sec-butylamine

Toxicity to reproduction

Administrative data

Endpoint:

one-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: GLP study, 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

Guideline:

OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]

Deviations:

yes

Remarks:

Dosing of females only until gd 21 No information on termination of male rats, no dosing during lactation until weaning; pathology of P-generation limited?

GLP compliance:

yes

Justification for study design:

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 IPA per cubic
meter.

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

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 d wks; (F1) x wks
- Weight at study initiation: (P) Males: 241 - 300 g; Females: 163 - 207 g
- Fasting period before study:

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

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

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

Remarks:

Doses / Concentrations:
20, 100, and 499 mg/m3
Basis:
analytical conc.
- Distribution: range 1.8-10% - Stability: range 11-15%

Doses / concentrations 2

Remarks:

Doses / Concentrations:
21, 109 and 526 mg/m3
Basis:
nominal conc.
average

Doses / concentrations 3

Dose / conc.:

20 mg/m³ air (analytical)

Doses / concentrations 4

Dose / conc.:

100 mg/m³ air (analytical)

Doses / concentrations 5

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

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 generation)

General toxicity (P0)

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

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

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

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

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

Histopathological findings: non-neoplastic:

no effects observed

Other effects:

not examined

Description (incidence and severity):

Test substance intake: not applicable (inhalation)

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)

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

Results: F1 generation

General toxicity (F1)

Clinical signs:

not specified

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

not examined

Gross pathological findings:

no effects observed

Histopathological findings:

no effects observed

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

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.

Executive summary:

The purpose of these studies was to examine the toxicity of inhaled isopropylamine (IPA) in Sprague-Dawley rats and their offspring.

This project consisted of three studies: a male fertility study, a female reproduction study, and a subchronic toxicity study.

Animals in these three studies were exposed concurrently.

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 IPA per cubic meter. 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.

The following information is taken into account for any hazard / risk assessment:

NOAEC = 500 mg/m3: No adverse effect on reproductive performance in the P-generation and no adverse effects on development of the progeny of the P-generation (F1)