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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: This study was selected as the key study because the information provided for the hazard endpoint is sufficient for the purpose of classification and labeling and/or risk assessment.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1991
Report date:
1991

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
Remarks:
The study was conducted according to the guideline in effect at the time of study conduct.
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Isophthalic acid
EC Number:
204-506-4
EC Name:
Isophthalic acid
Cas Number:
121-91-5
Molecular formula:
C8H6O4
IUPAC Name:
benzene-1,3-dicarboxylic acid
Details on test material:
- Purity: no data

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: females - 41 days; males - 60 days
- Weight at study initiation: not reported
- Fasting period before study: not reported
- Housing: The dams were housed in suspended polycarbonate cages except during the exposure periods when they were transferred to stainless steel wire mesh inhalation cages.
- Diet: Purina Rodent Chow 5001 ad libitum
- Water: Purified water ad libitum
- Acclimation period: not reported


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-25 °C
- Humidity (%): not reported
- Air changes (per hr): Air conditioned
- Photoperiod (hrs dark / hrs light): Fluorescent lighting was provided for 12 hours followed by 12 hours of darkness.

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
The test substance was administered by inhalation. The test article aerosol was generated using dry materials. Ground test substance was placed into the feeder reservoir and moved to the bottom of the feeder by slow peristaltic action of the flexible, tapered walls of the feeder. The aerosol entered through the top of the exposure chambers, via a venturi tube and was exhausted through a pipe located near the bottom of the chamber. Exposures were conducted in 2 meter cubed stainless steel and glass chambers. Chamber air was filtered through high efficiency particle absorbing (HEPA) filters and controlled for temperature and humidity.
Chamber air flow was maintained at 325 to 335 liters/min.

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Method of Analysis:
The test substance concentrations were determined gravimetrically as well as by UV spectrophotometric analysis. The exposure chambers were sampled at least twice during each exposure period.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 2 female to 1 male
- Proof of pregnancy: Sperm in vaginal smear referred to as day 0 of pregnancy
- Any other deviations from standard protocol: Non-detailed
Duration of treatment / exposure:
The rats were exposed 6 hours per day, 7 days per week on gestation day 6 through 15, for a total of 10 consecutive exposures.
Frequency of treatment:
The rats were exposed 6 hours per day, 7 days per week on gestation day 6 through 15, for a total of 10 consecutive exposures.
Duration of test:
The rats were exposed 6 hours per day, 7 days per week on gestation day 6 through 15, for a total of 10 consecutive exposures.
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0, 1.0, 5.0 and 10.0 mg/m³
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
0, 0.98, 4.23, 9.07 mg/m³
Basis:
analytical conc.
No. of animals per sex per dose:
25 timed-pregnant primiparous dams per dose
Control animals:
yes, sham-exposed
Details on study design:
No further details

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Rats were observed for signs of toxicity approximately 0-3 hours following each exposure on gestation days 6 through 15, and daily thereafter.
- Cage side observations were included.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Following treatment initiation, the rats were observed twice daily on weekdays and once daily on weekends for untoward effects of test article exposure.

BODY WEIGHT: Yes
- Time schedule for examinations: Day 0, 5, 6, 11, 16 and 20.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: The presence of lesions or abnormalities was described in the study record. The uterine horns of the dams with no observable implants were stained using a 10% ammonium sulfide solution to determine their pregnancy/resorption status.

Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: No data
- Number of late resorptions: No data
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: [all per litter half per litter
Statistics:
Analysis of the log transformed litter body weights were conducted using analysis of variance (ANOVA). Log transformed dam body weights were analysed by multivariate analysis of variance for repeated measures.
Indices:
The statistical significance of an increased incidence of variations scored as 1 was not determined as such significant is usually meaningful only in the presence of anomalies of still greater severity or other direct indicators of teratogenic effects.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
No toxic effects were observed.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEC
Effect level:
9.07 mg/m³ air (analytical)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEC
Effect level:
9.07 mg/m³ air (analytical)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
No toxic effects were observed.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Mean dam body weights and uterine weights (g) (mean ± standard deviation)

 

Control

Test substance (mg/m³)

Dams/Group

16

18

18

18

Gestation Day

 

1.0

mg/m³

5.0 

mg/m³

10.0

mg/m³

 

Mean Dam Body Weights

0

240 ±

20.0

237 ±

15.4

239 ±

11.4

240 ±

15.7

6

284 ±

20.6

282 ±

14.3

284 ±

15.0

283 ±

18.1

11

308 ±

21.2

301 ±

26.4

306 ±

22.1

307 ±

20.0

16

343 ±

26.1

336 ±

35.8

346 ±

27.4

340 ±

24.5

20

401 ±

40.7

394 ±

45.2

411 ±

49.0

399 ±

39.7

 

Mean Uterine Weights

 

66.4 ±

27.9

64.5 ±

30.3

77.8 ±

32.0

62.9 ±

27.1

 

Corrected Mean Full-Term Body Weightsa

 

334 ±

25.7

330 ±

26.4

334 ±

20.5

336 ±

21.2

a Corrected full-term body weight = full-term body weight minus uterine weight

Mean dam body weight gains (g) (mean ± standard deviation)

 

Control

Test substance (mg/m³)

Dams/Group

16

18

18

18

Gestation Day

 

1.0

 mg/m³

5.0 

mg/m³

10.0

mg/m³

 

Mean Dam Body Weights

6-0

44 ±

6.6

45 ±

4.6

45 ±

6.8

43 ±

5.4

11-0

68 ±

7.0

64 ±

24.2

67 ±

17.0

67 ±

8.1

16-0

102 ±

15.0

99 ±

32.9

107 ±

21.1

100 ±

6.7

20-0

160 ±

33.4

157 ±

42.4

173 ±

43.3

159 ±

34.0

 

Mean Uterine Weights

 

66.4 ±

27.9

64.5 ±

30.3

77.8 ±

32.0

62.9 ±

27.1

 

Corrected Mean Full-Term Body Weightsa

 

94 ±

14.5

93 ±

22.1

95 ±

15.6

97 ±

11.6

a Corrected full-term body weight = full-term body weight minus uterine weight

 

 

 

 

 

Number Examined

Study group

Filtered Air

Test substance (mg/m³)

Control

1

5

10

F(L)a

F(L)

F(L)

F(L)

185(15)

201(17)

242(16)

192(17)

Malformations:

  HEAD

 

-(-)b

 

2(1)

 

-(-)

 

-(-)

Cleft Palate

Minor Observations:

  HEAD

 

 

 

 

Dome-Shaped

-(-)

3(2)

-(-)

-(-)

Red Marks

10(7)

4(3)

13(7)

8(6)

  BODY

-(-)

2(2)

-(-)

-(-)

Edematous

a F(L) – Number of Fetuses (F), Number of Litters L

Applicant's summary and conclusion

Conclusions:
This study and the conclusions which are drawn from it fulfill the quality criteria (validity, reliability, repeatability).
Inhalation exposure of pregnant rats to 0.98, 4.23 or 9.07 mg/m³ during the major organogenesis period did not result in any significant toxic or teratogenic effects in the dam or fetus.
Executive summary:

Groups of 25 mated female Sprague-Dawley rats were exposed (whole-body) to atmospheres containing the test substance at measured concentrations of 0, 0.98, 4.23 or 9.07 mg/m³ for 6 hours/day on ten consecutive days (Day 6-15 of exposure). Dams were observed daily for clinical signs and bodyweights measured at regular intervals. Dams were sacrificed of gestation Day 20 and the uterine contents examined. Fetuses were assessed for external, skeletal and visceral findings.

No deaths occurred and no signs of toxicity were observed during the study period. Litter parameters were comparable in all groups and no treatment-related increase in the incidence of foetal findings was apparent. The maternal and developmental NOAEC for this study is therefore 9.07 mg/m³.

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