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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2001 - 2002
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to Guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2003
Report date:
2003

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:
yes
Remarks:
Range-finding study: Only limited histopathology performed and no special neurotoxicity examination included
Principles of method if other than guideline:
Range-finding study: Only limited histopathology performed and no special neurotoxicity examination included
GLP compliance:
no
Remarks:
no GLP required (range-finding study for long-term toxicity)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Tributyl O-acetylcitrate
EC Number:
201-067-0
EC Name:
Tributyl O-acetylcitrate
Cas Number:
77-90-7
Molecular formula:
C20H34O8
IUPAC Name:
tributyl 2-acetoxypropane-1,2,3-tricarboxylate
Test material form:
other: liquid
Details on test material:
Name of test material (as cited in study report): ATBC
Substance type: pure active
Physical state: liquid

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
Daily via the diet
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 96.02, 287.50 and 961.16 mg/kg
Basis:
actual ingested
No. of animals per sex per dose:
10 m / 10 f
Control animals:
yes, plain diet

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
Observation for mortality/viability were recorded twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
Time schedule: At least once daily. Palpation for tissue masses were performed at least once weekly

BODY WEIGHT: Yes
Time schedule for examinations: Weekly during pre-test, treatment and before necropsy

FOOD CONSUMPTION AND COMPOUND INTAKE:
Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day

FOOD EFFICIENCY: no

WATER CONSUMPTION AND COMPOUND INTAKE: no

OPHTHALMOSCOPIC EXAMINATION: Yes
Time schedule for examinations: During acclimatization and during week 13
Dose groups that were examined: All groups during acclimatization and all animals of the control and high dose group during week 13

HAEMATOLOGY: Yes
Time schedule for collection of blood: week 13 weeks
Anaesthetic used for blood collection: yes (light isoflurane anaesthesia)
Animals fasted: Yes
How many animals: all (10 m / 10 f per group)
Parameters examined: Erythrocyte count, haemoglobin, haematocrit, MCV, RDW, MCH, MCHC, HDW, reticulocyte, reticulocyte maturity index, leukocyte count, differential leukocyte count, prothrombin time, partial thromboplastin time

CLINICAL CHEMISTRY: Yes
Time schedule for collection of blood: week 13
Animals fasted: Yes
How many animals: all (10 m / 10 f per group)
Parameters examined: Glucose, urea, creatinine, bilirubin (total), cholesterol, tryglicerides, phospholipides, ASAT, ALAT, LDH, CK, ALP, GGT, Sodium, potassium, chloride, calcium, inorganic phosphorus, protein (total), albumin, globulin, albumin/globulin ration

URINALYSIS: no

NEUROBEHAVIOURAL EXAMINATION: no
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, all organs, all groups
HISTOPATHOLOGY: Yes.
Statistics:
Dunnett-test (many to one t-test) based on a pooled variance estimate if variables can be assumed to follow a normal distribution
Steel-test (many-one rank test) was applied instead of the Dunnett-test when data were not assumed to follow a normal distribution
Fisher's exact test was applied for ophthalmoscopic data and macroscopic findings
Armitage/Cochran Trend Test was used for non-neoplastic lesions, if appropriate

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL CHEMISTRY
In m and f at 1000 mg/kg bw/day, decreased bilirubin levels, decreased aspartate aminotransferase and lactate dehydrogenase activity, increased sodium level, decreased chloride and calcium levels, decreased globulin levels (which resulted in increased albumin/globulin ratio) were evident in m at 300 and 1000 mg/kg bw/d

ORGAN WEIGHTS
1000 mg/kg: increased liver weights in m and f

GROSS PATHOLOGY
1000 mg/kg: enlarged livers in 2 f

HISTOPATHOLOGY: NON-NEOPLASTIC
1000 mg/kg: minimal hepatocellular hypertrophy (non-adverse) in several animals

Effect levels

Dose descriptor:
NOAEL
Remarks:
1000 mg/kg bw/day
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
other: actuel ingested
Sex:
male/female
Basis for effect level:
other: see 'Remark'

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Table: Summary of test item-related findings for ATBC

 

Intended test item intake (mg/kg bw/day)

0

100

300

1000

 

 

 

 

 

Clinical chemistry

Males (means)

 

 

 

 

Glucose (mmol/L)

4.886

6.124**

5.895**

5.784*

Bilirubin (µmol/L)

2.055

1.955

1.767

1.305**

ASAT (U/L)

82.37

76.37

71.90**

66.08**

LDH (U/L)

136.50

120.88

92.29**

91.27**

Sodium (mmol/L)

144.58

145.00

154.52**

153.72**

Chloride (mmol/L)

100.94

101.33

89.18**

89.25**

Calcium (mmol/L)

2.834

2.811

2.666**

2.694**

Globulin (g/L)

26.356

26.474

24.431**

24.123**

Alb/Glob ratio (rel, %)

1.590

1.640

1.727*

1.755**

 

 

 

 

 

Females (means)

 

 

 

 

Bilirubin (µmol/L)

2.795

2.346

2.057

1.642**

 

 

 

 

 

Organ weights

Liver (means)

 

 

 

 

Males (abs., gram)

8.83

9.30

9.58

10.86**

Males (rel., %)

2.34

2.38

2.51

2.86**

 

 

 

 

 

Females (abs., gram

5.88

6.12

5.80

7.10**

Females (rel., %)

2.65

2.71

2.76

3.03*

 

 

 

 

 

Macroscopic findings

Liver (no. affected/10)

0/10

0/10

0/10

2/10

Females: Enlarged

 

 

 

 

Histopathology

Liver (no. affected/10)

 

 

 

 

Males: Hepatocellular hypertrophy

1/10

0/10

6/10

5/10

Females: Hepatocellular hypertrophy

0/10

0/10

1/10

2/10

 

  • * = 5% level (Anova and/or Dunnett-Test)
  • ** = 1% level (Anova and/or Dunnett-Test)

 

Applicant's summary and conclusion

Conclusions:
Based on the results of this study, dose levels of 100, 300 and 1000 mg/kg bw/d were proposed for the subsequent 2-year combined chronic/carcinogenicity study. Slight effects seen at 1000 mg/kg bw/d were considered due to hepatic metabolism adaption. Thus the NOAEL for m and f in this study was given with 1000 mg/kg bw/d
Executive summary:

This 13-weeks dietary toxicity study with acetyl tributyl citrate (ATBC) in Wistar rats was designed as dose range finding study for a subsequent combined chronic/carcinogenicity study. In principle, the study was performed according to OECD Guideline 408, but with restricted histopathological organ examinations. The administration at target doses of 100, 300 and 1000 mg/kg bw/d resulted in no unscheduled deaths. No test item-related clinical signs were observed. Treatment-related findings were restricted to slight changes in clinical biochemistry (males were more affected than females) and slightly increased liver weights accompanied by minimal hepatocellular hypertrophy at 1000 mg/kg bw/d. The findings were considered to be due to hepatic metabolic adaption rather than as sign of toxicity. The highest dose of 1000 mg/kg bw can be regarded as NOAEL. The proposed dose levels for a subsequent combined chronic/carcinogenicity study were 100, 300 and 1000 mg/kg bw/d. 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.