Propan-2-ol

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Information on the reproductive toxicity of IPA is available from an oral gavage study, conducted according to OECD Test Guideline 416 and in compliance with GLP in rats. The NOAEL for parental toxicity was 500 mg/kg bw/day. The NOAEL for reproductive effects was 1000 mg/kg bw/day. The NOAEL for offspring toxicity was 500 mg/kg bw/day.  

Additionally, the reproductive toxicity of IPA was assessed in a one-generation study in rats, conducted according to a method equivalent to OECD Test Guideline 415 and in compliance with GLP.  Based on a review of the data, it is proposed that the NOAEL for parental toxicity was 347 mg/kg bw/day (the lowest calculated parental IPA intake for 0.5% IPA in drinking water) and that the NOAEL for reproductive effects was 853 mg/kg bw/day (the lowest calculated maternal IPA intake for 1.0% IPA in drinking water). From the available data, it can be concluded that IPA does not affect male mating ability of fertility at doses up to approx. 1000 mg/kg bw/day.

A one-generation study involving administration of IPA at concentrations ranging from 1.25 to 2.5% in drinking water did not identify a NOAEL.

Link to relevant study records

Reference

Endpoint:

two-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1992

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Well documented, according to accepted guidelines

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)

Deviations:

no

GLP compliance:

yes

Limit test:

no

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, Inc, Kingston facility, Stone Ridge, New York.
- Age at study initiation: (P) 8 wks; (F1) 8 wks
- Weight at study initiation: (P) Males: 265.5-331.9 g; Females: 175.2-228.4 g; (F1) Males: 265.2-265.4 g; Females: 181.1-181.2 g
- Fasting period before study: None
- Housing: stainless steel and wire mesh cage, individually housed, except during the first week of quarantine, during mating, and during lactation
- Diet (e.g. ad libitum): Purina certified rodent chow ad libitum
- Water (e.g. ad libitum): automatic watering system, ad libitum (Elizabethtown Water Company, Elizabeth, New Jersey)
- Acclimation period: 21 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 24.4°C
- Humidity (%): 40 to 70 %
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: June 13, 1990 To: April 15, 1992

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Undiluted test material was thoroughly miscible in carrier (RO water) prior to dispensing. Test material dosing solutions were prepared at 6-15 day intervals, in consideration of laboratory scheduling/ Dosing solutions were aliquoted on or prior to the first scheduled day of dosing. Aliquoted dosing solutions were stored in the Compound Preparation Department refrigerator. Unused portions were returned to the Compound Preparation Lab for disposal.

DIET PREPARATION
not administered in diet

VEHICLE
- Justification for use and choice of vehicle (if other than water): vehicle used was water

Details on mating procedure:

- M/F ratio per cage: 1/1
- Length of cohabitation: when pregnant or 7 days had elapsed (then cohabited with a different male)
- Proof of pregnancy: copulatory plug or sperm in vaginal smear referred to as day 0 of pregnancy
- After 7 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: yes 3 attempts
- After successful mating each pregnant female was caged (how): individually

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Samples of isopropyl alchohol dose solutions in reverse osmosis water were analyzed by Gas Chromatography for concentration verification.

Duration of treatment / exposure:

All P1 and F1 (P2) male and female animals received test or control material daily for at least 10 weeks prior to mating, throughout the mating period, and until the day prior to euthanasia. Additionally, P1 and F1 (P2) females received test or control material during gestation, lactation, and until the day prior to euthanasia, following weaning of their offspring on day 21 postpartum. F1 neonates prior to selection for mating received test or control material beginning on postnatal day 21.

Frequency of treatment:

daily

Details on study schedule:

- F1 parental animals not mated until 11 weeks after selected from the F1 litters.
- Selection of parents from F1 generation when pups were 21 days of age.
- Age at mating of the mated animals in the study: 15 weeks

Remarks:

Doses / Concentrations:
100 mg/kg bw/day
Basis:
actual ingested

Remarks:

Doses / Concentrations:
500 mg/kg bw/day
Basis:
actual ingested

Remarks:

Doses / Concentrations:
1000 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

30/sex/dose

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: not reported
- Rationale for animal assignment (if not random): random

Positive control:

no

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: morning and afternoon


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: prior to selecton, first day of dosing and weekly thereafter until euthanasia (males) or weekly until post partum day 21 (females)


BODY WEIGHT: Yes
- Time schedule for examinations: prior to selecton, first day of dosing and weekly thereafter until euthanasia (males) or weekly until post partum day 21 (females)

Oestrous cyclicity (parental animals):

not reported

Sperm parameters (parental animals):

not reported

Litter observations:

STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, maximum of 8 pups/litter (4/sex/litter as nearly as possible); excess pups were killed and discarded.


PARAMETERS EXAMINED
The following parameters were examined in F1 / F2 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, and physical abnormalities.


GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals as soon as possible after the last litters in each generation were produced.
- Maternal animals: All surviving animals after the last litter of each generation was weaned.


GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations.


HISTOPATHOLOGY / ORGAN WEIGHTS
The following organs and tissues were prepared for microscopic examination: liver, kidney, vagina, uterus, ovaries, testes, epididymides, seminal vesicles, prostate, pituitary, liver, and any abnormal tissue

Postmortem examinations (offspring):

SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at 21 days of age.
- These animals were subjected to postmortem examinations macroscopic and microscopic examination


GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations

Statistics:

The following parameters were analyzed statistically for significant differences: mean body weights; mean food consumption; mean organ weights; mean relative organ weights

Reproductive indices:

calculated

Offspring viability indices:

calculated

Clinical signs:

no effects observed

Description (incidence and severity):

Free of any observable abnormalities

Mortality:

mortality observed, non-treatment-related

Description (incidence):

1 death in control and 1 death in mid-dose group considered to be incidental. 2 deaths in high-dose group, cause of death was not determined

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Males: no effects observed. Females: body weight gain of high-dose group increased relative to control during overall postpartum period.

Food consumption and compound intake (if feeding study):

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

no effects observed

Other effects:

no effects observed

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Dose descriptor:

NOAEL

Remarks:

parental toxicity

Effect level:

500 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

body weight and weight gain

Dose descriptor:

NOAEL

Remarks:

reproductive toxicity

Effect level:

> 1 000 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

reproductive performance

Clinical signs:

no effects observed

Mortality:

mortality observed, non-treatment-related

Description (incidence):

2 deaths in low-dose group, 1 death in mid-dose group, 2 deaths in high-dose group: cause of death was not determined

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Males: no effects observed. Females: body weight gain of mid- and high-dose groups increased relative to control during overall postpartum period.

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Mean absolute and relative liver weights in mid-dose P1 males and relative liver weights in high-dose P1 males were statistically significantly increased compared to controls. Relative kidney weights in high-dose P1 males were increased compared to controls.
In females, relative liver weight was increased in the mid-dose group and absolute and relative liver weight was increased in the high-dose group. Relative kidney weight was increased in the high-dose group.
These effects were not considered to be adverse.

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

centrilobular hepatocyte hypertrophy was observed in a few high-dose P1 male rats.

Reproductive performance:

no effects observed

Dose descriptor:

NOAEL

Remarks:

parental toxicity

Effect level:

500 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

organ weights and organ / body weight ratios

histopathology: non-neoplastic

Dose descriptor:

NOAEL

Remarks:

reproductive toxicity

Effect level:

> 1 000 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

reproductive performance

Clinical signs:

no effects observed

Mortality / viability:

mortality observed, treatment-related

Description (incidence and severity):

Increased mortality was observed in high-dose F1 offspring compared with controls from postnatal Days 0 to 4. Increased mortality in mid-dose F1 offspring compared with controls observed at postnatal Day 4. Several F1 weanlings died or were euthanized prior to P1 selection; 1 each in the low- and mid-dose groups, and 18 in the high-dose group.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

High-dose F1 male body weights were significantly lower on postnatal days 0 and 1 compared to controls.

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

Dose descriptor:

NOAEL

Remarks:

offspring toxicity

Generation:

F1

Effect level:

100 mg/kg bw/day

Sex:

male/female

Basis for effect level:

viability

body weight and weight gain

Clinical signs:

no effects observed

Mortality / viability:

mortality observed, treatment-related

Description (incidence and severity):

Increased mortality was observed in mid- and high-dose F2 offspring compared with controls at postnatal Days 1 and at postnatal Day 7, but not at postnatal Day 4.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

High dose F1 male and female body weights were significantly lower on postnatal days 0 to 4 compared to controls.

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

Dose descriptor:

NOAEL

Remarks:

offspring toxicity

Generation:

F2

Effect level:

100 mg/kg bw/day

Sex:

male/female

Basis for effect level:

viability

body weight and weight gain

Reproductive effects observed:

no

Executive summary:

In conclusion, a dose of 1000 mg of isopropanol per kg of body weight produced evidence of parental effects, as indicated by increases in absolute and/or relative liver and/or kidney weights compared wtih those of controls. In addition, increased absolute or relative liver weights were observed in parental animals dosed with 500 mg/kg compared with controls. These effects were not considered to be an adverse effect. However, treatment-related centrilobular hepatocyte hypertrophy was observed in a few high dose P2 male rats. Increased mortality was observed in high dose F1 offspring compared with controls. In addition, high dose offspring of both generations were lighter than controls at several intervals. Therefore, the parental NOAEL (No Observed Adverse Effect Level) was established at 500 mg/kg of isopropanol, while the reproductive NOAEL was established at greater than 1000 mg/kg under the conditions of this study. The offspring toxicity NOAEL was established at 500 mg/kg based on reduced offspring body weights and increased mortality observed at 1000 mg/kg. Subsequent review of the publication established the offspring toxicity NOAEL at 100 mg/kg bw/day based on increased mortality at 500 and 1000 mg/kg bw/day and reduced body weights at 1000 mg/kg bw/day in the F1 and F2 generations. Reprotoxicity was only observed in the presence of maternal toxicity.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

The key oral gavage, multi-generation study conducted according to a method equivalent to OECD Test Guideline 416 and in compliance with GLP is available (Beyer, 1992) The NOAEL for parental toxicity was reported to be 500 mg/kg bw/day due to increased organ weights at 1000 mg/kg bw/day. The NOAEL for reproductive effects was 1000 mg/kg bw/day. T The NOAEL for offspring toxicity was 100 mg/kg bw/day due to increased mortality at 500 and 1000 mg/kg bw/day and reduced body weights at 1000 mg/kg bw/day in the F1 and F2 generations.

The reproductive toxicity of isopropanol (IPA) was assessed in a study conducted according to a method equivalent to OECD Test Guideline 415 (one-generation reproduction toxicity study) and in compliance with GLP. Wistar rats were administered IPA at concentrations of 0 (tap water), 1.25, or 2.0% in drinking water (Faber, 2008). Based on water intake, these dose concentrations corresponded to IPA dose levels of 383, 686, and 1107 mg/kg bw/day during the premating period; and 347, 625, and 1030 mg/kg bw/day for 18 weeks of treatment in males. In females, IPA intake was calculated to be 456, 835, and 1206 mg/kg bw/day during the premating period; 668, 1330, and 1902 mg/kg bw/day during the gestation period; and 1053, 1948, and 2768 mg/kg bw/day during the post partum phase. F0 Generation: There were no mortalities, abortions, or early deliveries reported. Adult male food consumption was decreased in all dose groups compared to controls. This corresponded with decreased body weights in the 2.0% dose group, and a transient slight decrease in body weight in animals treated with 0.5 and 1.0% IPA. Water intake was decreased in male rats treated with IPA; however, intake returned to normal levels in the 0.5% group. Food consumption also was decreased in adult females treated with 1.0 and 2.0% IPA; however, decreases noted in the 1.0% group had recovered by the second day of gestation. Body weights in IPA-treated adult females were lower than those reported for the control group at the start of gestation, but had recovered during gestation except in the 2.0% group. Following parturition, body weights for all dose groups were initially similar to controls; however, decreased body weights were noted in the 2.0% dose group on and after post-natal day 4. Water consumption was initially decreased in females treated with 1.0 and 2.0% IPA, but had returned to control levels in the 1.0% IPA group by the third day of treatment.

A slight-dose dependent decrease in red blood cells in the 2.0% group adult males and 1.0 and 2.0% adult females was noted. For males, a slight increase in mean cell volume in the mid- and high-dose groups was observed. Increased absolute and relative kidney weights, and relative liver and spleen weights were noted in high-dose F₀ males. Statistically significant increased absolute liver and kidney weight, and relative liver weight were noted in the 2.0% F₀ females.

There were no effects of IPA exposure on fertility. The number of pups per litter on post-natal day 1 was decreased in the 2.0% group. This increase was attributed to the cannibalism of the pups by the Dam and decreased pup survival, as a decrease in litter size was not observed in the embryotoxicity study. In the embryotoxicity study, increased preimplantation loss, a decrease in mean litter weight, and a decrease in mean fetal body weight was noted in the 2.0% group.

F1 Generation: Average pup weight was decreased in the 2.0% group on post-natal day 7. Increased mean relative liver weight was reported in F₁ males and females at the 2.0% dose level. High-dose F₁ males also had higher relative kidney weights. Slight increases in absolute brain weight and increased relative empty caecum weight were noted in high-dose F₁ males and females. There were no gross abnormalities noted in the F₁ generation at necropsy.

Based on a review of the data it is proposed that the NOAEL for parental toxicity be considered to be 347 mg/kg bw/day (based on the lowest calculated parental IPA intake for 0.5% IPA in drinking water). The proposed NOAEL for reproductive toxicity is 853 mg/kg bw/day (based on the lowest calculated maternal IPA intake for 1.0% IPA in drinking water) on the basis of effects noted on pre-implantation loss, mean litter and fetal body weight, and fetal survival at the 2.0% dose level.

A supporting GLP-compliant pilot study equivalent to the OECD test guideline 415 in rats served as a range finding study. This study did not identify a NOAEL at IPA dose concentrations of 0, 1.25, 2.0, or 2.5% in drinking water (Gaunt, 1986). Decreased adult food and water consumption, decreased adult and pup body weight gain, evidence of embryotoxicity (i.e., fewer live pups, increase in pup mortality, and reduction in pup body weight gain), signs of anaemia, and increased liver and kidney weights were noted. These effects were mainly seen at the 2.0 and 2.5% dose concentrations compared to the control.

Effects on developmental toxicity

Description of key information

A GLP prenatal development study in rats, equivalent to OECD Test Guideline 414, identified an oral NOAEL of 0.5% (596 mg/kg bw/day) for maternal and developmental toxicity.  There were no teratogenic effects reported.  Supportive GLP developmental toxicity studies, similar to OECD Guideline 414, in New Zealand White rabbits and rats showed that isopropanol was not teratogenic at the dose levels administered.  In rabbits, the reported maternal and developmental NOAELs were 240 and 480 mg/kg bw/day, respectively.  In rats, the NOAEL for maternal and developmental toxicity was considered to be 400 mg/kg bw/day.

Effect on developmental toxicity: via oral route

Dose descriptor:

NOAEL

596 mg/kg bw/day

Additional information

The developmental toxicity of isopropanol (IPA) was assessed in a prenatal development toxicity study conducted according to a method equivalent to the OECD Test Guideline 414 and in compliance with GLP (Faber, 2008). Wistar rats were administered 0 (tap water), 0.5, 1.25, or 2.5% IPA in drinking water. These dose levels were equivalent to 0, 596, 1242, and 1605 mg/kg bw for the low-, mid-, and high-dose groups, respectively. There were no mortalities reported. Reduced food and water consumption was noted at the 1.25 and 2.5% dose levels. A slight decrease in water consumption was observed in the 0.5% dose group on the first day of dosing, but this did not achieve statistical significance. Body weight loss was noted from gestation days 6 to 8 in the 2.5% dose group, and decreased body weight gain was noted thereafter during the dosing period. Decreased body weight gain was noted in the low dose group on the first day of treatment, and for the first two days of treatment in the mid-dose group. After cessation of treatment, the dams in the 2.5% dose level reported increased weight gain comped to controls. Overall, body weights of the 2.5% dose group were lower than those reported for control animals from gestation day 7 through to termination. There were no effects on embryotoxic parameters. A slight dose-dependent decrease in fetal litter weight was observed. Statistically significant decreased mean fetal weight was noted at the 1.25 and 2.5% dose levels. A statistically significant increase in variations was reported in treated animals and was indicative of a lower degree of ossification. These changes may have been secondary to decreased water and food consumption, secondary to palatability problems. The authors proposed that fetotoxicity, as manifested by reduced fetal body weights, only occurred at dose levels that also caused maternal toxicity (decreased food and water consumption).

A NOAEL was not reported by the study authors. The NOAEL for maternal toxicity is considered to be 0.5% (596 mg/kg bw/day) due to decreased food and water consumption, and corresponding effects on body weight at higher dose levels. The NOAEL for fetal toxicity is considered to be 0.5% (596 mg/kg bw/day) on the basis of reduced body weights at higher dose levels.

The developmental toxicity of IPA has been tested in a study conducted according to a method similar to OECD Test Guideline 414 and in compliance with GLP using New Zealand White rabbits (Tyl et al., 1990b, cited in Faber et al. 2008). In this study maternal mortality, reduced body weight gain, reduced food consumption and severe clinical signs of toxicity were noted at 480 mg/kg bw/day. These findings were mild and nonspecific at lower dose levels. There was no evidence of fetotoxicity or teratogenicity at any dose tested.  The NOAEL for maternal toxicity was determined to be 240 mg/kg bw/day and the NOAEL for developmental toxicity was 480 mg/kg bw/day.

A supporting study is available in which IPA was tested in a oral gavage, prenatal development study in rats, conducted according to a method equivalent to the OECD Test Guideline 414 and in compliance with GLP (Tyl et al., 1990a, cited in Faber et al. 2008). This study showed no evidence of fetotoxicity or teratogenicity following IPA administration. The NOAEL for maternal and developmental toxicity was 400 mg/kg bw/day in rats. The basis of this NOAEL was maternal mortality noted at doses up to 1200 mg/kg bw/day.   

Justification for classification or non-classification

The substance does not meet the criteria for classification and labelling for reproductive or developmental toxicity according to Regulation (EC) No. 1272/2008.