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Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available

Effects on developmental toxicity

Description of key information

NOAEC: 9.07 mg/m3; OECD 414; GLP study; no significant toxic or teratogenic effects in the dam or fetus were observed at any exposure levels up to 9.07 mg/m³ in rats; reliability = 2. [CAS# 121-91-5]

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Justification for type of information:
The test substance rapidly hydrolyses to isophthalic acid (IPA). Therefore, the study with IPA is being used to fulfil this data requirement. Additional documentation, provided within the IUCLID Assessment Reports section, supports the read-across approach.
Reason / purpose:
read-across: supporting information
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals 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.
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.
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
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.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Gross pathological findings:
no effects observed
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
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
no effects observed
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.
Abnormalities:
no effects observed
Fetal body weight changes:
not examined
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): 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
Dose descriptor:
NOAEC
Effect level:
9.07 mg/m³ air (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No foetal effects were seen at the highest exposure concentration.
Abnormalities:
no effects observed
Developmental effects observed:
no

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

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.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
9.07 mg/m³
Study duration:
subchronic
Species:
rat
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

No developmental toxicity data was available for the test substance. The test substance rapidly hydrolyses to isophthalic acid (IPA). Therefore, the study with IPA is being used to fulfil this data requirement.Additional documentation, provided within the IUCLID Assessment Reports section, supports the read-across approach.

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. Fetuses were assessed for external, skeletal and visceral findings. No deaths occurred during the study. The incidences of clinical signs observed in the exposed rats were similar to controls. No statistically significant differences in mean dam body or uterus weights, litter weights or dam body weight gains were evident between the exposed and filtered air control rats at any time during the study. No statistically significant difference in pup viability was detected in the exposed rats compared to the filtered air controls. Gross external, skeletal and soft tissue examinations failed to show any significant increase in the incidence of fetal malformations or anomalies in the exposed litters compared to the controls. Inhalation exposure of pregnant rats of up to 9.07 mg/m³ of the test substance during the major organogenesis period did not result in any significant toxic or teratogenic effects in the dam or fetus. According to the results, the maternal and developmental NOAEC for this study is therefore 9.07 mg/m³.

Justification for classification or non-classification

Although no data are available for the test substance, developmental toxicity data are available for the read-across material IPA. Inhalation exposure of pregnant rats of up to 9.07 mg/m³ of IPA during the major organogenesis period did not result in any significant toxic or teratogenic effects in the dam or fetus. According to the results, the maternal and developmental NOAEC for this study is therefore 9.07 mg/m³. Based on these considerations, the test substance does not need to be classified for developmental toxicity according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.