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Effects on fertility

Link to relevant study records

Referenceopen allclose all

Endpoint:
two-generation reproductive toxicity
Remarks:
based on generations indicated in Effect levels (migrated information)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Publications based on an NTP study. The information available is limited
Qualifier:
no guideline followed
Principles of method if other than guideline:
NTP tested propylene glycol for reproductive/developmental toxicity. Using the reproductive assessment by continuous breeding (RACB) protocol, the reproductive function of male and female mice (COBS crl:CD-1 (ICR) BR outbred albino) exposed to propylene glycol in drinking water was investigated.
GLP compliance:
not specified
Limit test:
no
Species:
mouse
Strain:
Swiss
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Strain: COBS Crl:CD-l (ICR)BR
- Age/weight at study initiation: no data
- Housing: during breeding period 1 male + 1 female; other periods individually
- Diet: Purina rat chow or NIH-07 diet ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 2*C.
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 10/14
Route of administration:
oral: drinking water
Details on mating procedure:
- M/F ratio per cage: 1/1
- Length of cohabitation: 98 days
- After last mating each pregnant female was caged (how): individually and allowed to raise the pups until day 21
- Any other deviations from standard protocol: litters were removed within 12 hours after delivery
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analyses were performed by an independent laboratory at least for accuracy of preparation and stability.
All results were within 5% of nominal
Duration of treatment / exposure:
Continuous breeding phase begins with males and females separated for 1 week. The mating trial begins within a week of the start of treatment and cohabitation continues for 14 weeks to maximize the data collected on fertility. Maternal parent during gestation (3 weeks)
Last litter and mother for 21 days and mother was dosed through weaning and F1 mice were dosed until mated at 74 ± 10 days.
F1 during mating, F1Females during gestation and lactation of F2 (until day 21).

Frequency of treatment:
continuously in drinking water
Details on study schedule:
Animals were exposed to propylene glycol for a total of 18 weeks: one week prior to cohabitation, 14 weeks during cohabitation, and 3 weeks after cohabitation. A vehicle control group (40 males/40 females) and 3 dose groups of 20 males and 20 females per dose group were used. Drinking water concentrations were set at 0, 1, 2.5, 5% (w/v) propylene glycol. Chemical consumption estimates in this study were 0, 1.82, 4.80, and 10.1 g/kg bw/day for each of the respective dose groups; body weights of F0 parents were monitored on study days 0, 7, 28, 56, 84, and 112. Live litters born during the cohabitation phase were weighed, sexed, and examined for external abnormalities and then sacrificed. Approximate delivery time and number of dead and cannibalized pups were noted. Offspring from the last litter (5th litter) of the control and high-dose groups were allowed to mature and reproductive performance was evaluated.
F1 males and females (20 each/dose group) were randomly selected from the control and high-dose groups and mated on post natal day 64–84 to animals from the same dose group. Breeding pairs were separated after 7 days of cohabitation or after detection of a copulatory plug; the male and female were then housed singly. F1 animals were weighed at weaning, first day of cohabitation, and then weekly. Water consumption was monitored weekly starting the first week after cohabitation. The high-dose group animals received exposure to propylene glycol until day 21 from their dosed dam and then continuous exposure from drinking water (author estimated daily dose of propylene glycol, 14.4 g/kg bw/day).
Remarks:
Doses / Concentrations:
0, 1, 2.5, 5% (w/v)
Basis:
nominal in water
Remarks:
Doses / Concentrations:
0, 1.82, 4.80, and 10.1 g/kg bw/day
Basis:
actual ingested
Parental
Remarks:
Doses / Concentrations:
0 and 14.4 g/kg bw
Basis:
actual ingested
F1 and F2
No. of animals per sex per dose:
20 males + 20 females for treatment groups
40 males + 40 females for controls
Control animals:
yes
Details on study design:
A dose range-finding study was done with mice exposed to propylene glycol in drinking water for 14 days. Dose groups (8 male and 8 female mice/group; 2 mice of the same sex housed per cage) were 0, 0.5, 1.0, 2.5, 5.0, and 10.0% (w/v) propylene glycol. During the testing period, there was no mortality in any of the dose groups. However, in the high-dose group, males and females gained weight over control animals (2 and 7% heavier, respectively) and animals in the 10% dose group drank more water than the control group (60% more for males and 58% more for females). [Food consumption not reported; caloric intake among dose groups not standardized.]
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes

BODY WEIGHT: P No data; F1 weekly

FOOD CONSUMPTION: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): P no details, F1 weekly
Oestrous cyclicity (parental animals):
P no data; F1 estrous cycle
Sperm parameters (parental animals):
P no data; F1 motile sperm, epididymal sperm concentration and percentage abnormal sperm, vaginal cytology
Litter observations:
F1: number of litters, delivery time and number of dead and cannibalized pups, body weight, proportion of males, number of litters per pair, number of live and dead pups
F2:litter size, sex, and pup weight
Postmortem examinations (parental animals):
P no data
F1: selected organ weights and histology (no details)
Postmortem examinations (offspring):
not performed
Statistics:
Statistical significance was at the P = 0.05 level. Reproductive data were evaluated by the Cochran-Armitage Standard statistical analyses were done on the reproductive and fertility data. test for dose related trends in fertility and mating indices; pairwise comparisons between the control and dose groups were made using Fisher’s Exact test. Pup and litter data were evaluated by the Kruskal-Wallis test and Jonckheere’s test. Pairwise comparisons were made with Wilcoxon’s rank-sum test. All analyses were performed on males, females, and both sexes combined; to remove any potential effect of number of pups in litter on pup weight, an analysis of covariance was performed.
Reproductive indices:
For F1: mating index, fertility index
Clinical signs:
no effects observed
During the cohabitation phase, no chemical-related deaths and no significant chemical related clinical signs of toxicity were noted. Propylene glycol had no significant effect on any of the following reproductive parameters in F0 animals: number of litters per pair, number of live pups per litter, sex ratio, pup weights, number of days to litter, and dam weights at delivery. F0 parents were not necropsied. F1 pup survival and body weights through pnd 14 were monitored in the control (34/39 litters/breeding pairs) and the high dose groups (19/20 litters/breeding pairs) from the final litter (5th litter). Propylene glycol had no effect on F1 pup survival or body weight gain [note that dams were still being exposed to propylene glycol from the drinking waterduring the preweaning period].
Dose descriptor:
NOAEL
Effect level:
10 100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
Clinical signs:
no effects observed
There were no differences between the control and high-dose groups with respect to body weights or water consumption. The mating index for control and treated groups was 85%; the fertility index was 75% for control and 80% treated groups (nonsignificant). There were no significant differences in F2 litter size, number of live pups, sex ratio, or pup weights. After delivery of the F2 pups, the F1 adults were necropsied. Sperm morphology and vaginal cytology evaluations [on females that did not have pups] were conducted. There were no significant differences in body or kidney and liver weights or serum calcium concentrations (both sexes). In males, there were no significant differences in the average weights of seminal vesicles, right cauda, prostate, right testis, and right epididymis. Sperm motility, sperm counts, or incidence of abnormal sperm did not significantly differ from control animals. In females, there was no difference in estrual cyclicity when compared to control animals. No organs were examined histologically.
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
14 400 mg/kg bw/day (actual dose received)
Based on:
test mat.
Remarks:
actually ingested
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
Dose descriptor:
NOAEL
Generation:
F2
Effect level:
14 400 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Remarks:
actually ingested
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
Reproductive effects observed:
not specified
Conclusions:
No effect on reproduction at any of the doses tested.
Executive summary:

In a continuous dosing study exposure of mice to 0, 1, 2.5 and 5 % in drinking water did not induce any effects on reproduction in parental animals. In the F1 generation exposed at 0 and 5% also no effects were found on any of the parameters evaluated. Therefore it is concluded that the NOAEL for reproductive toxicity is 5% in drinking water (10100 mg/kg bw).

Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1987
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study under GLP with limited number of investigations. The information in the report is limited to what is included in the summary
Qualifier:
no guideline followed
Principles of method if other than guideline:
Mice were exposed to the substance for 13 weeks and thereafter selected for mating and reproduction testing. Exposure was continued during the mating period and pregnant females were allowed to deliver and nurse their pups until day 21 of lactation. The protocol resembles that of OECD 422.
GLP compliance:
yes
Remarks:
no QA statement and/or study director statement included in the report, but GLP is claimed
Limit test:
no
Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Taconic Laboratory Animals and Services (Germantown, NY)
- Age at study initiation: 6-7 weeks
- Average weight at study initiation: males 20.6-24.8 g; females 17.9-19.8 g (no additional information on animals used for mating)
- Housing: individually
- Diet: Pelleted NIH-07 feed (Zeigler Brothers, Inc., Gardners, PA) ad libitum during non-exposure
- Water: ad libitum during non-exposure
- Acclimation period: 11-14 days

ENVIRONMENTAL CONDITIONS (non-exposure)
- Temperature (°C): ca 22 °C
- Humidity (%): 50% ± 15%
- Air changes (per hr): 12-15
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
inhalation: aerosol
Type of inhalation exposure (if applicable):
whole body
Details on exposure:
For the inhalation studies, 1,6-hexanediamine was converted to 1,6-hexanediamine dihydrochloride (HDDC) by acidification with concentrated hydrochloric acid under a stream of nitrogen. The final pH was adjusted within the range of 4.5 to 5.5 before storage and again before use in the inhalation chambers.
The 70% aqueous HDDC solution was placed in a 9-liter glass reservoir and pressurized with N2 gas. HDDC was delivered to 5 Sonimist Ultrasonic Spray Nozzles (Model HS6002, Heat Systems-Ultrasonics, Inc., Farmingdale, NY) by a positive displacement metering pump. Up to this point, stainless steel lines carried the test substance. The nebulizer reservoir was kept in a separate exposure chamber (H-1000, Hazelton Systems, Inc., Aberdeen, MD). This chamber served as a mixing plenum where large droplets and nonnebulized liquid were impacted or sedimented out of the test atmosphere before the aerosol was delivered to the inhalation chambers. The HDDC aerosol was mixed with compressed breathing air that had been filtered through an ENMET (ENMET Air Filtration Panel, Model AFP-82, Enmet Co., Ann Arbor, MI) and supplied at 50 psi to generate an aerosol at a concentration equal to the highest exposure concentration. The resulting aerosol was transported to the inhalation chambers through a manifold constructed of 3-inch diameter PVC tubing. At each chamber, a metered amount of aerosol was removed from the manifold and mixed with the appropriate amount of HEPA/charcoal-filtered room air to obtain the desired test concentration, then delivered to the inhalation chamber. After exiting the chambers, the test atmospheres were delivered to a common duct and cleansed of the test substance by a Mystaire HS-7CM scrubber (Heat Systems Ultrasonics).


Method of holding animals in test chamber: individually in compartments of multi compartment wire mesh cages, during exposure in stainless steel andglass exposure chambers of 2 m3 volume, with 15 air changes per hour (500 L/min). During inhalation exposures, chambers were maintained at 22°C to 25°C and 70% to 80% relative humidity.

TEST ATMOSPHERE
- Brief description of analytical method used: forward light scatter with RAM-S real-time aerosol monitors (GCA Corporation,Technology Division, Bedford, MA) and gravimetric analyses of filter samples collected from each exposure chamber
- Samples taken from breathing zone: no, 6 RAM-S readings and 3 gravimetric samples were taken from each exposure chamber on each day of exposure.
Details on mating procedure:
- M/F ratio per cage: 1 male and 2 females
- Length of cohabitation: maximum 10 days
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of gestation
- No replacement of first male by another male with proven fertility.
- After successful mating each pregnant female was caged (how): individually
- Any other deviations from standard protocol: exposure for 13 weeks including the mating period, but no exposure of females during gestation and lactation
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Twice monthly during the 13-week studies, glass fiber filter samples from each chamber were analyzed by gas chromatography with flame ionization detection for total hexanediamine, using the technique supplied by Midwest Research Institute. Measured concentrations of HDDC in the exposure chambers were within 6% of the target concentrations in all samples.
Spatial homogeneity of the aerosol within the exposure chambers was determined using the calibrated RAM-S monitors. Chamber concentrations were measured at 12 points within each chamber and then were compared to a fixed reference point. Time spans required to reach stable concentrations after start up and to reach background concentrations at the end of exposure were determined by taking measurements of aerosol concentrations every 60 seconds. The time span required after start up to reach 90% of the target concentration was identified as the T90; the time span required after the end of the exposure period to reach 10% of the target concentration was identified as the T10.
Triplicate particle size measurements were obtained for each exposure chamber once in the first week and monthly thereafter, using an APS 3300 aerodynamic particle sizer (TSI, Inc., Minneapolis, MN). In addition, a CFM Ambient Impactor (Flow Sensor, McLean, VA) cascade impactor was used to determine the particle size distribution in the highest exposure level chamber once during the 13-week studies. The mass median aerodynamic diameter values for each chamber ranged from 1.62 to 1.72 microns, with a geometric standard deviation of 1.52 to 1.53. All control chamber respirable mass concentration values were less than 0.005 mg/m3.
Duration of treatment / exposure:
13 weeks (including mating period)
Frequency of treatment:
6 hours(+ T90 (=30 min))/day, 5 days per week
Details on study schedule:
Mating was between exposure day 68 and 80 of the study (only weekdays counted)
Males were terminated immediately thereafter. Females were checked upto 23 days after mating for signs of copulation and terminated thereafter if non-pregnant.
Remarks:
Doses / Concentrations:
0, 15, 50 and 160 mg/m3
Basis:
analytical conc.
No. of animals per sex per dose:
20 males and 40 females
Control animals:
yes
Details on study design:
no data
Positive control:
none included
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes no details

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT (GAIN): Yes
- Time schedule for examinations: both sexes at start; males at the end of the mating period; females at day 0 and 20 of gestation], day 0, 5, 14 and 21 of lactation

FOOD CONSUMPTION: No data

Oestrous cyclicity (parental animals):
see under repeated dose
Sperm parameters (parental animals):
see under repeated dose
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain (BW day 0, 5, 14 and 21 of lactation), physical abnormalities

Postmortem examinations (parental animals):
males: none
females: necropsy only on non-pregnant females: uterus examination for signs of pregnancy (includes ammonium sulfide staining to verify implementation)
Postmortem examinations (offspring):
none
Statistics:
Continuous, quantitative data, such as body weights, were analyzed by Dunnett's t-test for multiple comparisons to a single control group. Discrete, counting data, such as litter counts, were analyzed by the Mann-Whitney U nonparametric test. Percentage data, such as the fertility and survival indices, were analyzed by the Chi Square test.
Reproductive indices:
no data
Offspring viability indices:
no data
Clinical signs:
not examined
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
not examined
Histopathological findings: non-neoplastic:
not examined
Other effects:
not specified
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
MORTALITY (PARENTAL ANIMALS): 3 females at 16 mg/m3, 1 male and 1 female at 50 mg/m3

BODY WEIGHT (PARENTAL ANIMALS): no treatment related effects

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS):
pregnancy rate: 35, 32, 33 and 35 at 0, 16, 50 and 160 mg/m3
gestation length: significantly increased at 50 and 160 mg/m3 (no biological relevance)
Dose descriptor:
NOAEC
Effect level:
5 mg/L air (analytical)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: see repeated dose toxicity study
Clinical signs:
not examined
Clinical signs:
not examined
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined
VIABILITY (OFFSPRING): no treatment related effects

LITTER SIZE: no treatment related effects

SEX RATIO: no treatment related effects

CLINICAL SIGNS (OFFSPRING); no treatment related effects

BODY WEIGHT (OFFSPRING): no treatment related effects (significantly decreased in pups at 160 mg/m3 on day (14 and) 21 of lacatation)

Dose descriptor:
NOAEC
Generation:
F1
Effect level:
160 mg/L air (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see study
Reproductive effects observed:
not specified

Mean Body Weights and Length of Gestation for Female B6C3F1 Mice in the Mating Trial Study og 1,6 -hexanediamine Dihydrochloride

 

0 mg/m3

16 mg/m3

50 mg/m3

160 mg/m3

Dam Weight During Gestation1

 

22

25.6 ± 0.3

44.3 ± 0.8

18.7 ± 0.8

-

 

23

25.6 ± 0.4

44.4 ± 0.8

18.8 ± 0.8

100

 

27

27.2 ± 0.5*

43.4 ± 0.8

16.2 ± 0.9

98

 

24

26.2 ± 0.3

44.2 ± 0.5

18.0 ± 0.5

100

Lenght of Gestation1

 

30

17.68 ± 0.10

 

30

18.00 ± 0.12

 

31

18.11 ± 0.09**

 

31

18.11 ± 0.08**

Dam Weight During Lactation1

 

Lactation day 0

 

 

Lactation day 5

 

 

Lactation day 14

 

 

Lactation day 21

 

 

 

 

 

35

31.4 ± 0.3

 

34

35.3 ± 0.4

 

34

39.7 ± 0.5

 

34

34.8 ± 0.5

 

 

 

32

32.0 ± 0.4

 

32

35.7 ± 0.5

 

32

39.6 ± 0.6

 

32

34.2 ± 0.5

 

 

 

33

32.5 ± 0.4

 

33

35.3 ± 0.4

 

33

38.9 ± 0.6

 

33

34.7 ± 0.6

 

 

 

35

31.8 ± 0.3

 

35

34.9 ± 0.4

 

35

38.8 ± 0.6

 

35

33.9 ± 0.61

 

  1Data presented as mean ± standard deviation. Differences from the control group were evaluated by Williams’ or Dunnett’s test (weight) and Shirley’s test (gestation length)

* Significantly different (P<0.05) from the control group by Williams’ test.

** Significantly different (P<0.01) from the control group by Shirley’s test.

 

Survival, Sex Distribution and Mean Body Weights of B6C3F1 mouse Pups in the Mating trial Study of 1,6 -Hexanediamine Dihydrochloride.

 

0 mg/m3

16 mg/m3

50 mg/m3

160 mg/m3

Day 0

35

9.11 ± 0.38

8.86 ± 0.37

53.33 ± 3.51

1.37 ± 0.03

34

9.00± 0.44

8.53 ± 0.53

50.56 ± 3.562

1.39± 0.032

33

8.73± 0.46

8.61 ± 0.45

53.18 ± 2.11

1.41 ± 0.04

35

9.57± 0.25

9.37 ± 0.24

50.56 ± 3.25

1.37 ± 0.02

Day 5

35

8.54    

55.94 ± 3.533

3.57 ± 0.083

34

8.44 ± 0.52

50.79 ± 3.582

3.56 ± 0.082

33

8.58 ± 0.46

53.28 ± 2.11

1.41 ± 0.04

35

9.37 ± 0.24

50.32 ± 3.29

3.55 ± 0.06

Day 14

35

8.51 ± 0.44

56.43 ± 3.513

8.19 ± 0.213

34

8.41 ± 0.52

50.80 ± 3.582

7.95 ± 0.152

33

8.58 ± 0.46

53.28 ± 2.51

8.25 ± 0.27

35

9.34 ± 0.24

50.08 ± 3.33

7.63 ± 0.16

Day 21

35

8.46 ± 0.43

56.15 ± 3.583

10.94 ± 0.243

34

8.41 ± 0.52

51.11 ± 3.572

10.68 ± 0.172

33

8.58 ± 0.46

53.28 ± 2.51

10.93 ± 0.29

35

9.31 ± 0.24

50.03 ± 3.26

10.21 ± 0.19*

1 Data presented as mean ± standard deviation. Differences from the control group for percent of live male pups, litter size, and number of pups born alive are not significant by Dunn’s test. The significance of differences in pup weights between dosed and control groups was evaluated by Dunnett’s or William’s test.

2 n=32

3 n=34

* Significantly different (P<0.05) from the control group by William’s test

Conclusions:
There was no effect on male or female fertility, body weight (gain), gestation length and litter size. The reduced pupweights during part of the lactation period are considered not biologically relevant. No effects were noted on neonatal survival, sex ratios of pups and pup morphology in mice exposed to the substance.
Executive summary:

Male (n=20) and female (n=40) mice were exposed to the substance at 0, 16, 50 and 160 mg/m3 for 13 weeks (6 h/day, 5 d/wk). Animals were mated (1 male/2 females) and females showing signs of copulation and pregnancy were further evaluated during gestation and lactation (until day 21 of lactation). Males and non-pregnant females were terminated either immediately after mating (males) or after 23 days (non-pregnant females). The pups were checked for neonatal survival, weights, sex ratios and morphology. No treatment related mortality, effects on body weight(gain) or effects on reproductive performnce were observed in parental animals. No adverse effects were found in the offspring.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
10 100 mg/kg bw/day
Study duration:
subchronic
Species:
mouse
Quality of whole database:
limited report on potential metabolite propylene glycol
Effect on fertility: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
50 mg/m³
Study duration:
subchronic
Species:
mouse
Quality of whole database:
report on potential metabolite analogue 1,6-dihexanediamine
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Based on the results of the studies with the metabolites, it is most likely that the potential toxicity of the substance is expected to be determined by the diamine moiety, as the toxicity of propylene glycol is low. Therefore the NOAEL for reproductive toxicity will be based on the studies with 1,6 -hexanediamine.


Short description of key information:
1,6-hexanediamine: inhalation NOAEC rat and mouse 5 mg/m3 (local effects), rat 160 mg/m3 (systemic effects), mouse 50 mg/m3 (systemic effects)
1,6-hexanediamine: oral feed mouse NOAEL 150 mg/kg bw
propylene glycol: oral drinking water NOAEL 10100 mg/kg

Effects on developmental toxicity

Description of key information
1,6-hexanediamine: inhalation NOAEC rat 160 mg/m3 and mouse 50 mg/m3
1,6-hexanediamine: oral feed mouse NOAEL 150 mg/kg bw
propylene glycol: oral drinking water NOAEL 14400 mg/kg
From the results of the reproduction studies it can be concluded that both potential metabolites do not have adverse effects on development
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
50 mg/m³
Study duration:
subchronic
Species:
mouse
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

No effects on the offspring were reported at doses without apparent parental toxicity. The NOAEL as derived for reproductive toxicity is considered sufficiently protective for developmental effects.

Justification for classification or non-classification

No fertility effects were seen in studies on both metabolites and the developmental effects (reduced viability and reduced body weight gain in F1 and F2 pups in the feeding study at 500 mg/kg bw 1,6 -hexanediamine) or the only occurred secondary to maternal toxicity. Therefore, the substance is not classified for reproductive toxicity according to CLP (Regulation EC No 127272008).

Additional information