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Toxicological information

Toxicity to reproduction

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Administrative data

toxicity to reproduction
other: fertility and one generation
Type of information:
experimental study
Adequacy of study:
supporting study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
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)

Data source

Referenceopen allclose all

Reference Type:
Comparison of Behavioral Teratogenic Effects of Ethanol an N-Propanol administered by Inhalation to Rats
Nelson B.K., Brightwell W.S., Burg J.R
Bibliographic source:
Neurobehavioral Toxicology and Teratology, Vol. 7, 779-783
Reference Type:
Behavioral Teratology Investigation of 1-Propanol Administered by Inhalation to Rats
Nelson B.K., Brightwell W.S., Taylor B.J., Khan A., Burg J.R., Krieg E.F., Massari V.J.
Bibliographic source:
Neurotoxicol.Teratol. 11, 153-159

Materials and methods

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:

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Test material form:
Specific details on test material used for the study:
- Source: Matheson, Coleman, and Bell Manufacturing Chemists, Cincinnati, OH)
- Analytical purity: Grade I (> 99%)

Test animals

Details on test animals or test system and environmental conditions:
- 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

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

Administration / exposure

Route of administration:
Type of inhalation exposure (if applicable):
whole body
other: air
Details on exposure:

- 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:
Details on analytical verification of doses or concentrations:

- 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
Doses / concentrationsopen allclose all
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:

- 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

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

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

Litter observations:
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):
- Male animals: All surviving animals
- Maternal animals: All surviving animals

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

Results and discussion

Results: P0 (first parental generation)

Details on results (P0)

- 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

- 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)

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

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

Effect levels (P0)

Dose descriptor:
Effect level:
8 730 mg/m³ air
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.

Target system / organ toxicity (P0)

Critical effects observed:

Results: F1 generation

Details on results (F1)

- 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.

- 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

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

Effect levels (F1)

Dose descriptor:
Effect level:
8 730 mg/m³ air (nominal)
not specified
Basis for effect level:
other: tail shape

Target system / organ toxicity (F1)

Critical effects observed:

Overall reproductive toxicity

Reproductive effects observed:
Lowest effective dose / conc.:
17 460 mg/m³ air (nominal)
Treatment related:
Relation to other toxic effects:
reproductive effects in the absence of other toxic effects
Dose response relationship:
Relevant for humans:
not specified

Applicant's summary and conclusion