but reference lacks details
Qualifier:
no guideline followed
Principles of method if other than guideline:
Groups of animals were provided feed containing a milk solution of the test substance (ATBC) at doses of 50 and 250 mg/kg for 12 months
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
not specified
Details on test animals and environmental conditions:
TEST ANIMALS
Diet (e.g. ad libitum): ad libitum
Water (e.g. ad libitum): ad libitum
Route of administration:
oral: feed
Vehicle:
not specified
Details on exposure:
Groups of animals were provided feed containing a milk solution of the test substance (ATBC) at doses of 50 and 250 mg/kg for 12 months
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
In the 9th month of the study, a cross-mating of the animals was performed, male gonads were evaluated and embryotoxic effects were examined. The following indicators of embryotoxic effects were evaluated:
early and late embryonic death (determined by examining the numbers of corpora lutea and implantation sites)
number of normal, resorptive and deformed tissues
Duration of treatment / exposure:
12 months
Frequency of treatment:
continuously via diet
Duration of test:
12 months
Remarks:
Doses / Concentrations:
50 or 250 mg/kg
Basis:
nominal in diet
No. of animals per sex per dose:
1 replicate per dose, rest not reported
Control animals:
yes, concurrent no treatment
Maternal examinations:
Clinical signs, mortality, size and weight of the placenta
Fetal examinations:
early and late embryonic deaths (examining the numbers of corpora lutea and implantation sites)
number of normal, resorptive and deformed tissues
length of newborns
ear and eye openings, appearance of body hair and teeth, behaviour; and body weight
Statistics:
Not reported
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
50 mg/kg: no adverse effects
250 mg/kg: increases in body weight, length of the progeny and placental weight
No differences concerning fertility rate and number of pups born/pregnant female.
There were no significant effects on male gonads and at 250 mg/kg the spermatogenesis index was comparable with controls.
Dose descriptor:
NOEL
Effect level:
50 mg/kg bw/day (nominal)
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOEL
Effect level:
250 mg/kg bw/day (nominal)
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No adverse effects on eye and ear opening, body fur and incisor appearance.
No effects on behaviour and body weights.
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
Dosing with ATBC via diet over 12 months had no effects to male sexual cells, caused no embryotoxic effects and had no impact on the development in offspring.
Executive summary:
A Toxicological evaluation of Acetyltributylcitrate [Larionov AG & Cherkasova TE, 1977; cited in US EPA (2004) High Production Volume (HPV) Chemicals Challenge Program: Assessment of Data Availability and Test Plan for Acetyl Tributyl Citrate (ATBC) (CAS NR 77-90-7)] has been carried out as follows: Groups of rats were dosed with a milk solution of ATBC via diet at nominal doses of 50 and 250 mg/kg over 12 months. A cross-mating of the animals was performed. In the 9th month of the study, gonads were evaluated and the animals were evaluated for embryotoxic effects. The dosing caused no significant effects on male sexual cells, no embryotoxic effects and there also were no adverse effects on growth and foetal/litter development in the offspring. It can be assumed that the same applies to tributyl citrate (CAS 77-94-1) as it is a near analogue to the test substance acetyl tributyl citrate.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
250 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
good quality
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
A Toxicological evaluation of acetyltributylcitrate [Larionov & Cherkasova, 1977; cited in US EPA (2004) HPV Chemicals Challenge Program] has been carried out as follows: Groups of rats and mice were dosed with a milk solution of ATBC via diet at nominal doses of 50 and 250 mg/kg over 12 months. A cross-mating of the animals was performed. In the 9th month of the study, gonads were evaluated and the animals were evaluated for embryotoxic effects. The dosing caused no significant effects on male sexual cells, no embryotoxic effects and there also were no adverse effects on growth and foetal/litter development in the offspring. The NOEL values for maternal toxicity and developmental toxicity were given with 50 and 250 mg/kg, respectively. It can be assumed that the same applies to tributyl citrate (CAS 77-94-1) as it is a near analogue to the test substance acetyl tributyl citrate.

Justification for selection of Effect on developmental toxicity: via oral route:
Acceptable well documented publication which meets basic scientific principles (structural analogue ATBC).

Justification for selection of Effect on developmental toxicity: via inhalation route:
Inhalation is not a relevant route of exposure. No further studies are needed.

Justification for selection of Effect on developmental toxicity: via dermal route:
No further studies are needed. The feeding developmental study in rats is sufficient to cover possible effects after dermal exposure.

Justification for classification or non-classification

Developmental toxicity was not observed at dose levels up to 1000 mg/kg/day in a two-generation reproductive toxicity study nor in a 13-week toxicity study with an in utero exposure phase. The metabolites positively identified in the urine of rats have been demonstrated to undergo rapid clearance from the body and are not suspected to be developmental toxicants. Also several long-term studies gave no indications for adverse effects on reproductive organs. Therefore, there is no need for classification of ATBC. As the substance tributyl citrate (CAS 77-94-1) is a near analogue to ATBC it can be considered to be also not classified.