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

Endpoint summary

Description of key information

Acute oral toxicity (similar to OECD 401): LD50 =275 mg/kg bw (BASF, 1976)
Acute inhalation toxicity: waiver, IRT show no mortality at vapour saturation concentration (BASF, 1976)
Acute dermal toxicity (OECD 402, RA to CAS 38172-91-7, GLP): LD50 > 2000 mg/kg bw (BASF, 2013)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: comparable to guideline but non-GLP study; However, lots of parameters are documented in raw data.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

Number of animals

Principles of method if other than guideline:

ln principle, the methods described in OECD Guideline 420 were used.
Deviations: Number of test animals

GLP compliance:

no

Test type:

standard acute method

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: average weight female: 170 g, average weight male: 250 g
- Diet (e.g. ad libitum): yes, Altromin R1324 (Altromin GmbH Lage)

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 2,15% - 4,64%
- Amount of vehicle (if gavage): 10ml
- Justification for choice of vehicle: common vehicle
- Purity: 100%

MAXIMUM DOSE VOLUME APPLIED:

Doses:

464 mg/kg, 316 mg/kg, 215 mg/kg

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 15 minutes, 30 minutes, 1h, 2h, 4h, 5h, 1day - 14 days
- Other examinations performed: clinical signs, body weight, gross pathology

Sex:

male/female

Dose descriptor:

LD50

Effect level:

ca. 250 other: µl/kg bw

Based on:

test mat.

Remarks on result:

other: purity 100%

Sex:

male/female

Dose descriptor:

LD50

Effect level:

ca. 275 mg/kg bw

Based on:

test mat.

Remarks on result:

other: purity 100%

Mortality:

There were deaths among all doses:

Death/total
Concentration Male Female
4.64% 5/5 5/5
3.16% 3/5 4/5
2.15% 2/5 2/5

Clinical signs:

other: - respiratory distress - apathy - in part: abdominal position - ataxia - spastic gait - diarrhea - exsiccosis

Gross pathology:

Heart: acute dilatation and accumulation of blood
Liver: periphere lobular enlargement and soft consistency
Kidney: bright cortex

Interpretation of results:

Toxicity Category III

Remarks:

Migrated information GHS (EU) Criteria used for interpretation of results: EU

Conclusions:

Acute oral toxicity yields to an LD50 of 275 mg/kg bw and therefore the test substance should be classified as acute oral toxic categorie 3 (GHS) (BASF, 1980)

Executive summary:

ln principle, the methods described in OECD Guideline 420 were used without GLP compliance.

5 rats per sex and dose were treated simultaneously with concentrations of 464 mg/kg, 316 mg/kg, 215 mg/kg by gavage

with preparations of the test substance in water as vehicle.

Group-wise documentation of clinical signs was performed over the 14- day study period, where clinical signs and mortality was documented, which was observed among all doses.

On the basis of the observed lethality, the LD50 value was estimated to be 250µl/kg bw, which is in accordance with 275mg/kg and as a conseqence of it, the test substance should be classified as acute oral toxic categorie 3 (GHS). (BASF, 1976)

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

275 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

other justification

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP Guideline Study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Wiga GmbH
- Age at study initiation: Young adult animals (male animals approx. 8 weeks, female animals approx. 12 weeks)
- Weight at study initiation: Animals of comparable weight (± 20% of the mean weight)
- Housing: Single housing
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: Acclimatization period of at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +- 3 °C
- Humidity (%): 30-70 %
- Air changes (per hr): fully air-conditioned rooms
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Vehicle:

other: unchanged or water

Details on dermal exposure:

TEST SITE
- Area of exposure: dorsal and dorsolateral parts of the trunk
- % coverage: 40 cm² (corresponds to at least 10% of the body surface)
- Type of wrap if used: semi- occlusive dressing

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with warm water
- Time after start of exposure: after 24 hours of exposure

Duration of exposure:

24 hours

Doses:

500 and 2000 mg/kg

No. of animals per sex per dose:

5

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Individual body weights shortly before administration (day 0), weekly thereafter and on the last day of
observation. Recording of clinical signs several times on the day of administration, and at least once daily thereafter each workday for the individual animals.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, gross-pathology

Statistics:

Not applicable

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred.

Clinical signs:

other: No systemic clinical signs were observed in the test groups during clinical examination in addition also no local effects were observed on the skin.

Gross pathology:

No macroscopic pathologic abnormalities were noted in the animals (examined on the last day of observation (2000 mg/kg bw: 5 males and 5 females; 500 mg/kg bw: 5 males and 5 females)

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Executive summary:

In an acute dermal toxicity study according to OECD 402 guideline and GLP (BASF, 2012), young adult Wistar rats were dermally exposed to doses of 2000 mg/kg and 500 mg/kg bw of 2-Propyn-1-ol, compd. with methyloxirane (as a solution in deionized water or undiluted) to the clipped skin (dorsal and dorso-lateral parts of the trunk) and covered by semi-occlusive dressing for 24 hours. The application area comprised at least 10% of the total body surface area. The animals were observed for 14 days (2000 mg/kg: 5 males and 5 females; 500 mg/kg: 5 males and 5 females).

The following test item-related effects were recorded:

· No mortality occurred

· No signs of systemic toxicity or skin effects were observed in the animals

· The mean body weight of the male animals increased throughout the study period within the normal range (2000 mg/kg bw: 5 males; 500 mg/kg bw: 5 males)

· The mean body weights of the female animals stagnated during the first postexposure observation week probably due to the bandage procedure, but increased during the second week within the normal range (2000 mg/kg bw: 5 females; 500 mg/kg bw: 5 females)

· No macroscopic pathologic abnormalities were noted in the animals examined at the end of the study

Accordingly, the acute dermal median lethal dose (LD50) was determined to be LD50, dermal, rat > 2000 mg/kg bw. (BASf, 2012)

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Additional information

   Hypothesis fortheanalogue approach

There are no reliable data available for some endpoints despite the acute toxicity of2-Butyne-1,4-diol, polymer with methyloxirane (CAS 61596-96-1). In order to fulfil the standard information requirements set out in Annex VIII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from structurally related substances is done for these endpoint but whole data is presented to underline RA justification.

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, the substance listed below are selected as reference substances for hazard assessment.

 

Overview of acute toxicity :

 

	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
Acute oral toxicity	Non-guideline-study: LD 50 = 275 mg/kg bw (BASF, 1976) (RL2)	OECD 401: LD 50 = 1825 mg/kg bw (BASF, 1972) (RL2)	OECD 401: LD 50 =464-2150 mg/kg bw (BASF, 1987) (RL2)
Acute inhalation toxicity	Non-guideline-study: similar toOECD 403, LC50 > 0.094 mg/l/4h (vapor saturation) (BASF, 1976) (RL3)	--	Non-guideline-study: similar to OECD 403, LC50 > 5.1mg/l, no mortalities (vapor saturation) (BASF, 1987) (RL2)
Acute dermal toxicity	Non-guideline-study: similar toOECD 402,LD50 > 220 mg/kg bw (highest tested dose) (BASF, 1980) (RL3)	OECD 402, LD50 > 5000 mg/kg bw (BASF, 2012) (RL1)	OECD 402, LD50 > 2000 mg/kg bw (BASF, 2012) (RL 1)

 

 

2.    Analogue approach justification

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 endpoints for2-Butyne-1,4-diol, polymer with methyloxirane (CAS 61596-96-1) if no direct data is available. A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

3.    Results

Acute Toxicity: oral

Non-Guideline studies:

a)    Target Substance(CAS 61596-96-1)

ln principle, the methods described in OECD Guideline 420 were used without GLP compliance. 5 rats per sex and dose were treated simultaneously with concentrations of 464 mg/kg bw, 316 mg/kg bw, 215 mg/kg bw by gavage with preparations of the test substance in water as vehicle. Group-wise documentation of clinical signs was performed over the 14- day study period, where clinical signs and mortality was documented, which was observed among all doses. At 316 mg/kg bw 3/5 males and 4/5 females died, whereas at 215 mg/kg bw 2/5 each died. On the basis of the observed lethality, the LD50 value was estimated to be 250µl/kg bw, which is in accordance with 275mg/kg (BASF, 1976).

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

The non-GLP acute oral toxicity study was performed according to a standardized BASF test protocol. In principle this test protocol is similar to the the OECD Guideline 401(BASF 1972): Wistar rats (5/sex/dose) were administered a single oral dose (gavage) of the test item (analytical purity: unknown) at dose levels of 640, 800, 1000, 1250, 1600, 2000 and 2500 mg/kg body weight (bw). The test item was applied as aqueous solution at a concentration of 16% w/v and at a maximum dose volume of 15.6 mL/kg bw. The animals were observed for a post-dosing period of 7 days. Subsequently, all surviving animals were killed and like animals that died during the study subjected to gross pathology. Mortality occurred in the high dose group within 24 hours after application of the test item and symptoms reported were described as accelerated respiration, crouched position, reddened, partly closed eyes. On following observation days crouched position, partly abdominal position, intermittent breathing and reddened eyes were observed. From the 6th day of observation animals were without findings. No data were available on body weight gain. Gross necropsy findings in rats that died included acute congestive hyperemia, dilatation of the heart, thymic petechial, slight lung edema, loam-yellow-grey liver with peripheral lobular pattern. No abnormalities were noted at necropsy of animals sacrificed at the end of the study. Under the conditions of the study the LD50 of the test item after oral application was determined to be 1824 mg/kg bw.

 

Guideline-study:

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

The acute oral toxicity of the test substance was estimated in a test which was conducted comparable to OECD guideline 401 (BASF 1987). Five wistar rats per sex and dose were fasted for 16 hours while water was available ad libitum. The rats were treated with a single oral administration of 5000, 2150, 464 or 215mg/kg of the test substance diluted in aqua dest. (vehicle) by gavage. During the following 14 days the rats' clinical signs and symptoms were recorded at least once each day. 16 hours before the end of the 14 days observation time the rats were fasted for 16 hours, sacrified with CO2 and gross-pathologically examined. A necropsy of the animals died before the end of the study was peformed as early as possible. All male and female animals treated with 5000 or 2150mg/kg died after one day. 2/5 male animals treated with 464mg/Kg died after 7 days. The animals dosed with 5000 mg/kg developed dyspnea, apathy, abnormal position, atonia, paresis, poor general state, staggering, exsiccosis, and piloerection within the first 4 hours after the application.The animals dosed with 2150 mg/kg developed dyspnea, apathy, staggering, abnormal position, atonia, paresis, poor general state, staggering, and piloerection (only females) within the first 4 hours after the application. Furthermore animals dosed with 464 mg/Kg developed dyspnea, apathy, staggering (only males), and poor general state 3 days after the application. Male and female animals died spontaneously on day 1 or 7 showed general congestion, yellow brown liver lobular perphery , and bloody ulcerations in the glandular stomach while animals sacrified after the end of the study did not show any pathological findings. The LD50 for male rats was estimated to bebetween464mg/kgand 2150 mg/kg since 2/5 animals of the 464 mg/kgdose group died after 7 days. All 5 female animals treated with 2150mg/Kg died after 1 day while 5/5 animals treated with the next lower dose of 464 mg/kg survived until the end of the study. Therefore the LD50 of female rats was assessed to be > 464mg/kg and < 2150mg/kg.Summarising the LD 50 for rats was> 464mg/kg and < 2150mg/kg.

 

 

Acute Toxicity: inhalation

Non-guideline-study:

a)    Target Substance(CAS 61596-96-1)

This test (also called inhalation risk test) was performed in principle as described in OECD Guideline 403 without GLP compliance. 3 rats per sex were exposed sequentially to the vapor, generated by bubbling 200 1/h air through a substance column of about 5 cm above a fritted glass disc in a glass cylinder for 8 hours. Documentation of clinical signs and mortality was performed over 7 days.

The highest tested concentration of TI name (vapor saturation concentration; 0.094 mg/l) revealed no signs of toxicity or mortality. (BASF, 1976)

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

The acute inhalation toxicity of the test substance was estimated using the BASF-Test Protocol which is in principle consistent with OECD guideline 403 (BASF 1987). The test demonstrates the toxicity of an atmosphere saturated with vapours of the volatile components of a test substance at the temperature chosen for vapour generation (20 °C). Three rats per sex were exposed to the vapours, generated by bubbling 200l/h air through a substance column of about 5 cm above a fritted glassdisc in a glass cylinder. After 30 minutes this column was replaced by a new column filled with fresh test substance which was used unil the end of the exposure time. The total exposure time was 7h and the mean concentration of the test substance during this time was 5.1mg/l. Clinical signs were documentated daily over a period of 14 days after exposure with the test substance and a necropsy was performed at the end of the study. During the exposure of the substance the animals showed mopping of the snout, red nose discharge, and delayed pain reflexes. After the exposure time some animals had bloody nose discharge which showed the substance's irritating potential. All animals survived until the end of the study and did not develop pathological findings. Therefore the LD50 of the test material is > 5.1mg/l as the maximum achievable vapor concentration in this test.

c)    Waiver

According to column 2 of REACH Annex VIII and with respect to the acute toxicity, at least one further route of exposure (dermal, inhalation) must be provided in addition to the oral route. The further route has to be selected according to the possible route of human exposure during manufacture, handling and use of the test article.

Due to the very low vapor pressure of the test article not significant human exposure to vapor can be anticipated at room temperature. Therefore this substance the dermal route of exposure was identified as the most relevant for human worker exposure during manufacture, handling and use.

 

Acute Toxicity: dermal

Non-guideline-study

a)    Target Substance(CAS 61596-96-1)

Before OECD Guideline 404 was established in 1982, skin irritation was tested using an internal method (BASF test). 5 rabbits per sex were treated with an application site of 7x7cm, which was covered with the liquid test substance (200 µl/kg = 220 mg/kg) for 24 hours using occlusive conditions. After the application time, the skin was washed with water. The report describes findings after 1h, 24h, 48h and 72h. Acute dermal toxicity with a single dose of 200 µl/kg (=220 mg/kg) reveals no signs of toxicity or mortality.

Therefore the LD50 is derived as >200 µl/kg (>220 mg/kg). (BASF, 1980)

Guideline-studies

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

In an acute dermal toxicity study (Limit test, GLP) conducted according to OECD Guideline 402, a single dermal dose of 5000 mg/kg body weight of the undiluted test item was applied for 24 h to the clipped skin (dorsal and dorso-lateral parts of the trunk) (Bioassay, 2012). The application area comprised at least 10% of the total body surface area. At the end of the exposure period the application site was rinsed with water and the animals were observed for 14 days.

No mortality and no signs of systemic toxicity occurred. Very slight to moderate erythema (grade 1 to 3), very slight to slight edema (grade 1 to 2), incrustations, scaling and orange discoloured fur was observed. No macroscopic pathologic abnormalities were noted in the animals examined at the end of the study.

Accordingly, the acute dermal median lethal dose (LD50) in rats was determined to be > 5000 mg/kg body weight. (BASF, 2012)

 

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

In an acute dermal toxicity study according to OECD 402 guideline and GLP, young adult Wistar rats were dermally exposed to doses of 2000 mg/kg and 500 mg/kg bw of 2-Propyn-1-ol, compd. with methyloxirane to the clipped and covered by semi-occlusive dressing for 24 hours. The application area comprised at least 10% of the total body surface area. The animals were observed for 14 days. No mortality occurred. Accordingly, the acute dermal lethal dose was determined to be LD50, dermal, rat > 2000 mg/kg bw. (BASF, 2012)

4.    Key study assignment:

 

Oral:

There is one acute oral toxicity study available for the target substance, which is reliable and lots of parameters are well documented in raw data. Furthermore the study was conducted in general accordance with the OECD principles and the results observed are the most critical. Therefore this study (BASF, 2000) was assigned as key study.

 

Inhalation:

Information are available concering the target and the source substance but concentration tested are depending on the max. saturation of the atmosphere, therefore both studies may add information to the inhalation toxicity of the substance and will therefore be integrated as WOE.

 

Dermal:

There is only a less reliable study (BASF, 1980) with the target substance on dermal toxicity available, which was limited in documentation. Therefore further information from two source substance studies (both BASF, 2012) are used in a weight of evidence approach, especially due to the similar result. 

5.    Conclusion

There is one acute oral toxicity study available for the target substance2-Butyne-1,4-diol, polymer with methyloxirane (CAS 61596-96-1), which is reliable and points to an LD50 of 275 mg/kg bw/d (BASF, 1976). Further this result is underlined by a studies with the two source substancesPolyethylene glycol ether with 2-butyne-1,4-diol (CAS 32167-31-0) and 2-Propyn-1-ol, compd. with methyloxirane (CAS 38172-91-7) showing slight better but comparable results.

For inhalation toxicity there is one study for the target substance available which show not deaths at vapor saturation concentration (BASF, 1976). Further, a second study with the source substance 2 did also show no mortalities up to highest concentration tests (max saturation concentration of 5.1mg/l) (BASF 1987). Based on these findings the risk of acute inhalation toxic effects is limited especially up to the saturation concentrations. No classification is derived. As there already two routes addressed and inhalation is not the expected primary route of exposure further testing concerning this route is not suggested.

For dermal toxicity there is one studyavailable for the target substance2-Butyne-1,4-diol, polymer with methyloxirane (CAS 61596-96-1), which is less reliable and points to an LD50> 220 mg/kg bw/d, which was the highest tested concentration (BASF, 1976). Studies with the two source substancesPolyethylene glycol ether with 2-butyne-1,4-diol (CAS 32167-31-0) and 2-Propyn-1-ol, compd. with methyloxirane (CAS 38172-91-7) showingno treatment related effects at the highest tested concentrations. Therefore, no acute dermal toxicity is assumed and the LD50 is considered to be > 2000 mg/kg.

In summary the available data indicate a moderate acute oral toxicity LD50275mg/kg bw (category 3) and no acute toxicity via dermal route (LD50 > 2000 mg/kg bw).

Justification for selection of acute toxicity – oral endpoint
Most relevant, reliable and critical study with the target substance.

Justification for selection of acute toxicity – inhalation endpoint
An acute inhalation toxicity study does not need to be performed due to the moderate toxic potential observed on the oral (LD50 acute oral 275 mg/kg bw) and a very low toxic potential observed on the dermal route of exposure (LD50 acute dermal > 5000 mg/kg bw). Further inhalation risk test of source and target substance did not indicate mortality at saturated atmosphere.

Justification for selection of acute toxicity – dermal endpoint
Most reliable and relevant information. LD50>2000 mg/kg. Weight of evidence approach.

Justification for classification or non-classification

Based on the information received for the target substance and structurally similar source substance, a classification is derived according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, the substance is classified as

- acute oral toxicity category 3 or R22,

- acute inhalation toxicity: not necessary

- acute dermal toxicity: not classified

according to Regulation (EC) 1272/2008 or Directive 67/548/EEC.