Isopropylamine

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1988

Report date:

1988

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Version / remarks:

note: not mentioned in ACC IUC5

Deviations:

yes

Remarks:

Food consumption was not measured, while a deviation from standard reproductive toxicity testing, considered an acceptable deviation.

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Isopropylamine

EC Number:

200-860-9

EC Name:

Isopropylamine

Cas Number:

75-31-0

Molecular formula:

C3H9N

IUPAC Name:

propan-2-amine

Test material form:

liquid

Details on test material:

- Name of test material (as cited in study report): Isopropylamine (2-aminopropane)
- Substance type: organic
- Physical state: clear liquid
- Analytical purity: 99.77 %
- Lot/batch No.: LP-606

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

- Age (males): 10 weeks
- Weight at day 0 of gestation (females): 214-282 g
- Weight at day 0 of gestation (males): 317-389 g
- Number of animals: 25 females/group
- Thirty air changes per hour

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

air

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

- Method: Gas analyser
- Sampling time: at least 5 times/day (treatment); the control was checked for the presence of test material
twice during the study

Details on mating procedure:

- Mating: 1 female / 1 male
- Day 0 of gestation: presence of vaginal plug

Duration of treatment / exposure:

- Gestation days 6-15

Frequency of treatment:

- Six hours per day

Duration of test:

- Twenty days, Cesarean section on gestation day 20

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

50 mg/m³ air (analytical)

Doses / concentrations 2

Dose / conc.:

499 mg/m³ air (analytical)

Doses / concentrations 3

Dose / conc.:

1 000 mg/m³ air (analytical)

No. of animals per sex per dose:

25 mated females per group

Control animals:

yes

Examinations

Maternal examinations:

- Mortality: twice daily
- Clinical observations: on gestation days 0 and 6-20 (on treatment days after exposure)
- Body weight gain: gestation days 0, 6, 10, 13, 16 and 20
- Food consumption: not measured

ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC):
- Macroscopy: findings dams recorded
- Microscopy: not performed

Ovaries and uterine content:

- Examination of uterine content: number of corpora lutea; relative position and number of live and dead foetuses and early and late resorptions

Fetal examinations:

- Examination of fetuses: sex; weight; external, visceral (1/2 of each litter) and skeletal (1/2 of each litter) findings

Statistics:

- Dunnett's test; Mann-Whitney U test; Fisher's Exact test

Indices:

not calculated

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Clinical signs of rales, labored breathing and vaginal discharge (one female) were uniquely observed in the high exposure level maternal animals. Sneezing was observed in both the high and mid exposure groups with higher incidence in the high exposure group. Fur staining/encrustation/nasal discharge was obsened at a higher incidence in the high exposure group maternal animals than the other exposure groups or the control group. During exposure, clear nasal discharge was observed in the high exposure group and sneezing was observed in the high exposure group
Low incidence of nasal discharge and sneezing were observed in the mid dose group.

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

High exposure level: Mean maternal body weights were significantly lower than control values (about 14% lower on gestation day 20) and body weight loss or lower weight gains were observed for the periods of gestation days 6-10, 10-13, 13-16 and 6-20.
Mid exposure level: Reduced body weight gain for gestation days 6-10 and the overall period of gestation days 6-20. Absolute maternal body weights of mid exposure group animals were not significantly lower than control group values.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

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:

effects observed, treatment-related

Description (incidence and severity):

Reduced abdominal fat was observed in 9 high exposure level and 2 mid exposure level animals
Incidental hydronephosis, kidney stones and dilated ureter were observed without relationship to treatment.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not specified

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:

effects observed, non-treatment-related

Description (incidence and severity):

Early resorption and consequently postimplantation loss were slightly elevated above control values in the mid exposure
group (mean of l.O/dam vs. 0.6/dam); the difference was not statistically significant at the 5% confidence level with the
Bonferroni inequality. Early resorption for the high and low exposure groups were not statistically different from the control
value

Dead fetuses:

no effects observed

Changes in pregnancy duration:

no effects observed

Changes in number of pregnant:

no effects observed

Other effects:

no effects observed

Effect levels (maternal animals)

1

Key result

Dose descriptor:

NOAEC

Effect level:

500 mg/m³ air

Basis for effect level:

other: maternal toxicity

2

Key result

Dose descriptor:

NOEC

Effect level:

50 mg/m³ air

Basis for effect level:

other: maternal toxicity

Maternal abnormalities

Key result

Abnormalities:

effects observed, treatment-related

Localisation:

other: unspecific signs of toxicity

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

Changes in postnatal survival:

no effects observed

External malformations:

no effects observed

Skeletal malformations:

effects observed, non-treatment-related

Description (incidence and severity):

One malformation finding, bent limb bones, was observed in a single fetus in the high exposure group and eight fetuses from this litter exhibited bent rib variation findings. The malformation and variation findings observed in this litter are considered to be the result of factors unique to the dam that were not related to exposure. The fact that the dam of this litter uniquely exhibited a large body weight loss on gestation days 13-16 supports this conclusion. On a litter basis no significant increase in bent rib findings were observed and the increased number of fetuses with bent ribs in the high exposure group because of multiple findings in a single litter is not considered to be evidence for a treatment related effect.
An elevation in reduced 13th rib ossification was observed for the high exposure group, but the difference was not statistically different from the control group with the Bonferroni inequality applied and no supportive treatment related growth retardation findings such as reduced fetal weight or other reduced ossification findings were observed. For these reasons the elevation in reduced 13th rib ossification in the high exposure group was concluded not to be treatment related.

Visceral malformations:

no effects observed

Other effects:

no effects observed

Effect levels (fetuses)

Key result

Dose descriptor:

NOAEC

Effect level:

1 000 mg/m³ air

Basis for effect level:

other: teratogenicity

Fetal abnormalities

Key result

Abnormalities:

no effects observed

Overall developmental toxicity

Key result

Developmental effects observed:

no

Applicant's summary and conclusion

Conclusions:

Under the conditions of this study, there was no developmental toxicity observable in rats, even at maternal toxic levels

Executive summary:

Groups of 25 mated female Sprague-Dawley rats were exposed to target isopropylamine concentrations of 50, 500, or 1000 mg/m3 by inhalation, six hours per day, on days 6-15 of gestation. A concurrent control group received house-conditioned air only. Dams were sacrificed on gestation day 20, implantations were described, and fetuses were removed from the uterus. Fetuses underwent a gross external examination and were processed for subsequent visceral or skeletal examination. Analytically measured study mean exposure levels and standard deviations were 50 +/- 1, 499 +/- 5 and 1000 +/- 8 mg/m3 for the low, mid and high exposure levels. No spontaneous deaths occurred in any of the exposure groups or the control group. There were clear signs of maternal toxicity at the high exposure level. Mean maternal body weights were significantly lower than control values (about 14% lower on gestation day 20) and body weight loss or lower weight gains were observed for the periods of gestation days 6-10, 10-13, 13-16 and 6-20. Rales, labored breathing and vaginal discharge (one female) were uniquely observed clinical signs in high exposure group females. Treatment related clinical signs of nasal discharge, sneezing and fur staining/encrustation were also observed in high exposure group females. Slight toxicity was observed at the mid exposure level as evidenced by reduced body weight gain for gestation days 6-10 and the overall period of gestation days 6-20. Absolute maternal body weights of mid exposure group animals were not significantly lower than control group values. Low incidence of nasal discharge and sneezing were observed in the mid dose group. There was no apparent maternal toxicity at the low exposure level. The only maternal postmortem findings that were considered treatment related were observations of reduced abdominal fat in 9 high exposure level and 2 mid exposure level animals.There were no clear indications of embryotoxicity or fetotoxicity at any of the exposure levels. Pregnancy rates, numbers of fetuses and preimplantation loss were comparable between all exposure groups and the control group. Increased mean early resorptions/dam above the control value (less than two fold) in the mid exposure group were not considered to be treatment related because of lack of statistical significance with the Bonferroni inequality and lack of a dose response pattern. Fetal weights and sex distributions were comparable between all treatment groups and the control group. Morphological malformation findings were confined to sporadic incidence in a few fetuses and litters. No statistically significant malformation increases or dose response patterns were observed. One malformation finding, bent limb bones, was observed in a single fetus in the high exposure group and eight fetuses from this litter exhibited bent rib variation findings. The malformation and variation findings observed in this litter are considered to be the result of factors unique to the dam that were not related to exposure. The fact that the dam of this litter uniquely exhibited a large body weight loss on gestation days 13-16 supports this conclusion. On a litter basis no significant increase in bent rib findings were observed and the increased number of fetuses with bent ribs in the high exposure group because of multiple findings in a single litter is not considered to be evidence for a treatment related effect. An elevation in reduced 13th rib ossification was observed for the high exposure group, but the difference was not statistically different from the control group with the Bonferroni inequality applied and no supportive treatment related growth retardation findings such as reduced fetal weight or other reduced ossification findings were observed. For these reasons the elevation in reduced 13th rib ossification in the high exposure group was concluded not to be treatment related.

In conclusion, treatment of Sprague-Dawley rats by the inhalation exposure route at mean analytical levels of 50, 499 or 1000 mg/m3 during the period of major organogenesis did not induce embryotoxic, fetotoxic or teratogenic effects, although slight maternal toxicity was observed at the 499 mg/m3 exposure level and substantial maternal toxicity was observed at the 1000 mg/m3 level.