2-Butyne-1,4-diol, polymer with methyloxirane

Endpoint summary

Description of key information

oral
Repeated Dose Toxicity Study: NOAEL for systemic toxicity (males/females): 100 mg/kg bw /day based on the clinical, the clinical pathological and histopathological findings (RL 1, GLP, OECD 407 (rat, gavage), BASF 30C0587/11S098, 2012)
dermal
no data
inhalation
no data

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

100 mg/kg bw/day

Study duration:

subacute

Species:

rat

Additional information

1.    Hypothesis fortheanalogue approach

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across).

Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006 whereby substances may be predicted as similar provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity.

 

 

	Target Substance	Source Substance No 1	Source Substance No 2
Name	2-Butyne-1,4-diol, comp. with methyloxirane	2-Butyne-1,4-diol, comp. with oxirane (Polyethylene glycol ether with 2-butyne-1,4-diol)	2-Propyn-1-ol, compd. with methyloxirane
CAS	61596-96-1	32167-31-0	38172-91-7
Repeated dose (oral) (subacute)	--	OECD 407, NOAEL (male/female): 100 mg/kg bw above increased liver weights (BASF, 2013) (RL1)	OECD 422 NOAEL (male/female, systemic toxicity): 125 mg/kg bw based on increased liver weight and histopathological changes at higher doses

Lack of data for a given endpoint is indicated by “--“.

The above mentioned substances are considered to be similar on the basis of structural similarity resulting in similar properties and/or activities. The available endpoint information is used to predict the same endpoint for2-Butyne-1,4-diol, polymer with methyloxirane (CAS 61596-96-1).

 

Since no subacute or subchronic study investigating the repeated dose oral toxicity are available for2-Butyne-1,4-diol, polymer with methyloxirane (CAS 61596-96-1), a read-across from the structurally related analogue substance2-Butyne-1,4-diol, polymer with methyloxirane (CAS 61596-96-1)was usedin accordance to Regulation (EC) No. 1907/2006 Annex XI, 1.5. A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

 

2.    Results

Source Substance No 1 (CAS 32167-31-0)

In a repeated dose toxicity study according to GLP and OECD test guideline 407 (Repeated Dose 28-day Oral Toxicity Study in Rodents), the test substance was administered orally via gavage to groups of 5 male and 5 female Wistar rats (99.4% a.i. purity) at dose levels of 100, 300 and 1000 mg/kg bw/day over a period of 4 weeks (BASF 30C0587/11S098, 2012). Drinking water served as vehicle. Oral administration of the test item by gavage to male and female Wistar rats over a period of 4 weeks resulted in signs of systemic toxicity which were determined at a dose level of 300 mg/kg bw/d and above. A treatment related decrease in body weight changes was apparent in the high dose group, from study days 7-28, though this did not significantly influence the mean body weights at study termination. The liver was identified as the most sensitive target organ. When compared to the control group (set to 100%), the mean relative weight of the liver in males (100 mg/kg bw: 110%; 300 mg/kg bw: 117%; 1000 mg/kg bw: 138%) and in females (100 mg/kg bw/d: 107%, 300 mg/kg bw/d: 112%, 1000 mg/kg bw: 129%) were increased. In males, the dose-related increases of liver weights in all test groups were regarded to be treatment-related. In females, the increased relative liver weights in the high dose group (1000 mg/kg bw/d) were considered to be treatment-related. Increases in liver weight were accompanied by a histopathological correlate: histopathological findings in the mid and high dose group included diffuse hepatocellular hypertrophy, karyomegaly and very few apoptotic bodies or single cell necrosis. The increase of the relative liver weight in males of the low dose group (100 mg/kg bw/d) was assessed to be treatment-related, but regarded as non-adverse because there was no histopathological correlate. Further target organs were only affected in the high dose group and in presence of the described pronounced liver toxicity: e.g. minimal vacuolation of interstitial glands in ovaries and a decrease of absolute and relative organ weight of prostate and seminal vesicles. The no observed adverse effect level (NOAEL) was considered based on this results to be 100 mg/kg bw/d in male and female Wistar rats.

 

a)    Source Substance No 2 (CAS 38172-91-7)

A study according to OECD 422 guideline and GLP was conducted (BASF, 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 (Dose selection rationale: based on a 14-day range-finding study with maternal effects at 215 mg/kg) (highest dose, 68.4 mg/kg bw a.i.) 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). 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 behavior. 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. In males a marked treatment-related increase of kidney weight and liver weight were observed at the 125 mg/kg bw group, which was accompanied by a slight increase in alanine aminotransferase activity, bilirubin levels and bile acids. However, in absence of histopathological changes in the liver and kidney, these effects are considered treatment-related, but not adverse. In females a marked treatment-related increase of kidney weight and liver weight were observed at the highest dose of125 mg/kg bw group. However, in absence of histopathological changes in the liver and kidney, these effects are considered treatment-related, but not adverse. For males and females the No Observed Adverse Effect Level (NOAEL) for systemic toxicity and for fertility 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.

3.    Key study assignment:

 

For the target substance, there are no information according systemic toxicity after repeated dose available, but there are few information with the source substancesPolyethylene glycol ether with 2-butyne-1,4-diol (CAS 32167-31-0) and2-Propyn-1-ol, compd. with methyloxirane (CAS 38172-91-7). Both studies are well documented, reliable and the results were nearly identical (NOAEL 100 mg/kg bw/d respectively 125 mg/kg bw/d). Therefore both studies were used in a weight of evidence approach.

 

4.    Conclusion

The oral administration of the source substances 2-Butyne-1,4-diol, comp. with oxirane (CAS 32167-31-0) and 2-Propyn-1-ol, compd. with methyloxirane (CAS 38172-91-7) by gavage to male and female Wistar rats resulted in adverse signs of systemic liver toxicity which were determined at a dose level of 300 mg/kg bw/d and above for Polyethylene glycol ether with 2-butyne-1,4-diol (CAS 32167-31-0) and in the highest range finder dose 215 mg/kg bw of 2-Propyn-1-ol, compd. with methyloxirane (CAS 38172-91-7).

The highest no observed adverse effect level (NOAEL) was considered to be 100 mg/kg bw/d respectively 125 mg/kg bw/d (68.4 mg/kg bw a.i.) in male and female Wistar rats based on the both source substances. As both results are in the same range, both studies are used as weight of evidence but the most detrimental value of of 68.4 mg/kg bw is used for risk assessment representing the worst case value.

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)

The available studies are considered reliable and suitable for classification purposes under 67/548/EEC. No signs of systemic toxicity were observed at dose levels of 100 mg/kg bw after subacute exposure. As a result the substance is not considered to be classified for repeated dose toxicity under Directive 67/548/EEC.

 

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. Due to diffuse hepatocellular hypertrophy, karyomegaly and apoptotic bodies or single cell necrosis as well as oval cell proliferation the liver was identified as target organ in the 28 day repeated dose study with the source substance 1. The no observed adverse effect level (NOAEL) was considered to be 100 mg/kg bw/d in male and female Wistar rats. LOAEL was identified as 300 mg/kg bw. Further for source substance 2 the NOAEL was found to be 125 mg/kg bw (68.4 mg/kg bw a.i.) but range finder study indicated a LOAEL of 215 mg/kg bw. Taking the threshold orientation levels of 100 mg/kg bw (90 d study) into account and dividing the results by 3 resulting the calculated LOAELs are expected to be equal or below 100mg/kg bw if a 90 d study is conducted. Therefore in a worst case assumption the substance has to be classified for repeated dose toxicity under Regulation (EC) No. 1272/2008.

GHS: Cat 2, STOT RE 2, H373, oral, liver

DSD: no classification