Isopropylamine

Toxicity to reproduction

Administrative data

Endpoint:

one-generation reproductive toxicity

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1988

Report date:

1988

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

1-generation study. Treated males were mated to untreated female and vice versa.

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

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: (P) 54 days; (F1) from birth
- Weight at study initiation: (P) Males: 241 - 300 g; Females: 163 - 207 g
- Fasting period before study: no

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23
- Humidity (%): 35-60
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

air

Details on mating procedure:

- M/F ratio per cage: 1:1
- Length of cohabitation: maximally 7 d
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as [day 0 / day 1] of pregnancy
- Female reproduction (males unexposed): After 7 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Male fertility (females unexposed): After 7 days of unsuccessful pairing replacement of first female by another unexposed female

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Routinely sampled five times per exposure at approximately one hour intervals. Test atmosphere was drawn through a MIRAN 1A General Purpose Gas Analyzer

Duration of treatment / exposure:

- Duration of test: up to 15 weeks (males)
- Duration of test: 17-18 weeks (females)

Frequency of treatment:

untreated + treated males: Six hours per day, 5 days per week
treated and untreated females: Six hours per day, 5 days per week (premating and mating period)
treated females: Six hours per day, 7 days per week (during gestation period)

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

20 mg/m³ air (analytical)

Doses / concentrations 2

Dose / conc.:

100 mg/m³ air (analytical)

Doses / concentrations 3

Dose / conc.:

499 mg/m³ air (analytical)

No. of animals per sex per dose:

Twenty male rats per treatment
- Twenty-five female rats per treatment

Control animals:

yes

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

Oestrous cyclicity (parental animals):

not examined

Sperm parameters (parental animals):

not examined

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

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals after mating
- Maternal animals: All surviving animals on lactation day 21

GROSS NECROPSY
- Gross necropsy of P females, of F1 generation: all animals, tissues were obtained from 9-10 animals/sex/level (Internal cavities (abdominal, thoracic, cranial, and scrotal) organs were removed and examined

HISTOPATHOLOGY / ORGAN WEIGHTS
Tissues from control and high level animals were examined microscopically.

Postmortem examinations (offspring):

see above

Statistics:

- Dunnett's Multiple Comparison Test, Mann-Whitney Test, with with Bonferroni Inequality Procedure, Fisher’s Exact Test with Bonferroni Inequality Procedure, (partially uncorrected) chi-square Test

Reproductive indices:

copulation, fertility and pregnancy indices

Offspring viability indices:

not calculated

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

incidentally fur discolouration and focal hair loss (not treatment-related)

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

In males during the majority of the study, no significant effects in females

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

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 specified

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Details on results (P0)

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 discolouration 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)

Key result

Dose descriptor:

NOAEC

Remarks:

(highest concentration tested)

Effect level:

500 mg/m³ air

Sex:

male/female

Basis for effect level:

other: No significant effects on mating or fertility parameters

Target system / organ toxicity (P0)

Key result

Critical effects observed:

no

Results: F1 generation

General toxicity (F1)

Clinical signs:

not specified

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

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

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings:

no effects observed

Other effects:

not examined

Developmental neurotoxicity (F1)

Behaviour (functional findings):

not examined

Developmental immunotoxicity (F1)

Developmental immunotoxicity:

not examined

Details on results (F1)

- 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

Effect levels (F1)

Key result

Dose descriptor:

NOAEC

Remarks:

(direct exposure: P-generation / indirect (intrauterine) exposure: embryos/foetus)

Generation:

F1

Effect level:

500 mg/m³ air

Sex:

male/female

Basis for effect level:

other: based on neonatal and perinatal mortality and body weight

Target system / organ toxicity (F1)

Key result

Critical effects observed:

no

Overall reproductive toxicity

Key result

Reproductive effects observed:

no

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/m3, resulting in a NOAEL of 499 mg/m3.

Executive summary:

In the fertility and reproduction studies, four groups of 20 male and 25 female rats each were exposed for 6 hrs/day, 5 days/wk (except holidays) for approximately 10.5 weeks. Each exposed male was then consecutively cohoused (1:1) with two unexposed females; exposed females were cohoused (1:1) with unexposed males. Treated males and females were exposed during the mating period (5 days/wk). Once mating occurred, treated females were exposed 7 days/wk through gestation day 20. Untreated female mates of exposed males were terminated approximately two weeks after copulation to assess fertility. Exposed females were housed in delivery boxes and delivered their pups. Pups were weaned on lactation Day 21 and necropsied. Mean analytical exposure concentrations were 20, 100, and 499 mg/3 in air. The mean body weight of exposed high level males was significantly reduced throughout most of the study. There were no treatment-related effects on mating, fertility, or reproduction parameters in exposed males or females. No gross or microscopic pathology changes were noted in FO or F1 animals.