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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
125 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

A study according to OECD 422 guideline and GLP was conducted (TNO Triskelion, 2013) to provide data on the possible effects of the test item 2- propyn-1-ol with methyloxirane on systemic and local toxicity and on reproductive performance of Wistar rats and the development of pups following daily oral administration of the test item via gavage. Concentrations of 0, 5, 25 or 125 mg/kg were given to male and female rats during a premating period of 2 weeks and during mating (1 week), up to a total of approximately 4 weeks for males and including gestation and lactation until postnatal day 4 (PN day 4) for females (up to a total of approximately 6 weeks). The 2-propyn-1-ol was homogeneously distributed in the gavage liquids. Results from content analysis showed slightly higher, but acceptable concentrations of the gavage liquids as compared to the nominal concentration. Daily clinical observations during the premating, gestation and lactation period or neurobehavioural observations and motor activity assessment at the end of the study did not reveal any treatment-related changes in the animal’s appearance, general condition or behaviour. No treatment-related effects were observed in mean body weight, body weight changes and food consumption in 2-propyn-1-ol compound with methyl oxirane-exposed animals throughout the study. No treatment-related effects were observed on mating index, male and female fertility indices, gestation index, duration of gestation, number of corpora lutea, implantation sites, lost implantations. No effects were observed on litter size, pup sex and weight and pup survival. At autopsy absolute and relative kidney and liver weight were markedly increased in both males and females of the high dose group. In addition, relative liver weight was increased in males of the mid dose group. Slight increases in alanine aminotransferase activity, bilirubin levels and bile acids were noted in the high-dose group males. However, in absence of histopathological changes in the liver and kidneys, these effects were considered to be treatment-related, but not adverse.

In conclusion: For males the No Observed Adverse Effect Level (NOAEL) for systemic toxicity is established at the high dose level of 125 mg/kg bw 2-propyn-1-ol compound with methyl oxirane, based on the absence of adverse effects. Based on the treatment-related related effects observed on kidney weight and liver weight and parameters, the No Observed Effect Level (NOEL) for males is established at the low dose of 5 mg/kg bw. For males the NOAEL for fertility is established at the highest dose of 125 mg/kg bw, because no effects were seen on male fertility. For females the NOAEL for systemic toxicity is established at the high dose of 125 mg/kg bw, based on the absendce of adverse effects. Based on treatment-related effects on liver weight and kidney weight the No Observed Effect Level (NOEL) for females is established at the mid dose of 25 mg/kg bw. For females the NOAEL for fertility and development is established at the highest dose of 125 mg/kg bw, because no effects were observed on female fertility and development.


Short description of key information:
OECD 422 (TNO Triskelion, 2013): NOAEL = 125 mg/kg bw/day (parental, development and reproduction)

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
41 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Justification for NOAEL read-across: Based on their respective molecular weights, a hydrolyzation of a defined quantity, or rather mass, of the target substance (2-propyn-1-ol, compd. with methyloxirane) results in a 51% loss of the original mass regarding only the newly formed source substance (prop-2-yn-1-ol). Moreover, has the source substance only a purity of approximately 58% plus 2% of the source substance prop-2-yn-1-ol. The other 40% impurities have no toxicological relevance.In the read-across OECD guideline 414 study with prop-2-yn-1-ol, no signs of neither developmental toxicity nor teratogenicity were observed up to the highest dose tested, leading to a NOAEL of 12 mg/kg for the source substance.12 mg/kg bwdivided by 0.49 and 0.60 results in an NOAEL of 41 mg/kg bw for developmental toxicity for the target substance. More details can be found in the read-across justification in IUCLID chapter 13.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

There is no study on developmental toxicity for the test compound available. Nevertheless, a OECD Guideline 414 study is available for the read across substance prop-2-yn-1-ol. The read-across is based on the premise, that after uptake, the test substance is rapidly hydrolyzed to the source substance prop-2-yn-1-ol and propane-1,2-diol (see toxicokinetic assessment). Hence, source and target substances have similar toxicological properties (e.g. similar effects on liver and kidney) because the target substance degrades to the toxicologically relevant source product and to propane-1,2-diol, which is predicted to have no or very low toxicity. Details can be found in the attached read-across justification.

 

Read-across OECD 414 study

2-Propyn-1-ol was tested for its prenatal developmental toxicity in Wistar rats. The test substance was administered as an aqueous preparation to groups of 25 time-mated female Wistar rats by gavage at doses of 1, 4 and 12 mg/kg body weight/day (mg/kg bw/d) on gestation days (GD) 6 through 19. The control group, consisting of 25 females, was dosed with the vehicle (drinking water) in parallel. A standard dose volume of 10 mL/kg body weight was used for each test group. At terminal sacrifice on GD 20, 22-24 females per group had implantation sites. The analytical values of the low-, mid- and high-dose samples (1, 4 and 12 mg/kg bw/d) were below the expected range of 90% to 110% of the nominal concentrations. The mean values of 54, 65 and 75% of the nominal concentrations correspond to an actual low-, mid- and high dose of 0.5, 2.6 and 9 mg/kg bw/d, respectively. This did not affect the validity of the study. In the following report, the target doses were used.

OBSERVATIONS

Food consumption and body weights of the animals were recorded regularly throughout the study period. The state of health of the animals was checked each day. On GD 20, all females were sacrificed by decapitation (under isoflurane anesthesia) and assessed by gross pathology (including weight determinations of the liver, unopened uterus and placentas). For each dam, corpora lutea were counted and number and distribution of implantation sites (differentiated between resorptions, live and dead fetuses) were determined. The fetuses were removed from the uterus, sexed, weighed and further investigated for external findings. Thereafter, one half of the fetuses of each litter were examined for soft tissue findings and the remaining fetuses for skeletal (inclusive cartilage) findings.

RESULTS

• The stability of the test substance preparations over a period of 5 days at room temperature was demonstrated.

• Concentration control analysis: for the low-, mid- and high-dose (1, 4 and 12 mg/kg bw/d), the three analytical samples of each test group resulted in mean values of 54, 65 and 75% of the nominal concentrations, respectively.

The following test substance-related adverse effects/findings were noted:

Test group 3 (nominal concentration of 12 mg/kg bw/d):

• No test substance-related adverse effects on dams, gestational parameters or fetuses

Test group 2 (nominal concentration of 4 mg/kg bw/d):

• No test substance-related adverse effects on dams, gestational parameters or fetuses

Test group 1 (nominal concentration of 1 mg/kg bw/d):

• No test substance-related adverse effects on dams, gestational parameters or fetuses

CONCLUSION

Under the conditions of this prenatal developmental toxicity study, the oral administration of 2 - Propyn-1-ol to pregnant Wistar rats from implantation to one day prior to the expected day of parturition (GD 6-19) at doses as high as 12 mg/kg bw/d caused neither evidence of maternal nor developmental toxicity. In conclusion, the no observed adverse effect level (NOAEL) for maternal and prenatal developmental toxicity is the highest tested dose with a nominal concentration of 12 mg/kg bw/d (actual dose of 9 mg/kg bw/d).

Justification for classification or non-classification

Based on the available data, the test substance is not classified with regard to toxicity to reproduction according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP), respectively.