Isophthaloyl dichloride

Endpoint summary

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 for cross-reference:

read-across: supporting information

Qualifier:

equivalent or similar to guideline

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 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.

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 Weights^a
	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 Weights^a
	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.