2-Propyn-1-ol, reaction product with 1-2.5 moles of oxirane

Endpoint summary

Description of key information

Acute oral toxicity (OECD 401, RA to CAS 38172-91-7): LD50 > 232 < 1075 mg/kg bw, Calculated lowest LD50 (m) 526 mg/kg bw. (BASF, 1987)
Acute inhalation toxicity (comparable to OECD 403): LC50 of 1.67 mg/l/4h (BASF, 1975)
Acute dermal toxicity (OECD 402, RA to CAS 38172-91-7, GLP, WoE ): LD50 > 2000 mg/kg bw  (BASF, 1977 and 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 study with acceptable restrictions. Source substance for RA information according to analogue justification.

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Dr. K. Thomae GmbH, Biberach, Germany
- Weight at study initiation: male (mean): 186g, female (mean): 184g
- Fasting period before study: 16 hours
- Housing: 5 animals per cage (grouped according to doses)
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24°C
- Humidity (%): 30 - 70%
- Air changes (per hr): fully airconditioned
- Photoperiod (hrs dark / hrs light): 12 hours / 12 hours

Route of administration:

oral: gavage

Vehicle:

water

Doses:

215, 464, 2150, 5000 mg/kg

No. of animals per sex per dose:

5

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: at least once per day (observation), after 7 and 13 days (weighing)
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 464 - < 2 150 mg/kg bw

Based on:

test mat.

Remarks on result:

other: all male and female animals dosed with 2150mg/Kg died after 1 day, 2/5 males dosed with 464mg/Kg died after 7 days, 0/5 females dosed with 464mg/Kg died until the end of the study

Sex:

female

Dose descriptor:

LD50

Effect level:

> 464 - < 2 150 mg/kg bw

Based on:

test mat.

Remarks on result:

other: all female animals dosed with 2150mg/Kg died after 1 day; all female animals dosed with 464mg/Kg survived until the end of the study

Sex:

male

Dose descriptor:

LD50

Effect level:

ca. 464 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 2/5 male animals dosed with 464mg/Kg died 7 days after treatment

Mortality:

male/female:
5000mg/Kg: 5/5 animals after 1 day
2150mg/Kg: 5/5 animals after 1 day

male:
464mg/Kg: 2/5 animals after 7 days

No mortality was observed after administration of 215 mg/kg in males and females as well as after treatment of females with 464 mg/kg.

female:
5000mg/Kg: 5/5 animals after 1 day
2150mg/Kg: 5/5 animals after 1 day

Clinical signs:

other: 5000mg/Kg, males and females: dyspnea, apathy, abnormal position, atonia, paresis, poor general state after <15min - 4h staggering: <15min - 1h exsiccosis: 4h piloerection: 1h - 4h 2150mg/Kg, males and females: dyspnea, apathy, staggering, paresis, poor

Gross pathology:

male and female animals that died spontaneously on day 1 or 7:
general congestion, liver: lobular perphery yellow brown, stomach: bloody ulceration in the glandular stomach

sacrified animals (male, female): no pathological findings

LD50 male animals: ca. 464 mg/kg; LD50 female animals > 464 < 2150 mg/kg

Interpretation of results:

Toxicity Category IV

Remarks:

Migrated information GHS Criteria used for interpretation of results: EU

Executive summary:

ln principle, the methods described in OECD Guideline 401 were used without GLP compliance.

5 rats per sex and dose were treated simultaneously with concentrations of 5000, 2150, 464 and 215 mg/Kgby gavage with preparations of the test substance in water as vehicle.

Group-wise documentation of clinical signs was performed over a 14- day study period, where clinical signs and mortality were documented at least once daily. Mortality was observed among the high doses in both sexes after 24 hours: 5000 mg/kg (5/5) and 2150 mg/kg (5/5). At 465 mg/kg 2 of 5 male animals died.

On the basis of the observed lethality, the LD50 value was estimated to be > 464 <2150 mg/kg bw for female and about 464 mg/kg bw for male. As a conseqence of it, the test substance should be classified as acute oral toxicity category 4 (GHS). (BASF, 1987)

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

526 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: Non-GLP study; however, basic parameters are documented and study was conduced similar to OECD 403.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

yes

Principles of method if other than guideline:

This test was performed in principle as described in OECD Guideline 403.
Deviations: 3 rats per sex were exposed, two exposure times (8hours and 3 hours) instead of 4h, clinical signs was perfomred over 7 days

GLP compliance:

no

Test type:

acute toxic class method

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: average 168 g (8hours-study) and 185g (3hours-study)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20
- Air changes (per hr): 200Ltr

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Details on inhalation exposure:

Vapor was generated by bubbling 200l/h air through a substance column of about 5cm above a fritted glass disc.

Analytical verification of test atmosphere concentrations:

no

Duration of exposure:

8 h

Remarks on duration:

another timepoint was 3 hours of exposure

Concentrations:

1,33 mg/l

No. of animals per sex per dose:

3

Control animals:

yes

Details on study design:

Several groups of 3 rats per sex were exposed sequentially to the vapors,
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 3 and 8 hours.
Group-wise documentation of clinical signs was performed over a 7- day study period. Body weight of groups was determined before the start of the study and at the end of the Observation period in surviving animals.

- Duration of observation period following administration: 7 days
- Frequency of observations and weighing: daily
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, gross pathology

Sex:

male/female

Dose descriptor:

LC50

Effect level:

1.33 mg/L air

Based on:

act. ingr.

Exp. duration:

8 h

Remarks on result:

other: Attention, increased exposure time (8h) instead of todays used 4h. See "Remarks on results"

Sex:

male/female

Dose descriptor:

LC50

Effect level:

ca. 1.34 mg/L air

Based on:

act. ingr.

Exp. duration:

3 h

Mortality:

No mortality occured in this study after 3hours of exposure.

Exposure of 8hours conducted to one dead animal after 24h, one dead animal after 48h and one dead animal after 72h, so that half of the animals were dead after 72hours.

Clinical signs:

other: 3h-Exposure: no effects 8h-Exposure: -strong mucosa irritation - nose, discharge, bloody - dyspnea

Gross pathology:

Heart: acute dilatation and accumulation of blood
Liver: yellow coloured
stomach: dilatation
lung: acute flatulence

Other findings:

8h exposure: 3 of 6 animals were dead within 3 days after exposure. Survivors showed no effects after 3 days and were killed at the end of this study after 7 days.

Interpretation of results:

Toxicity Category II

Remarks:

Migrated information GHS Criteria used for interpretation of results: EU

Executive summary:

This 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 3 hours and 8 hours. Documentation of clinical signs and mortality was performed over 7 days.

No mortality occured in this study after 3hours-exposure. Exposure of 8hours conducted to one dead animal after 24h, one dead animal after 48h and one dead animal after 72h, so that half of the animals were dead after 72hours.

The classification criteria for acute inhalation toxicity relate to a 4h experimental exposure period. After adjustment to a 4h-equivalent by Haber´s law (c^n*t=constant), an LC50 of 1,67 mg/l/4h could be calculated and therefore the test item should be classified as inhalation toxic category 2. (BASF, 1975)

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

1 670 mg/m³ air

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, Source substance for RA information according to analogue justification.

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

Conclusions:

At maximal concentration (2000 mg/kg bw) no mortality occured, therefore the LD50 was determined to be > 2000 mg/kg bw.

Executive summary:

In an acute dermal toxicity study (OECD 402), 5 young adult Wistar rats of both sexes 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 skin and covered by semi-occlusive dressing for 24 hours under GLP conditions. The application area comprised at least 10% of the total body surface area.

The animals were observed for 14 days, where no mortality occurred and no other signs of systemic toxicity were observed.

 

Accordingly, the acute dermal median lethal dose (LD50) was determined to be LD50, dermal, rat > 2000 mg/kg bw and no classification concerning GHS (EU) is recommended. (BASF 2013)

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

2 000 mg/kg bw

Additional information

Justification for grouping of substances and read-across

There are no reliable data available for the acute toxicity of 2-Propyn-1-ol, polymer with ethylene oxide (CAS 25749-64-8). 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 was conducted.

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

CAS	Acute toxicity oral	Acute toxicity inhalation	Acute toxicity dermal
Target substance 2-Propyn-1-ol, polymer with ethylene oxide (CAS 25749-64-8)	LD 50 = 2184 mg/kg bw (RL3) LD 50 = 2500 mg/kg bw (RL3)	LC50 = 1.67 mg/l/4h (RL3) LC50 > 2.41 mg/l/4h (RL3)   (values adjusted by Haber´s law)	LD50 > 2000 mg/kg bw (RL3)
Source substance 2-Propyn-1-ol, compd. with methyloxirane (CAS 38172-91-7)	LD50: 464-2150 mg/kg bw (RL2) purity appro. 50%; Calculated lowest LD50 (m) 526 mg/kg bw (a.i.)	--	LD50 > 2000 mg/kg bw (RL1)   purity appro. 55%

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 endpoints for 2-Propyn-1-ol, polymer with ethylene oxide(CAS 25749-64-8). A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

 

Acute toxicology: oral

 

a)     Target substance (CAS 25749-64-8)

 

The test was performed in principle with the methods described in OECD Guideline 423 without GLP compliance. 5 rats per sex and dose were treated simultaneously with concentrations of 4640 µl/kg, 3160 µl/kg, 2150 µl/kg (4756 mg/kg, 3239 mg/kg, 2204 mg/kg) by gavage with preparations of the test substance in water as vehicle. Group-wise documentation of clinical signs was performed over a 14- day study period, where clinical signs and mortality were documented. Mortality was observed among all doses. Most critical value was 2150 µl/kg  bw (2204 mg/kg) with 3 of 5 dead female.

The authors concluded on the basis of the observed lethality, the LD50 value to be 2184 mg/kg bw (2100 µl/kg bw) (BASF, 1975).

 

b)     Target substance (CAS 25749-64-8)

 

This test was performed in principle as described in OECD guideline 420 without GLP compliance. 5 rats per sex and dose were treated simultaneously with concentrations of 3160 mg/kg, 2150 mg/kg and 1470 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 3160 mg/kg and 2150 mg/kg.

On the basis of the observed lethality, the mean LD50 (female/male) value was estimated to be 2500 mg/kg bw. (BASF, 1976).

 

c)     Source substance (CAS 38172-91-7) (Read-across)

 

This test was performed in principle as described in OECD guideline 401 without GLP compliance. 5 rats per sex and dose were treated simultaneously with concentrations of 5000, 2150, 464 and 215 mg/kg by gavage with preparations of the test substance (purity approx. 50%) in water as vehicle. Group-wise documentation of clinical signs was performed over a 14- day study period, where clinical signs and mortality were documented at least once daily. Mortality was observed among the high doses in both sexes after 24 hours: 5000 mg/kg (5/5) and 2150 mg/kg (5/5). At 465 mg/kg 2 of 5 male animals died but no females. At 215 mg/kg no mortality was observed.

On the basis of the observed lethality, the LD50 value refered to the active ingredient was estimated to be > 232 < 1075 mg/kg bw for females and about > 232 mg/kg bw for male (BASF, 1987). Linear regression using the both lowest deads rates for males lead to an LD50 (m) 526 mg/kg bw, which represents the most critical value.

 

Acute toxicology: inhalation

 

a)     Target substance (CAS 25749-64-8)

 

This 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 3 hours and 8 hours. Documentation of clinical signs and mortality was performed over 7 days.

No mortality occured in this study after 3h-exposure. Exposure of 8hours reveals one dead animal after 24h, one dead animal after 48h and one dead animal after 72h, so that half of the animals were dead after 72h.

The classification criteria for acute inhalation toxicity relate to a 4h experimental exposure period. According to the applicant, an adjustment to a 4h-equivalent by Haber´s law (c^n*t=constant) result in an LC50 of 1.67 mg/l/4h (BASF, 1975).

 

b)     Target substance (CAS 25749-64-8)

 

This 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 3 and 7 hours. Documentation of clinical signs and mortality was performed over 14 days. The highest tested concentration of test substance (vapour saturation concentration 2.01 mg/l) shows one dead animal after 1 day but no further mortality in the following 13 days.

The classification criteria for acute inhalation toxicity relate to a 4h experimental exposure period. According to the applicant an adjustment to a 4h-equivalent by Haber´s law (c^n*t=constant) resulted in an LC50 of > 2.41 mg/l/4h (BASF, 1976).

 

 

Acute toxicology: dermal

 

a)     Target substance (CAS 25749-64-8)

 

Before OECD Guideline 404 was established in 1982, skin irritation was tested using an internal method. 3 rats per sex were treated with an application site of 5cm²with the test substance (2000 mg/kg). The report describes findings after 1hour, after the first day and daily from day 4 to day 8 and daily from day 11 to day 14. Acute dermal toxicity tested with a single dose of 2000 mg/kg reveals no signs of toxicity or mortality.

Therefore the LD50 is derived as >2000 mg/kg (BASF, 1977).

 

 

b)     Source substance  (CAS 38172-91-7) (Read across)

 

In an acute dermal toxicity study (OECD 402), 5 young adult Wistar rats of both sexes were dermally exposed to doses of 2000 mg/kg and 500 mg/kg bw of 2-Propyn-1-ol, compd. with methyloxirane (purity approx. 55%) to the clipped skin and covered by semi-occlusive dressing for 24 hours under GLP conditions. The application area comprised at least 10% of the total body surface area. The animals were observed for 14 days. No mortality occurred and no other signs of systemic toxicity were observed.

Accordingly, the acute dermal median lethal dose (LD50) was determined to be LD50, dermal, rat > 2000 mg/kg bw (TI) or > 1100 mg/kg bw (active ingredient).(BASF 2013).

 

Key study assignment:

 

Acute oral:

There are few information according acute oral toxicity available. For the target substance the available studies (BASF 1975, 1976), are not well documented and thus judged as less reliable especially as the studies are not more critical than the study conducted with the source substance. Therefore information from the study with the source substance (BASF, 1987) was assigned as key study and less reliable information was assigned as supporting studies.

 

Acute inhalation:

Both inhalation studies (BASF 1975, BASF 1976) conducted with the target substance are less reliable due to a lack in documentation and therefore entered as weight of evidence. Nevertheless the most critical result will be used for hazard assessment in a worst case approach.

 

Acute dermal:

There is a only less reliable study (BASF, 1977) with the target substance on dermal toxicity available, which was limited in documentation. Therefore further information from a source substance study (BASF, 2013) is used espacially due to the similar result (no effects) and entered as a WoE approach showing no dermal toxicity. 

 

 

Conclusion for acute toxicity

In summary, two less reliable acute oral toxicity studies from 2-Propyn-1-ol, polymer with ethylene oxide(CAS 25749-64-8) are available which points to an LD50 in the area of 2000 mg/kg bw. Therefore another reliable acute oral toxicity study from source substance (read across substance) 2-Propyn-1-ol, compd. with ethyloxirane (CAS 38172-91-7) was used as additional information source to assess the oral toxicity.  Based on the observed lethality of 2/5 dead male and 0/5 female animals at 464 mg/kg and 5/5 females and males died at 2150 mg/kg, the oral LD50 is estimated in the range of > 464 < 2150 mg/kg bw. Using linear regression (only the two lowest dosages for males) a LD50 (m) = 526 mg/kg bw can be calculated. Take this value into account as well as the hints from the less reliable studies with the source substance leading to LD 50 category >300 mg/kg < 2000 mg/kg as most suitable.

 

For acute inhalation toxicity, one study with 2-Propyn-1-ol, polymer with ethylene oxide(CAS 25749-64-8)and one inhalation risk test are available. These studies resulted after adjustment with Haber´s law in the LC50 value of 1.67 and > 2.41 mg/L/4h. Both studies are less reliable and were used as weight of evidence. In compliance with worst case assumption, the substance is judged as moderate toxic via inhalation and an LC50 of 1.67 mg/L/4h will be used for classification.

 

Two acute dermal toxicity studies conducted 2-Propyn-1-ol, polymer with ethylene oxide(CAS 25749-64-8)and one read-across study with 2-Propyn-1-ol, compd. with ethyloxirane (CAS 38172-91-7)showed no treatment related effects at the limit dose of 2000 mg/kg (> 1100 mg/kg concerning active ingredient). Both studies show that a low dermal toxicity can be expected for the target as well as for the source substance, therefore, the dermal LD50 is considered to be greater than 2000 mg/kg bw respectively and the target substance should not be classified concerning GHS (EU).

 

In summary the available data indicate a low acute oral toxicity LD50 (m) 526 mg/kg bw, a moderate acute inhalation toxicity with an LC50=1.67 mg/L/4h and no acute toxicity via dermal route (LD50 > 2000 mg/kg bw).

Justification for selection of acute toxicity – oral endpoint
Most reliable and relevant information. LD50 > 232 <1075 mg/kg bw. Calculated lowest LD50 (m) 526 mg/kg bw.

Justification for selection of acute toxicity – inhalation endpoint
Most reliable and relevant information. Weight of evidence approach.

Justification for selection of acute toxicity – dermal endpoint
Most reliable and relevant information. 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.

The substance is classified as:

- acute oral toxicity category 4

- acute inhalation toxicity category 2

- acute dermal toxicity: not classified

Due to the irritation of the lung during the inhalation test, the substance has further to classified as

- H335: May cause respiratory