Registration Dossier

Administrative data

Description of key information

Tributyl citrate is non toxic if administered to animals via the most relevant routes. The substance therefore does not need to be classified for acute toxicity.
Acute toxicity: oral
1) Finkelstein (1959): LD50 (rat) > 30 mL/kg bw [=31.3 g/kg bw (= 30 cm³; based on density of 1.0432)]
2) Finkelstein (1959): LD50 (cat) > 50 mL/kg bw
Acute toxicity: dermal
2) A LD50 (rat) > 2000 mg/kg has been determined for ATEHC in a GLP test according to OECD 402. [Read-across data from acetyltri-2-ethylhexylcitrate (CAS 144-15-0)]

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well-documented publication which meets basic scientific principles
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
not specified
GLP compliance:
not specified
Test type:
other: no data
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
not specified
Route of administration:
oral: gavage
Vehicle:
not specified
Doses:
Single dosing with 10 - 30 mL/kg
No. of animals per sex per dose:
5 rats
Control animals:
not specified
Sex:
not specified
Dose descriptor:
LD50
Effect level:
> 30 mL/kg bw
Based on:
not specified

Shortly after the administration, the oily material began to leak from the rectum. The animals became somewhat sluggish, but recovered promptly, and in the following period of 3 weeks of observation showed no signs suggesting systemic toxicity. In view of the fact that the largest doses corresponded to approximately 2 liters of the material for an average human, it was clear that tributyl citrate by oral administration in rats was free of toxicity in terms of the general appearance of the animal. It did not seem profitable to extend this phase of the study of the acute effects.

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: other: EU-GHS
Conclusions:
LD50 (rat)> 30 mL/kg bw
Executive summary:

According to "Toxicology of the Citric Acid Esters: Tributyl Citrate, Acetyl Tributyl Citrate, Triethyl Citrate and Acetyl Triethyl Citrate" (Finkelstein M & Gold H, 1959) the acute oral toxicity of tributyl citrate was studied in 5 rats in the range of doses from 10 to 30 mL/kg administered by stomach tube.

Shortly after the administration, the oily material began to leak from the rectum. The animals became somewhat sluggish, but recovered promptly, and in the following period of 3 weeks of observation showed no signs suggesting systemic toxicity. In view of the fact that the largest doses corresponded to approximately 2 liters of the material for an average human (LD50 > 30 mL/kg), it was clear that tributyl citrate by oral administration in rats was free of toxicity in terms of the general appearance of the animal. It did not seem profitable to extend this phase of the study of the acute effects.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
31 300 mg/kg bw
Quality of whole database:
good quality

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
other justification
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2000-05-09 - 2000-06-19
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well documented GLP study
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
other: EEC Directive (67/548/EEC), 7th Amended Directive (92/32/EEC) & EEC Directive 93/21/EEC
Deviations:
not specified
Qualifier:
according to
Guideline:
other: GefahrstoffVerordnung (GefStofiV) of 29 September 1994 (BGB1.1, p. 2557)
Deviations:
not specified
Principles of method if other than guideline:
None
GLP compliance:
yes (incl. certificate)
Test type:
fixed dose procedure
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: male: 225 - 246 g; female: 168 - 182 g
- Housing: Before the animals arrived, the study room and cages were cleaned and disinfected. During the study, the room and cages were cleaned at regular intervals. The rats were housed individually in cages (Makrolon II).
- Diet (e.g. ad libitum): Pelleted diet, offered ad libitum
- Water (e.g. ad libitum): Tap water as for human consumption was continuously available ad libitum via drinking bottles.
- Acclimation period: 6 days (range finding); 8 days (main test)
- Other: Identification with coloured markings; cage labelled with sex, study no., date of study initiation

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3° C (monitored twice daily)
- Humidity (%): between 30 and 70 % (monitored twice daily)
- Air changes (per hr): Air was changed about 16 times per hour and filtered adequately.
- Photoperiod (hrs dark / hrs light): Artificial light was set to give a cycle of 12 hours light and 12 hours dark with light on at 7.00 a.m.
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Duration of exposure:
24 h
Doses:
2000 mg/kg
No. of animals per sex per dose:
5 male and 5 female animals
Control animals:
not required
Details on study design:
A single dermal administration of the undiluted test article was performed. Since the density of the liquid test article was 0.97 g/mL, the animals were administered a volume of 2.06 ml/kg body weight which corresponded to the dose of 2000 mg/kg. The test article was held in contact with the skin by an occlusive dressing using a 4 x 5 cm patch (filter paper), Leukosilk® and Elastoplast®. The exposure period was 24 h.
All animals were weighed before dosing and the individual doses expressed as ml/kg were adjusted according to the body weight.
Preliminary study:
There were no deaths in the preliminary study.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: after 24h and 14 d
Mortality:
No animal died during the course of the main test after the single dermal administration of 2000 mg/kg.
Clinical signs:
No abnormal clinical signs were observed.
Body weight:
There was no influence of the treatment on the body weight development in the male animals during the 14-day observation period.
In the female animals, a reduced body weight or a very slight weight gain was observed after the first week of treatment followed by a slight weight gain after the second week of treatment.
Gross pathology:
Gross pathological examinations at day 14 p.a. (terminal necropsy) revealed no test article-related findings. In one female animal, red discolouration of the thymus was observed.
Other findings:
Skin Reactions: Neither erythema nor oedema or other skin reactions were observed.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: other: EU-GHS
Conclusions:
LD50 (rat, after 24 h and 14 d) >2000 mg/kg
Executive summary:

The acute dermal toxicity of acetyltri-2 -ethylhexylcitrate (ATEHC) was assessed in a fixed dose procedure in one group of rats comprising 5 males and 5 females according to OECD 402 and EU method B.3 and in compliance with GLP (2000). On the basis of the range finding test, the animals were given a single dermal administration of the test substance at the dose of 2000 mg/kg. The skin was exposed to the test article for 24 h. Clinical observations were carried out at regular intervals during the 14-day observation period. Signs of erythema and oedema were evaluated once daily for 14 days. Body weights were determined immediately before treatment and on days 7 and 14 p.a. Gross pathological examinations were carried out at study termination on all animals and the following results were obtained: No animal died during the 14-day observation period, no abnormal clinical signs, neither signs of erythema nor oedema were observed. There was no influence of the treatment on the body weight development in the male animals during the 14-day observation period. In the female animals, reduced body weight and very slight to slight weight gain were recorded during the 14-day observation period. Gross pathological examinations on day 14 p.a. did not reveal test article-related findings in the rats. Since no deaths were caused in Wistar rats after the dermal treatment with the test substance at a dose of 2000 mg/kg, the LD50 values after 24 h and 14 days were as follows: Male and female > 2000 mg/kg.

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 acetyltri-2 -ethylhexylcitrate (ATEHC).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw
Quality of whole database:
good quality

Additional information

Acute oral toxicity:

The acute oral toxicity of tributyl citrate was studied in 5 rats in the range of doses from 10 to 30 mL/kg administered by stomach tube (Finkelstein & Gold, 1959). Shortly after the administration, the oily material began to leak from the rectum. The animals became somewhat sluggish, but recovered promptly, and in this ensuing period of 3 weeks of observation showed no signs suggesting systemic toxicity. In view of the fact that the largest doses corresponded to approximately 2 litres of the material for an average human (LD50 > 30 mL/kg), it was clear that tributyl citrate by oral administration in rats was free of toxicity in terms of the general appearance of the animal. It did not seem profitable to extend this phase of the study of the acute effects.

The acute oral toxicity of tributyl citrate was also studied in 3 cats by single dosing via feed with 30 -50 mL/kg bw. Additional test was made in one cat: It received 50 mL/kg bw of the test substance by stomach tube.

The animals showed signs of slight nausea, and within a few hours they developed a diarrhoea with loosing of oily material from the rectum. The diarrhoea subsided in less than 24 hours in all but one (50 mL tributyl citrate per kg) in which some diarrhoea was still present on the following day. The animals were observed for periods up to 2 months. There were no signs of systemic tonicity as judged by the general appearance and behaviour of the animals. There were no appreciable changes in the general behaviour or appearance of the animals. Sixteen specimens of urine which were examined showed no abnormalities. It may also be noted that tributyl citrate produced no appreciable changes in the blood count or blood chemistry. The LD50 in cats has been determined to be > 50 mL/kg.

Acute dermal toxicity:

The acute dermal toxicity of acetyltri-2 -ethylhexylcitrate (ATEHC) was assessed in a fixed dose procedure in one group of rats comprising 5 males and 5 females according to OECD 402 and EU method B.3 and in compliance with GLP (Bien, 2000). On the basis of the range finding test, the animals were given a single dermal administration of the test substance at the dose of 2000 mg/kg. The skin was exposed to the test article for 24 h. Clinical observations were carried out at regular intervals during the 14-day observation period. Signs of erythema and oedema were evaluated once daily for 14 days. Body weights were determined immediately before treatment and on days 7 and 14 p.a. Gross pathological examinations were carried out at study termination on all animals and the following results were obtained: No animal died during the 14-day observation period, no abnormal clinical signs, neither signs of erythema nor oedema were observed. There was no influence of the treatment on the body weight development in the male animals during the 14-day observation period. In the female animals, reduced body weight and very slight to slight weight gain were recorded during the 14-day observation period. Gross pathological examinations on day 14 p.a. did not reveal test article-related findings in the rats. Since no deaths were caused in Wistar rats after the dermal treatment with the test substance at a dose of 2000 mg/kg, the LD50 values after 24 h and 14 days were as follows: Male and female > 2000 mg/kg. 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 acetyltri-2 -ethylhexylcitrate (ATEHC).

Taking all these result into account, it can be concluded that tributyl citrate is non toxic if administered to animals via the most relevant routes.


Justification for selection of acute toxicity – oral endpoint
Well-documented publication which meets basic scientific principles.

Justification for selection of acute toxicity – inhalation endpoint
Inhalation is not a relevant route of exposure, oral and dermal route are the main routes of possible exposure.

Justification for selection of acute toxicity – dermal endpoint
GLP and guideline study with the structural analogue ATEHC.

Justification for classification or non-classification

Acute oral toxicity:

The test material does not meet the criteria for classification and will not require labelling for oral toxicity in accordance with European Regulation (EC) No. 1272/2008.

Acute dermal toxicity:

There is only old data available for acute toxicity potential of tributyl citrate. Therefore, the data for its structural analogue tris (2 -ethylhexyl)-O-acetylcitrate is taken into account to assess the toxicity level.

The test material does not meet the criteria for classification and will not require labelling for dermal toxicity in accordance with European Regulation (EC) No. 1272/2008. As the substance tributyl citrate (CAS 77-94-1) is a near analogue to acetyltri-2 -ethylhexylcitrate (ATEHC) it can be considered to be also not classified.