Potassium tert-butanolate

Toxicity to reproduction

Administrative data

Endpoint:

two-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:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well documented publication similar to guideline

Data source

Reference

Reference Type:

publication

Title:

Two-generation Reproduction Toxicity Study with Isopropanol in Rats

Author:

C. Bevan

Year:

1995

Bibliographic source:

JOURNAL OF APPLIED TOXICOLOGY, VOL . 15(2), 117-123 (1995

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)

Deviations:

yes

Remarks:

Oestrus cycle and sperm parameters including sperm motility and morphology were not evaluated

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

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

Test material form:

other: colorless liquid

Details on test material:

- Name of test material (as cited in study report): Isopropanol
- Physical state: colorless liquid
- Analytical purity: 99 %

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Kingston, NY
- Housing: during mating co-housed, afterwards single housing
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 68-80°F
- Humidity (%): 18-70 %
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Test material was administered by gavage as a single daily dose in reverse osmosis water at a volume of 5 ml/kg.

Details on mating procedure:

- M/F ratio per cage: 1 male rat was co-housed with 1 female
- Length of cohabitation: 7 days
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy: observation of a copulatory plug or presence of sperm in a vaginal rinse .
- After 7 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: yes, same procedure was repeated after 7 days
- After successful mating each pregnant female was caged (how): single

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analyses for concentration were performed periodically throughout the study to confirm isopropanol concentrations in dosing solutions.

Duration of treatment / exposure:

10 weeks prior to mating, during mating, gestation, lactation and until the day prior to euthanasia, following weaning of the offspring

Frequency of treatment:

once daily

Details on study schedule:

Offspring of the P1 generation were designated as F1 generation. At weaning on postnatal day 21 (PND 21), two pups of each sex per litter were selected to become a pool of animals from which the P2 generation would be chosen. The selected P2 populations consisted of 30 neonates of each sex, while the selected P2 of the 1000 mg/kg group consisted of 26 neonates of each sex. They began receiving treatment on PND 21 .

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 100, 500 or 1000 mg/kg
Basis:
actual ingested

No. of animals per sex per dose:

30 rats per sex per group

Control animals:

yes, concurrent vehicle

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations checked: viability

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

Results and discussion

Results: P0 (first parental generation)

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS): Seven parental animals died during the study, but deaths were due to intubation errors and not treatment-related

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): increased body weight gain in P1 females at 1000 mg/kg bw and P2 females at 500 and 1000 mg/kg bw; no effects on food consumption occurred

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS): Male mating index was significantly reduced in the P2 generation at 1000 mg/kg.

ORGAN WEIGHTS (PARENTAL ANIMALS): Absolute (abs) and relative (rel) liver weights of P1 male animals treated with 1000 mg/kg were increased. Abs liver weights of P2 males were increased in the 500 mg/kg group, rel. liver weights of the P2 male animals were increased in the 500 and 1000 mg/kg groups. Rel. kidney weights were increased in P2 males receiving 1000 mg/kg. Abs. liver weights of the P2 females were increased in the 1000 mg/kg group, whereas rel. liver weights were increased in P1 and P2 females receiving 500 and 1000 mg/kg. Rel. kidney weights were increased in the P1 and P2 female animals dosed with 1000 mg/kg.

GROSS PATHOLOGY (PARENTAL ANIMALS): no treatment-related finding were observed

HISTOPATHOLOGY (PARENTAL ANIMALS): Kidney effects at the mid- and high-dose group of male animals were characterized by an increased number of hyaline droplets in epithelial cells of the proxima convoluted tubules, increased incidence and severity of epithelial degeneration and hyperplasia, increase incidence of proteinaceous casts in the renal tubules and increased incidence of focal interstitial mononuclear cell infiltration.
Regarding liver effects centrilobular hepatocyte hypertrophy was observed in six of 26 P2 male animals dosed with 1000 mg/kg (P<0 .01).

OTHER FINDINGS (PARENTAL ANIMALS): No treatment-related microscopic changes could be observed in the reproductive tissues, liver, kidneys or tissues with gross abnormalities at post-mortem examination.

Effect levels (P0)

Dose descriptor:

NOAEL

Effect level:

ca. 500 mg/kg bw/day

Based on:

test mat.

Sex:

male

Basis for effect level:

other: decreased male mating index

Results: F1 generation

Details on results (F1)

VIABILITY (OFFSPRING): In the F1 generation, live birth index was decreased at 1000 mg/kg as well as survival index day 1 and 4; in the F2 generation, Survival index was decreased at day 1, 4, and 7; here, lactation index was also significantly decreased

CLINICAL SIGNS (OFFSPRING): no effects were observed

BODY WEIGHT (OFFSPRING): were significantly decreased during the first 4 days in the highest dose group

GROSS PATHOLOGY (OFFSPRING): no treatment related findings

HISTOPATHOLOGY (OFFSPRING):

OTHER FINDINGS (OFFSPRING): no treatment-related abnormalities could be detected, milk was present in the stomach

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

ca. 100 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: reduced body weight and reduced survival during the first 4 days

Results: F2 generation

Effect levels (F2)

Dose descriptor:

NOAEL

Generation:

F2

Effect level:

ca. 100 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: decreased body weight and decreased survival during the first 7 days

Overall reproductive toxicity

Reproductive effects observed:

not specified

Any other information on results incl. tables

Increased female liver weights in the absence of histopathological findings were considered to be adaptive changes in response to increased metabolism. The kidney effects noted in the treated male rats are characteristic of hyaline droplet nephropathy, also known as a2u-globulin nephropathy and are not considered to be relevant for human beings.