Propan-1-ol

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

An OECD 443 extended one-generation study is currently beeing conducted. This information will be submitted later based on ECHA communication/decision number CCH-D-2114567364-43-01/F.

Link to relevant study records

Reference

Endpoint:

toxicity to reproduction

Remarks:

other: fertility and one generation

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

Study meets basic scientific principles with acceptable restrictions (only 15 females/dose group, only two doses tested, premating duration of males was only 6 weeks, no exposure during mating, treatment of females limited to gestation (F1 weaning period not included), no evaluation of male sexual parameters, limited clinical signs of toxicity, no gross pathology, no histopatholgy)

Principles of method if other than guideline:

Male animals were treated for 42 days, then mated with untreated virgin females . Resulting pregnant females were sham exposed on gestation days 1-19 (experiment 1). Another group of untreated males and females were mated. Resulting pregnant females were then exposed to the test substance on gestation days 1-19 (experiment 2). Examination of parental and pup- weights, as well as parental food consumption were performed. Uterus examinations were performed on sperm positive non-pregnant females.

GLP compliance:

no

Specific details on test material used for the study:

- Source: Matheson, Coleman, and Bell Manufacturing Chemists, Cincinnati, OH)
- Analytical purity: Grade I (> 99%)

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, Wilmington, MA
- Weight at study initiation: (P) Males: > 300g; Females: 175-200g
- Housing: males were housed individually throughout study, females were housed 3/cage and individually after mating
- Diet: ad libitum (except during exposure), NIH-07 rodent pellets (Zeigler Bros., Inc., Gardner, PA)
- Water: ad libitum (except during exposure), tap water
- Acclimation: 1-2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 +/-2
- Humidity (%): 50+/-10
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation

Type of inhalation exposure (if applicable):

whole body

Vehicle:

other: air

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 0.5 m3 Hinner inhalation chambers (Charles Spengler and Associates, Cincinnati, OH)
- Air change rate: 1 air change per minute
-Air flow rate: 0.5 m3/min
- Chamber conditions: 50 +/- 10% humidity and 23.3-25.6°C
- System of generating particulates/aerosols: Greensmith impinger

After terminatiion of vapour generation, the animals were degassed in exposure chambers for 15 min

Details on mating procedure:

Exposed males (42d), after a two day non-exposure delay, were mated individually with unexposed virgin females for a maximum of 5 days. Subsequently females were sham exposed on gestation days 1-19. Another group of untreated virgin females were mated with untreated breeder males before exposure of females on gestation days 1-19. Mating was confirmed in both cases by the presence of sperm plugs under the cages or by vaginal smears. After breeding, females were housed individually until parturition. After mating, all except the last six males were discarded. Because of infertility observed in the males exposed to the high level of propanol, the final six exposed males were remated at biweekly intervals to test for reversibility of infertility. These animals were not included in the behavioral teratology phase

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

TEST ATMOSPHERE
- Brief description of analytical method used: Using Miran 1A Infrared Analyzer attached to a strip chart recorder and charcoal tube analyses
- Time schedule for verification: 5 min and daily means range as well as time-weighted average concentrations were calculated. For charcoal tube analysis, sampling times varied from 10 to 30 min, with 13 samples collected each week over a two-day period


RESULT: Actual concentrations measured were close to target concentrations: 3510 ppm +/- 20 (daily mean averaging) and 3510 ppm +/- 20 (charcoal tube averaging) versus 3500 ppm target concentration for the lower dose and 7030 ppm +/- 80 (daily means generated from 5 min computer mean) versus 7000 ppm target concentration

Duration of treatment / exposure:

Experiment 1
- Males : 6 weeks premating
- Females: sham exposed


Experiment 2
- Males: sham exposed
- Females: day 1-19 of gestation

Frequency of treatment:

7 h /day, 7 days a week for the respective exposure period

At the end of each 7 h exposure, females of the treatment and control groups were left in the chambers for an additional 15 min degassing after vapor generation terminated

Dose / conc.:

8 730 mg/m³ air (nominal)

Dose / conc.:

17 460 mg/m³ air (nominal)

No. of animals per sex per dose:

- Females: 15
- Male: 18

Control animals:

other: Yes, sham exposed (only for experiments with maternal exposure)

Details on study design:

- Dose selection rationale: based on considerations of the exposures that produced teratogenicity in previous research
- Because exposures were conducted 2 months apart, seperate controls were run for each concentration of propanol.

Parental animals: Observations and examinations:

BODY WEIGHT: Yes
- Time schedule for examinations: weekly (both sexes), maternal body weights were mesured as follows;. measurements on gestation days 0, 7, 14, and 21). Within 16 hr after parturition, the dam was weighed

FOOD CONSUMPTION: Yes
- Time schedule for measurements: weekly (both sexes), measurements on gestation days 0, 7, 14, and 21 for females

WATER CONSUMPTION: Yes
- Time schedule for examinations: weekly, measurements on gestation days 0, 7, 14, and 21 for females

Litter observations:

STANDARDISATION OF LITTERS
Within 16 hr after parturition, the dams as well as her litter were weighed. All litters were culled to four pups/sex and forstered to untreated dams which had delivered within two days previously. On postnatal day 10 (birth=day 0), pups were randomly assigned to groups. Two pups from each of 5 foster litters were used as unhandled controls for neurochemistry. All extra pups, including those from the foster dams, were discarded. Although the occurrence was rare, litters not having at least three pups of each sex (i .e ., an abnormal sex ratio). discarded. Rats were weaned on day 25, and weighed individually on days 7, 14, 21, 28, and 35 (birth=day 0).

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals
- Maternal animals: All surviving animals

Statistics:

Data were analyzed as appropriate for each test including parametric (multivariate analysis of variance) or non-parametric analyses (m-ranking procedure) where assumptions that the data fit the normal distribution were tenuous. In all cases, p<= 0.05 was required for significance. When the same dose group of animals were used for multiple comparisons, Bonferroni corrections were made to adjust the probablilities required for significance.
Neurochemical data was analysed using multivariate analysis of variance and analysis of variance. For litter evaluations, the green house-Geisser correction was used on all within litter variable

BODY WEIGHT (PARENTAL ANIMALS)
- 3500 ppm: (male); the weights during 6 week exposure were 510(±24) g, 504(±26) g, 514(±29) g, 527(±30) g, 539(±32) g, and 554(±34) g.
- 3500 ppm (female) not affected by the test susbtance, weight gain also not affected
- 7000 ppm: (male), Although a group of sham-exposed males was not included, the lack of weight gain in the exposed males suggested that their weight gain was retarded during the first week of exposure, but likely normal thereafter. Weekly mean weights (±SD) for the six weeks the males were were 444(±40) g, 444(±38) g, 466(±36) g, 489(±38) g, 511(±38) g, and 528(±40) g.
- 7000 ppm (female): not affected by test substance

FOOD CONSUMPTION (PARENTAL ANIMALS)
- 3500 ppm (male): no data
- 3500 ppm (female): feed intake not influenced by the test substance
- 7000 ppm:(male); no data
- 7000 ppm:(female); feed intake was significantly (m-ranking technique; p< 0.05) reduced. Averages were 107(±13) vs. 134(±20) g in controls after 7d (79% of controls), 122(±12) vs 145(± 18) g in controls after 14d (84% of controls), and 137(±14) vs. 158(± 18) g in controls after 21d (86.7% of controls)


REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
3500 ppm: The number pregnant/number bred were 17/18 for maternally exposed rats, 17/18 for paternally exposed rats, 18/18 for controls and 52/56 for forster rats in the 7000 ppm group
7000 ppm: The number pregnant/number bred were 17/17 for maternally exposed rats, 2/16 for paternally exposed rats, 18/18 for controls and 38/40 for forster rats in the 7000 ppm group. Inspite of sperm plugs, 16 paternally exposed males (one died because of fighting, and another did not mate) only two litters resulted with populations of 12 and 2 pups, respectively. Because of the infertility in the males of this dose group, 6 of the animals (including the one male, which fathered the litter with 12 pups) were retained and mated at biweekly intervals. In week 1, 1 of the 6 (animal with proven fertility) produced litters, in week2 (2 of 6), in week 5 (4 of 6), in week 7 (4 of 5), in week 11 (3 of 6) and in week 13 and 15 (6 of 6) males produced litters. This indicates that the infertility was not permanent

OTHER:
No significant differences were found among any of the groups for the number of live pups per litter, the length of gestation, the birth weights, or neonatal survival

Dose descriptor:

NOAEC

Remarks:

(fertility)

Effect level:

8 730 mg/m³ air

Sex:

male

Basis for effect level:

other: Based on the reversible fertility effects [reduced pregnancy rate of females (non-exposed)] of males treated with 7000 ppm propan-1-ol (17.9 mg/l). Only 2 of 16 males produced litters in sperm positive females.

Critical effects observed:

no

TERATOGENIC EFFECTS
- 3500 ppm: no adverse effect observed
- 7000 ppm: 2 of 15 litters had several pups (2-3/litter) with crooked tails initially noted after birth. Effect persisted. There were no effects on offspring weight gain.

BEHAVIOUR
- 3500 ppm: the only significant differences between exposed animals and controls were in the activity measures. In the Open Field test, females from the paternally-exposed group were less active than the controls on days 44, 45, and 46. On the activity wheel, this same group was less active than the controls. In the optical activity monitor, males the maternally-exposed group were less active than control males on days 44, 45, and 46. No other significant differences were observed.
- 7000 ppm: exposed animals were not significantly different from controls on any of the tests

NEUROCHEMISTRY
- No significant difffences were noticed between offsprings of treated animals and controls

Dose descriptor:

NOAEC

Generation:

F1

Effect level:

8 730 mg/m³ air (nominal)

Sex:

not specified

Basis for effect level:

other: tail shape

Critical effects observed:

no

Reproductive effects observed:

yes

Lowest effective dose / conc.:

17 460 mg/m³ air (nominal)

Treatment related:

yes

Relation to other toxic effects:

reproductive effects in the absence of other toxic effects

Dose response relationship:

yes

Relevant for humans:

not specified

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

An OECD 443 extended one-generation study is currently beeing conducted. This information will be submitted later based on ECHA communication/decision number CCH-D-2114567364-43-01/F.

Further, in a study reported by Nelson et al 1985 &1989, adult male Sprague Dawley rats were exposed to vapours of propan-1-ol (> 99.1% purity) at concentrations of 0, 8730 mg/m³ and 17460 mg/m³. Males (18/dose) were dosed for 42 days before mating with female Sprague Dawley rats(15/dose). Females were sham exposed on gestation days 1 -20 at a frequency of 7 hours per day. While in the low dose group, 94% (17 out of 18 animals) of the males successfully produced offsprings, reproduction capacity was appreciably diminished in the high dose group with only 2 out of 16 males (12.5%) being able to father offsprings. This concentration also caused body weight reduction in the paternal animals. Within 6 weeks post termination of exposure, the males were again fertile with a 100 % successful pregnancy rate. Based on the observed reversible infertility at a concentration of 17560 mg/m³, the NOAEC for fertility can be set at 8730 mg/m³. According to the exposure conditions of the study, the statements related to female fertility are limited to the functional aspects of maintaining adequate and sufficient conditions for early extrauterine development and for its nidation.

Effects on developmental toxicity

Description of key information

Based on the available study with Sprague-Dawley rats a NOAEC for developmental toxicity of 8730 mg/m³ is established.

Link to relevant study records

Reference

Endpoint:

developmental toxicity

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

Remarks:

(only 15 females/dose group, treatment of females from gestation day 1-19)

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

(only 15 females/dose group, treatment of females from gestation day 1-19)

Principles of method if other than guideline:

The alcohols were administered by inhalation for 7 hours per day on gestation days 1-19 to groups of approximately 15 pregnant Sprague-Dawley rats. For developmental toxicology evaluations, dams were sacrificed on gestation day 20. Fetuses were serially removed, weighed, sexed, and examined for external malformations. The frequency of visceral malformations and variations was determined in one-half of the fetuses, and the frequency of skeletal deviations was determined in the other half.

GLP compliance:

not specified

Specific details on test material used for the study:

- Source: Matheson, Coleman, and Bell Manufacturing Chemists, Cincinnati, OH)
- Analytical purity: The purity of n-propanol, as measured by gas chromatography, was greater than that of the standard sample (102.1%). Infra-red spectra indicated that the purity of isopropanol was 97.6% (by vol.), with approximately 1% water detected .

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Wilmington, MA
- Weight at study initiation: (P) Males: >300g g; Females (virgin): 176-200 g
- Housing: males were housed individually throughout study, females were housed 3/cage and individually after mating
- Diet: ad libitum,(except during exposure periods), NIH-07 rodent pellets (Zeigler Bros., Inc ., Gardner, PA)
- Water: ad libitum (except during exposure periods), tap water
- Acclimation: 1-2 weeks (animals were free of mycoplasma, Sendai virus and external parasites)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24+/-2
- Humidity (%): humidity was not controlled but was generally about 40% (range 20-70%)
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

other: air

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 0.5 m3 Hinner inhalation chambers (Charles Spengler and Associates, Cincinnati, OH)
- Air change rate: 1 air change per minute
- Air flow rate: 0.5 m3/min
- Chamber conditions: 50 +/- 10% humidity and 23.3-25.6°C
- System of generating particulates/aerosols: Greensmith impinger

Analytical verification of doses or concentrations:

yes

Remarks:

chamber concentrations were monitored continuously by infra-red analyser; additionally charcoal tube samples were collected from the chamber atmosphere for independent verification of chamber concentrations and analysed by NIOSH analyticla methods

Details on analytical verification of doses or concentrations:

TEST ATMOSPHERE
- Brief description of analytical method used: Using Miran 1A Infrared Analyzer attached to a strip chart recorder and charcoal tube analyses ()
- Time schedule for verification: hourly and daily means, range and time weighted average concentrations were calculated. For charcoal tube analyses, sampling times varied from 10 to 30 min with a rate of sampling of 10 samples/week. Periodically, samples were collected from the control chamber filtered room air, and these were of approximately 6 hr duration. These samples were independently analysed by NIOSH analytical methods 1401

RESULT: Actual concentrations measured were close to target concentrations with no more than 10% deviations.

Details on mating procedure:

Breeder males were mated individually over a four day period with unexposed virgin females (200-300g). Mating was confirmed by the presence of sperm plugs under the cages or by vaginal smears (gestation day 0). After breeding, females were housed individually until parturition.

Duration of treatment / exposure:

- Females (postmating): day 1-19 of gestation

Frequency of treatment:

7 h/day, daily

Dose / conc.:

3 500 ppm (nominal)

Remarks:

nominal conc.

Dose / conc.:

7 000 ppm (nominal)

Dose / conc.:

10 000 ppm (nominal)

No. of animals per sex per dose:

females: 15

Control animals:

other: Yes (filtered air)

Details on study design:

After the termination of exposure, animals were left for a degassing period of 30 min in the exposure chambers

Maternal examinations:

BODY WEIGHT: Yes
- Time schedule for examinations: daily for the first week of exposure, then weekly thereafter.

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
- Time schedule for measurements: weekly, measurements on gestation days 0, 7, 14, and 20).

WATER CONSUMPTION: Yes
- Time schedule for measurements: weekly, measurements on gestation days 0, 7, 14, and 20).

ALCOHOL BLOOD LEVEL
- Number of animals: three young non pregnanat female rats were exposed for 1, 10 or 19 days.
- Concentration: 10,000 ppm
- Time schedule of examination: 5 min post termination of vapour generation
- Sampling: 5 ml blood from inferior vena cava (frozen in EDTA or heparin until analysis)
- Method of analysis: Sigma Ethyl Alcohol kit (no. 332-UV; Sigma Chemical Co.)

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of early and middle resorptions: Yes
- Number of late resorptions: Yes
- Number of live foetuses: Yes

Fetal examinations:

After sacrifice of dams on day 20, fetuses were serially removed, weighed, sexed, and examined for external malformations. The frequency of visceral malformations and variations was determined in one-half of the fetuses, and the frequency of skeletal deviations (malformations and variations) was determined in the other half.

Statistics:

Maternal data: parametric (multivariate analysis with baseline as covariate) or non-parametric multivariate analyses followed where appropriate by a Kruskal-Wallis test with paired comparisons. For the comparisons of corpora lutea, Kruskal-Wallis test was used

Foetal data: Analysis of variance was used to compare fetal weights across groups by sex. Group comparisons of litter size, percentage of live litter, percentage of normal foetuses/litter and percentage of females/litter were made using the Kruskal-Wallis test. For skeletal and visceral malformations and variations, external malformations and abnormal foetuses, the numbers of litters with one or more of the variables of interest were compared between groups using Fisher's exact test. Significance levels were set at P<= 0.05 and the results tests were adjusted for multiple comparisons using Bonferroni technique when necessary.

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
- 3500 ppm: reductions in maternal feed intake (10% below control values) which was however not statistically significant
- 7000 ppm: reductions in maternal feed intake in the last 2 weeks of gestation, but body weights were not affected
- 10000 ppm: reductions in maternal feed intake throughout gestation, reduced body weight gain seen only at the end of gestation,

Dose descriptor:

NOAEC

Effect level:

17 460 mg/m³ air (nominal)

Basis for effect level:

other: maternal toxicity

Abnormalities:

no effects observed

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
See attachment below for detailed results

3000 ppm: no adverse effects observed
7000 ppm: body weights were significantly less than controls (see table 1 below), incidence of skeletal malformations (primarily rudimentary cervical ribs), significantly increased from controls
10000 ppm: body weights were significantly less than controls (see table 1 below), incidence of external malformations (ectrodactyly or missing tail, in at least 1/3 of the foetuses) significantly increased compared to controls, incidence of skeletal malformations (mostly rudimentary cervical ribs) significantly increased compared to controls, incidence of visceral malformations (primarily cardiovascular or urinary defects) significantly increased compared to controls, incidence of resorptions significantly increased compared to controls (3/15 litters totally resorbed; 57% resorptions/litter versus 6% in control resorptions/litter), incidence of live implants/litter significantly reduced compared to controls with 43% vs 94% in controls.

Overall, in order of increasing concentrations of n-propanol, the numbers of litters with skeletal or visceral malformations/number of litters examined were 5/15, 2/15, 9/15 and 12/12.

Dose descriptor:

NOAEC

Effect level:

8 730 mg/m³ air (nominal)

Basis for effect level:

other: Based on reduced fetal body weights and higher incidence of rudimentary cervical rips

Dose descriptor:

LOAEC

Effect level:

17 460 mg/m³ air (nominal)

Basis for effect level:

other: developmental toxicity

Abnormalities:

effects observed, treatment-related

Localisation:

other: body weights

Description (incidence and severity):

foetal body weights were sigificantly less than controls (dose groups 7000 and 10000 ppm)

Abnormalities:

effects observed, treatment-related

Localisation:

skeletal: rib

other: rudimentary cervical ribs

Description (incidence and severity):

dose group 7000 ppm and 10000 ppm

Abnormalities:

effects observed, treatment-related

Localisation:

external: limb

external: tail

other: ectrodactyly; missing tail

Description (incidence and severity):

Dose group 1000 ppm

Abnormalities:

effects observed, treatment-related

Localisation:

visceral/soft tissue: urinary

visceral/soft tissue: cardiovascular

Description (incidence and severity):

Dose group 10000 ppm

Abnormalities:

effects observed, treatment-related

Localisation:

other: resorptions

Description (incidence and severity):

significantly increased incidence of resorptions in dose group 10000 ppm

Abnormalities:

effects observed, treatment-related

Localisation:

other: live implants

Description (incidence and severity):

significantly reduced incidence of alive implants/litter in dose group 1000 ppm

Developmental effects observed:

yes

Lowest effective dose / conc.:

17 460 mg/m³ air (nominal)

Treatment related:

yes

Relation to maternal toxicity:

not specified

Dose response relationship:

yes

Relevant for humans:

not specified

Table 1: Reproductive observations made at the time of caesarean section of rats exposed for 7 h/d to n- propanol

Parameter	0 ppm	3500 ppm	7000 ppm	10000 ppm
Number bred	16	15	15	15
Number pregnant	15	15	15	15
Mean no. of corpora lutea/dam	15.1	15.9	14.1	14.6
Mean no. of implants/dam	15.6	15.5	13.9	14.1
Implants resorbed/litter (%)	6	4	11	57*
Implants alive/litter (%)	94	96	89	43*
Mean foetal weights ± SD (g)
Female	3.16 ± 0.26	3.14 ± 0.33	2.6 ± 0.32*	1.7 + 0.25*
Male	3.33 ± 0.26	3.3 ± 0.34	2.77 ± 0.30 *	1.79 ± 0.29 *

* significantly different from controls (p= 0.05; Kruskal-Willis test for corpora lutea comparisons and ANOVA for foetal data

BLOOD CONCENTRATIONS

8 young female rats were treated with 10000 ppm of n-propanol. They were all completely narcotized at the end of the 7 hour exposure period. 3 were killed for blood analysis (see table 2 below). The remaining 5 were still under narcosis 90 min after exposure and were dead by the next morning

Table 2: Blood levels of n-propanol after exposure of groups of three non pregnant adult female and young rats by inhaltion for 7h/d for up to 19 days

	Blood levels (mg/dl) after
Concentration	1	10	19
3500	2.6 (2.4-3.1)	ND	ND
7000	4.2 (3.3-5.9)	4.9 (2.1-9.1)	4.3 (3.1-5.8)
10000*	6.6 (6.1 and 7.7)	-	-
10000**	164 (147-198)	-	-

* The third rat had a blood level of 66.5 which was assumed to be an error and was deleted

** Young rats weighing 110-120g were exposed to 10,000 ppm n-propanol

ND: not detectable

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEC

17 460 mg/m³

Species:

rat

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

An OECD 414 developmental toxicity study in rabbits is currently beeing conducted. This information will be submitted later based on ECHA communication/decision number CCH-D-2114567364-43-01/F.

 

One study of adequate reliability is available for the assessment of developmental toxicity (Nelson et al 1996). This developmental toxicity study is comparable to the guideline (OECD 414) requirement for a developmental toxicity study in rats. Deviations from guideline were in the chosen treatment period and the number of pregnant females per dose group.In this study, propan-1-ol was administered via inhalation to 15 pregnant Sprague Dawley rats per dose at dose levels of 0, 8730, 17460 and 24940 mg/m³, 7 hours/day from days 1 through 19 of gestation. Significantly reduced body weight gain and reduced feed intake were toxic responses to propan-1-ol manifested by the dams exposed to concentrations of 24960 mg/³ and above. At 17460 mg/m³ maternal feed intake was reduced during the last two weeks of gestation. NOAEC for maternal toxicity was 8730 mg/m³. Fetal body weight were significantly reduced from the 17460 mg/m³ dose group and above. Also, there were increased incidences of primary rudimentary cervical ribs in the two highest doses. Significantly increased incidences of missing tail and visceral malformations (primarily cardiovascular and urinary defects) were also noted. Increased incidences of dead implantations and resorptions in comparison to controls were present in the 25940 mg/m³ dose group. Thus, the NOAEC for developmental toxicity is 8730 mg/m³ based on reduced fetal body weights and an increased incidence of primary rudimentary cervical rips. To summarize, developmental toxic effects were noted at very high doses where also maternal toxic effects were observed. The toxic concentrations of 17460 and 23940 mg/m³ can be converted to an oral uptake of approximately 4350 and 6225 mg/kg bw/day, assuming respiratory rate of 0.8 L/min/kg for rats and a inhalatory resorption of 75% (see chapter "Toxicokinetics, metabolism and distribution"). The calculated oral uptake of 4350 mg/kg bw/day is more than 4 -fold of the limit dose for classification. The NOAEC of 8730 mg/m³ would be equivalent to a daily dose of 2175 mg/kg bw/day which corresponds to 150 g/person/day for a 70 kg person.

 

Further, in a study by Grant and Samson (1984) neonatal rats were exposed to propan-1-ol via an artificial milk formula for 4 consecutive days and a recovery period of 10 days. On postnatal days 5, 6, 7 and 8 the neonates received propan-1-ol doses of 3800, 7500, 3000 and 7800 mg/kg bw respectively via stomach tube. Twenty-one of the animals completed the experiment. Seven of the animals died: four resulting from surgical complications and three to apparent propanol overdose. It is reported that during the period of propanol administration, the alcohol exposed animals were observed to be intoxicated, frequently showing an impaired righting response. After the 18th day of age there were no effects on body weight or on absolute weight of kidneys, heart, or liver. But the absolute and relative brain weights were decreased in the exposed neonatal rats. The amount of DNA was in all brain areas decreased. Cholesterol levels were decreased in the forebrain and cerebellar samples (Grant and Samson 1984). The study by Grant and Samson (1984) is of limited validity and not appropriate to be used as a study to derive a NOAEL for developmental toxicity (or repeated dose toxicity) due to the following reasons: a completely artificial rearing procedure had been used including implantation of a gastric catheder by surgical procedure to 5 day old pups; the pups were taken off their dams during the whole treatment period and kept isolated in individual plastic cups to compensate for maternal deprivation; 25% of neonates died due to surgical complications as well as from apparent propan-1-ol overdose. It is reported that the alcohol exposed pups were intoxicated during the period of propan-1-ol administration (cf. impaired righting response indicating acute neurotoxic effects) and, furthermore, that pups suffered from acute withdrawl symptoms 8 h after the last exposure (including spontaneous seizures, full body shakes, severe head bobbing, etc.). Therefore this study can not be used for teh assessment of effects on developmental toxicity via oral route of administration.

Justification for classification or non-classification

An OECD 443 extended one-generation study in rats and an OECD 414 developmental toxicity study in rabbits are currently beeing conducted. This information will be submitted later based on ECHA communication/decision number CCH-D-2114567364-43-01/F.

Reversible effects on male fertility revealed in the study reported by Nelson occurred at very high inhalatory concentrations of 17460 mg/m³. Assuming a respiratory rate of 0.8 l/min/kg this concentration would be equivalent to an uptake of 5800 mg/kg bw/day which is more than 5 -fold of the limit dose relevant for classification. Thus, a classification as toxic to reproduction is considered to be not warranted.

Developmental toxic effects were observed at concentrations at which also maternal toxic effects occurred. Furthermore, these concentrations corresponds to very high oral uptakes which are far above the limit dose relevant for classification (s. above). Thus, the classification of propan-1-ol under the criteria of Regulation (EC) No 1272/2008 is not warranted.