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
Study period:
19 June to 7 July 1989
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Cross-reference
Reason / purpose for cross-reference:
reference to same study

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)
GLP compliance:
not specified
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:
isophthalic acid
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
- Name of test material (as cited in study report): Isophthalic acid (IPA)
- Physical state: White powder
- Lot/batch No.: 10820-59-A
Specific details on test material used for the study:
- Name of test material (as cited in study report): Isophthalic acid (IPA)
- Physical state: White powder
- Lot/batch No.:10820-59-A

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Raleigh, NC
- Age at study initiation: Circa 41 and 60 days plus approximately two weeks for females and males respectively
- Weight at study initiation: Not stated
- Fasting period before study: Not stated
- Housing: The dams were housed in suspended polycarboate cages except during the exposure periods when they were transfered to stainless steel wire mesh inhalation cages.
- Diet (e.g. ad libitum): Purina Rodent Chow 5001 ad libitum
- Water (e.g. ad libitum): Purified water ad libitum
- Acclimation period: Not stated


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-25
- Humidity (%): Not stated
- 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
Vehicle:
unchanged (no vehicle)
Details on exposure:
Isophthalic acid (IPA) was adminstered by inhalation. The test article aerosol was generated using dry materials. Ground IPA 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:
IPA concentrations were determined gravimetrically as well as by UV spectrophotometeric analysis. The exposure chambers were sampled at least twice during each exposure period.
Details on mating procedure:
- Impregnation procedure: Co-housed
- 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
Dose / conc.:
0.98 mg/m³ air
Remarks:
For 6h/day on Days 6-15 of gestation
Dose / conc.:
4.23 mg/m³ air
Remarks:
For 6h/day on Days 6-15 of gestation
Dose / conc.:
9.07 mg/m³ air
Remarks:
For 6h/day on Days 6-15 of gestation
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 affects 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 were 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
- Other:
Fetal examinations:
- External examinations: Yes, all the litter
- Soft tissue examinations: Yes, half per litter
- Skeletal examinations: Yes, half per litter
- Head examinations: Yes, 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.
Historical control data:
Not relevant.

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)

Key result
Dose descriptor:
NOAEC
Effect level:
9.07 mg/m³ air (analytical)
Based on:
test mat.
Remarks on result:
not determinable due to adverse toxic effects at highest dose / concentration tested

Results (fetuses)

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

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

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEC
Effect level:
9.07 mg/m³ air
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects

Fetal abnormalities

Key result
Abnormalities:
no effects observed

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)

Dams/Group

Study group

Filtered Air Control

Isophthalic acid (mg/m³)

16

18

18

18

Gestation Day

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)

Dams/Group

Study group

Filtered Air Control

Isophthalic acid (mg/m³)

16

18

18

18

Gestation Day

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 ± 16.7

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

Summary of gross external anomalies

Number Examined

Study group

Filtered Air

Isophthalic acid (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

    Cleft Palate

-(-)b

2(1)

-(-)

-(-)

Minor Observations:

  HEAD

 

 

 

 

    Dome-Shaped

-(-)

3(2)

-(-)

-(-)

    Red Marks

10(7)

4(3)

13(7)

8(6)

  BODY

    Edematous

-(-)

2(2)

-(-)

-(-)

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

b  -(-) = zero incidence

Applicant's summary and conclusion

Conclusions:
Inhalation exposure of pregnant rats to 0.98, 4.23 or 9.07 mg IPA/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 isophthalic acid at 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. Foetuses 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.