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Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Study period:
1996
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable and well documented publication which meets basic scientific principles.
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1996

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Female rats were exposed by oral route to the trifluoroacetic acid during the gestation (from day 10 to day 20). On day 21, the delivery occured and then the pups were examined until day 49 postnatal (PND 49).
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Trifluoroacetic acid
EC Number:
200-929-3
EC Name:
Trifluoroacetic acid
Cas Number:
76-05-1
Molecular formula:
C2HF3O2
IUPAC Name:
trifluoroacetic acid
Details on test material:
- Name of test material (as cited in study report): Trifluoroacetic acid (TFAA)
- Physical state: no data
- Lot/batch No.: no data
- Expiration date of the lot/batch: no data
- Stability under test conditions: subsequent analyses by gas chromatography indicated that purity of the test chemicals remained stable over the course of the study.
- Storage condition of test material: no data
- Other: source: Aldrich Chemical Co, Saint Louis, USA

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: IFFA CREDO breeding laboratories (Saint Germain sur l’Arbresle, France)
- Age at study initiation: no data
- Weight at study initiation: male rats: 350 g, female rats: 200-220 g
- Housing: no data
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): no data
- Acclimation period: 1 or 2 weeks before breeding
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C (+/- 1°C)
- Humidity (%): 50% (+/- 5%)
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 hrs/ 12hrs
IN-LIFE DATES: From: To: no data

Administration / exposure

Route of administration:
oral: gavage
Type of inhalation exposure (if applicable):
other: not applicable
Vehicle:
water
Remarks:
distilled water
Details on exposure:
The actual volume administered (2mL/kg bw) was based on body weight taken on day 10 of gestation.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
not applicable
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: one male with 2 or 3 females
- Length of cohabitation: overnight
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility: no data
- Further matings after two unsuccessful attempts: no data
- Verification of same strain and source of both sexes: no data
- Proof of pregnancy: females were examined for vaginal smear on the following morning. Sperm-positive females were considered to be on gestation day 0 (GD 0).
- Any other deviations from standard protocol:
Duration of treatment / exposure:
10 days: TFAA was administered from GD 10 to GD 20.
Frequency of treatment:
daily
Duration of test:
no data
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 75 and 150 mg/kg/day
Basis:
nominal in water
No. of animals per sex per dose:
See details in Table 7.8.2/1
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
- Rationale for animal assignment (if not random): The gravide females were randomly assigned to treatment groups so that neam of body weights on GD 6 were the same across groups.
- Other: In parallel to the treatment with TFAA, halothane was adminsitered by inhalation route to other groups of gravide females.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: maternal animals exposed to TFAA were checked for delivery at 08.00 and 17.00 h, beginning on GD 21.
- Cage side observations checked were included.

DETAILED CLINICAL OBSERVATIONS: no data
- Time schedule:

BODY WEIGHT: Yes
- Time schedule for examinations: at GD 6, GD 10, GD 15 and GD 21

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No data
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations:

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day: no data
- Organs examined: liver and kidney weight, serum and urine analyses

OTHER:
Ovaries and uterine content:
not examined
Fetal examinations:
not examined
Statistics:
Student test
Indices:
no data
Historical control data:
no data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Maternal body weight change was significantly reduced at 150 mg/kg bw for GD 10-15.
Both absolute and relative (% bw) liver weights were significantly increased at both treatment levels (75 and 150 mg/kg/d). No meaningful differences in kidney weights or serum and urinary indicators or renal damage were observed between control and TFAA-treated rats. The statistically significant reductions od GGT excretion in the 75 and 150 mg/kg bw groups were considered to be biological variations and unrelated to treatment.
See details in Table 7.8.2/1 and Table 7.8.2/2

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
150 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Basis for effect level:
other: developmental toxicity
Remarks on result:
not determinable
Remarks:
no NOAEL identified

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Length of gestation, litter size and offspring survival in the first 3 days were not adversely affected by TFAA treatment. Slight but non-significant decreases in pup weights were observed in both TFAA-treated groups on postnatal day (PND) 1 and 3. External examination of the pups did not reveal any malformation. See details in table 7.8.2/1, 7.8.2/2 and 7.8.2/3.
There were significant increases in the activities of GLDH and ASAT on PND3. Elevations were dependent on the odse and were more potent for GLDH than ASAT. Serum urea concentration was significantly elevated at 150 mg/kg. There were no significant differences between control and treated groups in the glomerular filtration rate as measured by absolute creatinine clearance. There was a significant decrease in GGT excretion in the 150 mg/kg bw group. Urinary excretion of beta2-m showed a twofold increase at 150 mg/kg bw on PND3.
None of the serum and urinary parameters were affected on PND12 but by 49 days of age a statistically significant but biologically slight increase in beta2-m excretion was noted at 75 mg/kg bw. All other serum and urinary examination showed no treatment-related alterations in liver G-6-Pase activity or renal ALP activity.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Table 7.8.2/1: Effects of prenatal exposure to TFAA on maternal and offspring growth and viability

 

 

Dose of TFAA (mg/kg bw)

 

Gestational day (GD)

0

75

150

Number of female pregnant

 

40

40

38

Number of female pregnant that died during gestation

 

0

1

0

Maternal weight (g)

6

268 +/- 21

272 +/- 19

266 +/- 22

10

292 +/- 24

297 +/- 23

288 +/- 26

15

331 +/- 30

336 +/- 30

320 +/- 34

21

431 +/- 44

443 +/- 44

412 +/- 58

Maternal weight gain (g)

6-10

24 +/- 5

25 +/- 6

23 +/-5

10-15

39 +/- 8

39 +/- 9

32 +/- 13*

15-21

100 +/- 18

107 +/- 19

93 +/- 29

10-21

140 +/- 24

146 +/- 24

124 +/- 39

Length of gestation (d)

-

21.1 +/- 0.3

21.1 +/- 0.3

21.1 +/- 0.4

 

 

 

 

 

 

Postanatal day (PND)

0

75

150

Pups per litter

1

13.2 +/- 3.7

14.1 +/- 3.0

11.7 +/- 4.6

Percent surviving

3

98.45

95.83

95.60

Pup weight (g)

1

6.61 +/- 0.53

6.38 +/- 0.60

6.30 +/- 0.81

3

8.06 +/- 0.78

7.76 +/- 1.02

7.51 +/- 1.15

*: significant difference from control, P<0.05

Table 7.8.2/2:Maternal serum and urinary parameters following exposure to TFAA during pregnancy

 

Dose of TFAA (mg/kg bw)

 

0

75

150

Number tested

6

6

5

Body weight (g)

430 +/- 32

405 +/- 27

400 +/- 38

Absolute Liver weight (g)

12.79 +/- 1.31

15.79 +/- 1.80*

15.60 +/- 1.36*

Relative Liver weight (% of bw)

2.97 +/- 0.20

3.92 +/- 0.52*

3.94 +/- 0.61*

Absolute Kidney weight (g)

0.78 +/- 0.07

0.85 +/- 0.09

0.84 +/- 0.10

Relative Kidney weight (% of bw)

0.18 +/- 0.01

0.21 +/- 0.02

0.21 +/- 0.02

Serum GLDH (IU/L)

3.2 +/- 0.4

16.1 +/- 30.1

3.2 +/- 0.4

Serum ASAT (IU/L)

52 +/- 7

55 +/- 11

53 +/- 6

Serum Urea nitrogen (g/L)

0.39 +/- 0.03

0.37 +/- 0.07

0.34 +/- 0.02

Serum creatinine (mg/L)

7.1 +/- 0.4

6.8 +/- 0.5

6.5 +/- 0.8

Urine volume (mL)

5.9 +/- 2.2

9.6 +/- 3.0

10.1 +/- 3.6

Urine GGT (IU/17h)

2.0 +/- 0.8

0.9 +/- 0.3*

0.9 +/- 0.4*

Urine ALP (IU/17 h)

1.3 +/- 0.7

1.0 +/- 0.4

0.9 +/- 0.6

Urine beta2-m (µg/17h)

11.3 +/- 8.9

16.2 +/- 20.9

6.8 +/- 1.4

*: significant difference from control, P<0.05

Table 7.8.2/3: Serum and urinary parameters in 3-, 12- and 49- day-old rats prenatally exposed to TFAA

 

PND 3

PND 12

PND 49

 

Dose (mg/kg/bw)

Dose (mg/kg/bw)

Dose (mg/kg/bw)

 

0

75

150

0

75

150

0

75

150

Number of litter tested

11

11

10

8

8

8

5

5

5

Body weight (g)

8.0 +/- 0.3

7.7 +/- 0.5

7.5 +/- 0.5

22 +/- 2

21 +/- 2

21 +/- 1

14 +/- 7.5

13.3 +/- 6.9

13.6 +/- 7.0

Absolute Liver weight (g)

-

-

-

-

-

-

10.6 +/- 0.9

11.3 +/- 0.7

11.1 +/- 0.5

Relative Liver weight (% of bw)

-

-

-

-

-

-

0.41 +/- 0.03

0.38 +/- 0.01

0.39 +/- 0.02

Absolute Kidney weight (g)

-

-

-

-

-

-

0.88 +/- 0.02

0.88 +/- 0.06

0.86 +/- 0.05

Relative Kidney weight (% of bw)

-

-

-

-

-

-

0.41 +/- 0.03

0.38 +/- 0.01

0.39 +/- 0.02

Serum GLDH (IU/L)

31 +/- 15

126 +/- 65*

161 +/- 72*

18 +/- 5

15 +/- 4

14 +/- 3

4.2 +/- 0.6

5.0 +/- 0.3

5.3 +/- 1.4

Serum ASAT (IU/L)

188 +/- 29

238 +/- 27*

287 +/- 56*

180 +/- 15

172 +/- 16

164 +/- 10

54 +/- 5

56 +/- 3

64 +/- 20

Serum Urea (g/L)

0.87 +/- 0.25

1.01 +/- 0.19

1.26 +/- 0.39*

0.61 +/- 0.10

0.67 +/- 0.15

0.70 +/- 0.13

0.29 +/- 0.04

0.31 +/- 0.02

0.30 +/- 0.05

Serum creatinine (mg/L)

-

-

-

-

-

-

5.2 +/- 0.4

5.4 +/- 0.6

5.5 +/- 0.6

Urine Volume (mL)

168 +/- 38

186 +/- 29

176 +/- 29

329 +/- 63

333 +/- 36

369 +/- 77

8.0 +/- 1.3

7.8 +/- 1.9

9.8 +/- 2.2

Urine GGT (mLU/6.5 or 24h)

24 +/- 6

22 +/- 4

18 +/- 5*

44 +/- 7

37 +/- 9

38 +/- 4

4.1 +/- 1.1

5.0 +/- 1.4

4.1 +/- 1.0

Urine ALP (mLU/6.5 or 24h)

19 +/- 5

20 +/- 5

18.8 +/- 8

27 +/- 2

23 +/- 5

24 +/- 2

2.4 +/- 0.9

2.1 +/- 0.3

2.5 +/- 0.4

Urine Beta2-m (µg/6.5 or 24h)

45 +/- 32

78 +/- 40

109 +/- 87*

41 +/- 8

46 +/- 12

51 +/-12

15.2 +/- 3.4

23.6 +/- 7.3*

14.9 +/- 2.7

*: significant difference from control, P<0.05

Applicant's summary and conclusion

Conclusions:
In conclusion the prenatal exposure to TFA induced only slight but transient changes in the neonatal rat liver without being predictive of any developmental effect as no external malformations were observed. These effects were considered as reversible and adaptative to the TFA exposure.
Executive summary:

In a developmental toxicity study, trifluoroacetic acid (TFA) diluted in water at the dose of 75 and 150 mg/kg bw/d was administered to pregnant female rats by oral route for a period of 10 days from the gestation day 10 (GD10) to the GD20. The males used for the mating were not treated with the TFA. The females were not killed before the end of gestation, so that the delivery occured approximately on gestation day 21. Then, the pups were examined until day 49 postnatal (PND 49). Mothers and pups were examined for the body weight and the only liver and kidney weight. In addition, the urine and serum analysis were performed in both the dams and the pups to examine the hepatic and renal biochemistry and/or function. Hence, hepatotoxicity was assessed by the serum glutamate dehydrogenase (GLDH) and aspartate aminotransferase (ASAT) activities while the nephrotoxicity was assessed by the serum urea, the urinary gammaglutamyl transferase (GGT) and alkaline phosphatase (ALP) activities and the urinary beta2 -microglobulin concentrations. Moreover, the creatinine clearance was calculated as a measure of the rate of glomerular filtration.

Maternal body weight change was significantly reduced at 150 mg/kg bw for GD 10-15. Both absolute and relative liver weights were significantly increased at both treatment levels (75 and 150 mg/kg bw/d) providing a clue that TFA is absorbed after oral administration.

No meaningful differences in the kidney weights, serum and urinary indicators, renal damage were observed between the control and the TFA dosed dams. The statistically significant reductions of GGT excretion in the 75 and 150 mg/kg bw groups were considered to be biological variations and unrelated to the dosing by the authors.

The length of gestation, the litter size and the offspring survival in the first 3 days were not adversely affected by the TFA dosing at both levels. Slight but non-significant decreases in pup weights were observed in both TFA-dosed groups on postnatal day (PND) 1 and 3. External examination of the pups did not reveal any malformation.

Regarding the offspring, there were significant increases in the activities of GLDH and ASAT on PND3. Elevations were dose-dependent and were more potent for GLDH and ASAT. Serum urea concentration was significantly elevated at 150 mg/kg bw/d. These changes should be considered as adaptative and reversible since they were not recorded at PND12 and PND49 in the offsprings. They may provide that the TFA was systemically absorbed after oral exposure of the dams and then distributed inducing in utero exposure.

There were no significant differences between the control and the treated groups in the glomerular filtration rate as measured by absolute creatinine clearance. There was a significant decrease in GGT excretion in the pups from the 150 mg/kg bw/d group. Urinary excretion of the beta2-microglobulin showed a two fold increase at 150 mg/kg bw/d on PND3 providing a functional deficit of the proximal tubule in the newborns, according to the authors. None of the serum and the urinary parameters were affected on PND12 but by 49 days of age a statistically significant but biologically slight increase in beta2-microglobulin excretion was noted at 75 mg/kg bw/d but not at the highest dose. In the absence of TFA- related dose-effect, these changes should not be considered as relevant or predictive of any developmental effect in rats and by consequence in humans.

All other serum and urinary examination showed no treatment-related alterations considering the liver glucose-6 phosphatase activity or renal ALP activity.

In conclusion the prenatal exposure to TFA induced only slight but transient changes in the neonatal rat liver without being predictive of any developmental effect as no external malformations were observed.

This study is scientifically acceptable even if it doesn't satisfy to the criteria of a developmental toxicity study OECD 414.

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