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Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated 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:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Cross-reference
Reason / purpose for cross-reference:
reference to same study
Reference
Endpoint:
developmental toxicity
Type of information:
migrated 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:
other: Peer-reviewed published report of a study mandated by the US Environmental Protection Agency as part of the TSCA Section 4 Test Rule
Reason / purpose for cross-reference:
reference to same study
Qualifier:
according to guideline
Guideline:
EPA OTS 798.4900 (Prenatal Developmental Toxicity Study)
Deviations:
not specified
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Raleigh, NC USA
- Age at study initiation: 10 weeks
- Weight at study initiation: 213.6 to 274.6 g
- Housing: Singly in polycarbonate cages with wire mesh lids
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 72 F
- Humidity (%): 59
- Photoperiod (hrs dark / hrs light): 12:12

IN-LIFE DATES: From: To:
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

0.0, 80.0, 160.0 and 240.0 mg/ml corresponding to 0.0, 400.0, 800.0 and 1200 mg/kg/day at a dosing volume of 5.0 mg/kg.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Dosing solution concentration confirmed by gas chromatography; all formulations were within range 97-106% of target.
Details on mating procedure:
Bred overnight in ratio 1:1 to mating colony of males of the same strain from the same source. 100 Sperm-positive females were selected
Duration of treatment / exposure:
Gestation days 6 to 15
Frequency of treatment:
Daily
Duration of test:
20 days
Dose / conc.:
400 mg/kg bw/day (nominal)
Dose / conc.:
800 mg/kg bw/day (nominal)
Dose / conc.:
1 200 mg/kg bw/day (nominal)
No. of animals per sex per dose:
25
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on a range finder study. All dams at 2500mg/kgbw/day died or were sacrified moribund. At 1250mg/kgbw/day, 2/12 dams died or were sacrified moribund. Dams also showed clear signs of toxicity (body weight, food consumption, clinical signs) and fetal weight was reduced. There were no adverse changes seen at 625mg/kgbw/day.
Maternal examinations:
DETAILED CLINICAL OBSERVATIONS: Yes / No / No data
- Time schedule: twice per day during dosing and 1-2 hr post-dosing. Daily outside dosing period.

BODY WEIGHT: Yes
- Time schedule for examinations: on days GD 0, 6, 9, 12, 15, 18, 20

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- Time schedule for examinations: on days GD 0, 6, 9, 12, 15, 18, 20

POST-MORTEM EXAMINATIONS: Yes / No / No data
- Sacrifice on gestation day 20
- Organs examined: Thoracic and abdominal organs examined after euthanasia on gestation day 20. Body, liver and uterine weights recorded.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes / No / No data
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes
- Uteri with no visible implantation sites were stained to visualise sites. Number of total sites, resorptions and dead and live foetues recorded.
Ovarian corpora lutea were counted
Fetal examinations:
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [ half per litter] Decapitated and bodies examined for visceral changes by longitudinal dissection. Bodies then eviscerated, macerated and stained (alizarin red S) for ossified parts and Alcian blue for cartilaginous areas.
- Skeletal examinations: Yes: [all per litter] examined for skeletal alterations.
- Head examinations: Yes: [ half per litter ] Head decalcified and sectioned for examination for soft tissue craniofacial alterations
Statistics:
Apppropriate parametric and general linear model (GLM) procedures. Arcsine-square root transformation on litter-derived percentage data with tests for homogeneity (Bartlett), ANOVA (Winer, 1962), William's multiple comparison test and/or Dunnett's test applied one- or two-tailed as appropriate. Non-parametric tests included Chi-squared and Fisher's exact probability test.
Indices:
Corpora lutea per dam
Implantation sites per litter
Preimplantation loss (%)
Resorption/litter (%)
% litters with resorptions
% late foetal death/litter
No of litters with late foetal deaths
% adversely affected implants/litter
Live litters
Live foetuses per litter
Average foetal bodyweight per litter (all, male and female foetuses).
Historical control data:
Designation of malformation based upon published (Kimmel and Wilson, 1973; Khera, 1981; marr et al., 1992) and on historical control data in the Research Triangle Institute.
Clinical signs:
no effects observed
Mortality:
mortality observed, treatment-related
Description (incidence):
2 animals (8%) died at top dose and 1 animal (4%) died at middle dose, death occuring soon after treatment in all cases. Deaths therefore attributed to treatment. All dams were pregnant.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Weight change was statistically significantly reduced in the top dose animals (~10% reduction) although this may be due to reduced litter weights as the dam weights minus the uterine contents were statistically equivalent across the dose groups.
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
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
Description (incidence and severity):
Slight increase observed in top dose but not to statistically significant levels.
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
Pregnancy rate was high and approximately equivalent across all dose groups.
Details on maternal toxic effects:
No effects on number of corpora lutea
Dose descriptor:
NOAEL
Effect level:
400 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
mortality
Abnormalities:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
effects observed, non-treatment-related
Description (incidence and severity):
The percentage of males was significantly higher in the mid dose group but not the top dose group and was considered a chance occurence
Changes in litter size and weights:
effects observed, treatment-related
Description (incidence and severity):
Reduced gravid uterine weight: (89.2% of control) at top dose. The average fetal body weight was significantly reduced in the high dose group animals (-8%). When considered by sex however, the male and female weights were signficantly reduced in both the mid and high dose groups (although the former was only just significant and the reduction represented a reduction of 5-6%. The trend towards reduced fetal weight was however highly signficant.
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Details on embryotoxic / teratogenic effects:
No treatment related patterns of incidence or severity.
Dose descriptor:
NOAEL
Effect level:
400 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
changes in litter size and weights
Remarks on result:
other: marginal and conservative interpretation.
Abnormalities:
no effects observed
Developmental effects observed:
no

A range finder study found severe maternal toxicity at a dose of 1250mg/kgbw/day.

Conclusions:
The NOAELs for both maternal and developmental toxicity were 400 mg/kg/day in rats with no signs of teratogenicity. The only foetotoxicity recorded was a reduction in bodyweight per litter
Executive summary:

In a well conducted developmental toxicity test using isopropanol dosed by oral gavage in rats, the NOAEL for maternal toxicity was 400 mg/kgbw/day with no evidence of teratogenicity up to the maximum tested dose of 1200mg/kgbw/day. Signs of maternal toxicity were mortality, reduced gestational weight gain and reduced gravid uterine weight. There was also evidence of fetotoxicity at higher doses, manifest as reduced foetal bodyweights per litter. The NOAEL for this effect was also 400mg/kgbw/day. The NOAEL for maternal and developmental toxicity was 400 mg/kg/day.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1994

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
EPA OTS 798.4900 (Prenatal Developmental Toxicity Study)
Deviations:
not specified
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
Isopropanol
IUPAC Name:
Isopropanol
Constituent 2
Reference substance name:
2-propanol
IUPAC Name:
2-propanol
Constituent 3
Reference substance name:
67-73-0
IUPAC Name:
67-73-0
Constituent 4
Reference substance name:
Propan-2-ol
EC Number:
200-661-7
EC Name:
Propan-2-ol
Cas Number:
67-63-0
IUPAC Name:
propan-2-ol
Details on test material:
- Name of test material (as cited in study report): Isopropanol
- Purity 99.95%
- Stability under test conditions: Stable for at least 49 days
- Storage conditions: refrigerated.

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Hazleton Reearch Product, Denver USA
- Age at study initiation: 5.5 months
- Weight at study initiation: 2750-3800 g
- Housing: Singly in stainless steel cages with wire mesh lids
- Diet: ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 66.9 +/- 1.2 F
- Humidity (%): 51.4 +/- 3%
- Photoperiod (hrs dark / hrs light): 12:12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

0.0, 60.0, 120.0 and 240.0 mg/ml corresponding to 0.0, 120.0, 240.0 and 480 mg/kg/day at a dosing volume of 2.0 ml/kg.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Test solutions confirmed by gas chromatography; all formulations were within range 97-106% of target.
Details on mating procedure:
- Impregnation procedure: Artificially inseminated
Duration of treatment / exposure:
Gestation days 6 to 18
Frequency of treatment:
Daily
Duration of test:
30 days
Doses / concentrationsopen allclose all
Dose / conc.:
120 mg/kg bw/day (nominal)
Dose / conc.:
240 mg/kg bw/day (nominal)
Dose / conc.:
480 mg/kg bw/day (nominal)
No. of animals per sex per dose:
15
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on range-finder study. All animals at 1250mgkgbw/day died or were sacrified moribund. 7/10 similarly at 625mg/kgbw/day. There was no maternal or developmental toxicity at 312.5mg/kgbw/day

Examinations

Maternal examinations:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily, at dosing and 1-2 hr post-dosing. Daily outside dosing period.

BODY WEIGHT: Yes
- Time schedule for examinations: on days 0, 6, 9, 12, 15, 18, 21, 24 and 30.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- on days 0, 6, 9, 12, 15, 18, 21, 24 and 30.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes / No / No data
- Time schedule for examinations:

POST-MORTEM EXAMINATIONS: Yes / No / No data
- Sacrifice on gestation day 30
- Organs examined: Thoracic and abdominal organs examined. Body, liver and uterine weights recorded.
Ovaries and uterine content:
Uteri with no visible implantation sites were stained to visualise sites. Number of total sites, resorptions and dead and live foetues recorded.
Ovarian corpora lutea were counted.
Fetal examinations:
Bodies eviscerated, macerated and stained (alizarin red S) for ossified parts and Alcian blue for cartilaginous areas.
- External examinations: Yes: [all per litter ]
- Soft tissue examinations: Yes: [all per litter]. Sexed internally. Visceral changes examined by longitudinal dissection. Bodies then eviscerated, macerated and stained (alizarin red S) for ossified parts and Alcian blue for cartilaginous areas.
- Skeletal examinations: Yes: [all per litter] examined for skeletal alterations.
- Head examinations: Yes: half per litter. Head decalcified and sectioned for examination for craniofacial alterations
Statistics:
Apppropriate parametric and general linear model (GLM) procedures. Arcsine-square root transformation on litter-derived percentage data with tests for homogeneity (Bartlett), ANOVA (Winer, 1962), William's multiple comparison test and/or Dunnett's test applied one- or two-tailed as appropriate. Non-parametric tests included Chi-squared and Fisher's exact probability test.
Indices:
Corpora lutea per doe
Implantation sites per litter
Preimplantation loss (%)
Resorption/litter (%)
% litters with resorptions
% late foetal death/litter
%non-live implants per litter
No of litters with late foetal deaths
% adversely affected implants/litter
Live litters
Live foetuses per litter
% male foetuses per litter
Average foetal bodyweight per litter (all, male and female foetuses).
Historical control data:
Designation of malformation based upon published (Kimmel and Wilson, 1973; Khera, 1981; marr et al., 1992) and on historical control data in the Research Triangle Institute.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Signs of stress including flushed ears (peripheral vasodilation with capillary fragility - regarded as symptoms of intoxication); cyanosis, lethargy, laboured respiration, diarrhoea and perinasal/perioral wetness but only at the top dose. Isolated findings in other dose groups were regarded as incidental.
Mortality:
mortality observed, treatment-related
Description (incidence):
4 does died or sacrificed moribund at top dose (GD 11, GD 12, 2xGD19). All were pregnant and sacrificed just after treatment.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weight dropped in the top dose group on start of treatment and remained statistically significantly suppressed throughout the study. Body weight gain over the treatment period was only 45.4% of control in top dose and Body weights for the two lower dose groups were above those of controls. The corrected average weight at the end of the study for the high dose group (rabbit minus gravid uterine weight) was substantially reduced compared to controls but the difference was not statistically significant due to large animal to animal variations.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Food consumption significantly reduced in top dose group (~81% of control values over treatment period.)
Organ weight findings including organ / body weight ratios:
no effects observed

Maternal developmental toxicity

Number of abortions:
no effects observed
Description (incidence and severity):
No does aborted, delivered early or were removed from the study.
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
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
Description (incidence and severity):
Pregnancy rate was high and equivalent across all groups.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
240 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
body weight and weight gain
clinical signs
food consumption and compound intake
mortality
Remarks on result:
other: Effects seen predominantly non-specific indicators of stress.

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
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:
effects observed, treatment-related
Description (incidence and severity):
Slight reduction in average litter weight in top dose group (-14%). This was only statistically significant for trend for female fetuses.
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Description (incidence and severity):
No statistically significant differences between dose groups.
Visceral malformations:
no effects observed
Description (incidence and severity):
No statistically significant differences between dose groups.
Other effects:
no effects observed

Effect levels (fetuses)

open allclose all
Dose descriptor:
NOAEL
Effect level:
240 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
fetal/pup body weight changes
Dose descriptor:
NOAEL
Based on:
test mat.
Sex:
male
Remarks on result:
not determinable due to absence of adverse toxic effects

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Any other information on results incl. tables

A range finder study found severe maternal toxicity at a dose of 650mg/kgbw/day.

Applicant's summary and conclusion

Conclusions:
The NOAELs for both maternal and developmental toxicity were 400 mg/kg/day in rats with no signs of teratogenicity. The only foetotoxicity recorded was a reduction in bodyweight per litter
Executive summary:

In a well conducted developmental toxicity test using isopropanol dosed by oral gavage in NZ rabbits, the NOAEL for maternal toxicity was 240 mg/kgbw/day with no evidence of teratogenicity up to the maximum tested dose of 480mg/kgbw/day. At 480mg/kgbw/day, maternal mortality was also evident. The only effect on pups was a reduction in weight, which mirrored the reduction in dam weight. Other adverse effects included reduced gestational weight gain in dams, reduced food consumption and adverse clinical signs. The NOAEL for developmental toxicity was 480 mg/kg/day there being no developmental toxicity evident at this top dose (the MTD).