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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
one-generation reproductive toxicity
Remarks:
based on test type (migrated information)
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: GLP study that is similar to OECD Test Guidelines with acceptable deviations.

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:
OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
Deviations:
yes
Remarks:
(1) No information on male pre-mating exposure regimen (needs to be 70 days in rats) (2) No information on termination of male rats
Principles of method if other than guideline:
Toxicity to fertility
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
isopropylamine, purity 99.7%

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
- Age: 54 days
- Mean weight at study initiation (females): 183-184 g
- Mean weight at study initiation (males): 273 g
- Number of animals: 25 females/treatment

Administration / exposure

Route of administration:
inhalation
Details on exposure:
- Groups of 20 male rats were exposed for 10.5 weeks before mating
- Groups of 25 female rats were exposed for 10.5 weeks before mating
Details on mating procedure:
- 1:1 until copulation or up to 7 days (if no mating occurred, the male was replaced once)
- Mating success was determined by presence of copulatory plugs and/or spermatozoa in a vaginal smea
- During mating, exposure continued
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
- Method: Gas Analyzer/IR
- Sampling times: 5 times/exposure
Duration of treatment / exposure:
- Exposure period: 12-13 weeks (males)
- Exposure period: 14-15 weeks (females)
Frequency of treatment:
- Six hours per day, 5 days per week
Details on study schedule:
- Duration of test: up to 15 weeks (males)
- Duration of test: 17-18 weeks (females)
Doses / concentrations
Remarks:
Doses / Concentrations:
20, 100, and 499 mg/m3
Basis:
analytical conc.
- Corresponding to nominal concentrations of 21, 109 and 526 mg/m3
No. of animals per sex per dose:
- Twenty male rats per treatment
- Twenty-five female rats per treatment
Control animals:
yes
Details on study design:
- Female exposures were terminated 13 days after copulation (presence of vaginal plug or sperm in vaginal smear)

Examinations

Parental animals: Observations and examinations:
ADMINISTRATION / EXPOSURE:
- Premating period: 10.5 weeks
- Route of administration: inhalation
- Post exposure period: from day 21 of gestation until day 21 of lactation
- Exposure duration: 6 hours/day, 5 days/week (after mating 7 days/week until day 20 of gestation)
- Preparation of particles: using a Laskin-style nebulizer
- Air changes: 12/hour

STANDARDIZATION OF LITTERS:
- On day 4 of lactation litters were culled to 4 pups/sex

PARAMETERS ASSESSED IN PARENTS:
- Detailed observations and body weight were assessed on a weekly basis
- Mortality/clinical observations: daily during and after exposure
- Body weight females: weekly until mating, thereafter on day 0, 6, 13 and 20 of gestation and on day 0, 4, 7, 14 and 21 of lactation
- Number of live pups at delivery
- After termination, females were examined and the number of implantations and the number of corpora lutea were determined

ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC):
- Gross necropsy of dams and pups on day 21 of lactation
- Histopathology on tissues of pups of control and high dose group
Litter observations:
OFFSPRING:
- Body weight: day 0, 4, 7 and 14 of lactation (litter weight by sex) and on day 21 (individual weights)
- External examination on day 0, 4, 7, 14 and 21 of lactation

ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC):
- Gross necropsy of dams and pups on day 21 of lactation
- Histopathology on tissues of pups of control and high dose group
Statistics:
- Dunnett's test, (uncorrected) chi-square test

Results and discussion

Results: P0 (first parental animals)

Details on results (P0)

- Actual concentration: 20, 100 and 499 mg/m3 (nominal 21, 109 and 526 mg/m3)
- Distribution: range 1.8-10%
- Stability: range 11-15%

PATERNAL TOXIC EFFECTS BY DOSE LEVEL:
- Two males in the high dose group died (week 1 and first week of mating)
- Males in the high dose group had a significantly lower body weight during the majority of the study
- No significant differences appeared in mating and fertility parameters
- Maternal mortality: none
- Body weight: no treatment related effects
- Clinical signs: incidentally fur discoloration and focal hair loss (not treatment-related)
- Mating success: 23/25, 25/25, 23/25 and 25/25 at 0, 20, 100 and 500 mg/m3, respectively
- Number pregnant per dose level: 21, 19, 17 and 19 at 0, 20, 100 and 500 mg/m3, respectively
- Gestational length: 22-23 days
- Gross pathology incidence and severity: no treatment related effects
- The number of corpora lutea, implantations and resorptions was not affected by treatment

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
500 mg/m³ air
Sex:
male/female
Basis for effect level:
other: - No significant effects on mating or fertility parameters

Results: F1 generation

Details on results (F1)

OFFSPRING DATA
- Mean litter size (day 0): 14, 13, 14 and 14 at 0, 20, 100 and 500 mg/m3, respectively
- Mean litter size (day 21): 8, 8, 8 and 8 at 0, 20, 100 and 500 mg/m3, respectively
- Sex ratio: no treatment related effects
- Body weight (day 0): 6.3, 6.6, 6.5 and 6.2 g at 0, 20, 100 and 500 mg/m3, respectively
- Body weight (day 21): 55, 58, 57 and 56 g at 0, 20, 100 and 500 mg/m3, respectively
- External abnormalities: none
- Histopathology: no treatment related effects

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
No effects on mating or fertility parameters were observed in Sprague-Dawley rats after exposure to an aerosol of isopropylamine at analytical concentrations up to 499 mg/m^3, resulting in a NOAEL of 499 mg/m^3.