Registration Dossier

Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

Currently viewing:

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions

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:
gestation day 6 through 15, for a total of 10 consecutive exposures.
Frequency of treatment:
6 hours per day, 7 days per week
Doses / concentrationsopen allclose all
Dose / conc.:
0.98 mg/m³ air
Dose / conc.:
4.23 mg/m³ air
Dose / conc.:
9.07 mg/m³ air
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

General toxicity (maternal animals)

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):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
no effects observed

Effect levels (maternal animals)

Dose descriptor:
NOAEC
Effect level:
9.07 mg/m³ air (analytical)
Based on:
test mat.
Basis for effect level:
other: No maternal effects were seen at the highest exposure concentration.

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed

Effect levels (fetuses)

Dose descriptor:
NOAEC
Effect level:
9.07 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No foetal effects were seen at the highest exposure concentration.

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

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:
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.