Butane-1,4-diol

Long-term toxicity to fish

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

long-term toxicity to fish, other

Remarks:

Chronic toxicity to fish

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

QSAR prediction

Qualifier:

no guideline followed

Principles of method if other than guideline:

ECOSAR v1.11: Estimation of chronic toxicity to fish for chemical class "Neutral Organic SAR (Baseline Toxicity)"

GLP compliance:

no

Test organisms (species):

other: fish

Water media type:

freshwater

Total exposure duration:

30 d

Remarks on exposure duration:

chronic exposure

Key result

Duration:

30 d

Dose descriptor:

other: Chronic toxicity (ChV)

Effect conc.:

557.3 mg/L

Nominal / measured:

estimated

Conc. based on:

act. ingr.

Basis for effect:

other: chronic toxicity (not specified)

Remarks on result:

other: ECOSAR chemical class: "Neutral Organic SAR (Baseline Toxicity)"

Reference 2

Endpoint:

long-term toxicity to fish, other

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

1. SOFTWARE
QSAR Toolbox 4.4, Database version: 4.4

2. MODEL (incl. version number)
Trend analysis developed in QSAR Toolbox (see attached QSAR report in "Attached justification")

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
see attached QSAR report in "Attached justification"

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
see attached QSAR report in "Attached justification"

5. APPLICABILITY DOMAIN
see attached QSAR report in "Attached justification"

6. ADEQUACY OF THE RESULT
- The model is scientifically valid (see attached QSAR report in "Attached justification").
- The model estimates the toxicity to aquatic organisms: Long-term toxicity to aquatic invertebrates (NOEC); this data can be used to support the assessment regarding the toxicity of a substance to
aquatic organisms (see attached QSAR report in "Attached justification").

Qualifier:

no guideline followed

Principles of method if other than guideline:

- Principle of test:
Estimation method for NOEC; Growth; Cyprinodon variegatus, Danio rerio, Fundulus heteroclitus, Jordanella floridae, Oncorhynchus mykiss, Oryzias latipes; 28 d;
Data gap filling method: Trend analysis

Report based on:
- "Guidance document on the validation of (quantitative) structure-activity relationships models" OECD, September 2007
- "Guidance on information requirements and chemical safety assessment / Chapter R.6: QSAR and grouping of chemicals" ECHA, May 2008

The Toolbox has multiple functionalities to perform a number of operations:
- identify analogues for a chemical, retrieve experimental results available for those analogues and fill data gaps by read-across or trend analysis
- categorize large inventories of chemicals according to mechanisms or mode of action
- fill data gaps for any chemical by using the library QSAR models
- evaluate the robustness of a potential analogue for read-across
- evaluate the appropriateness of a (Q)SAR model for filling a data gap for a particular target chemical
- build QSAR models

Analytical monitoring:

no

Vehicle:

no

Test organisms (species):

other: Cyprinodon variegatus, Danio rerio, Fundulus heteroclitus, Jordanella floridae, Oncorhynchus mykiss, Oryzias latipes

Test type:

not specified

Water media type:

freshwater

Limit test:

no

Total exposure duration:

28 d

Key result

Duration:

28 d

Dose descriptor:

NOEC

Effect conc.:

94.2 mg/L

Nominal / measured:

nominal

Conc. based on:

test mat.

Basis for effect:

growth rate

Remarks on result:

other: The substance is within the applicability domain of the model.

Summary:

Toxicity of the target chemical (94.2 mg/L) is predicted from category members using Trend analysis based on 9 values wiithin the range of 0,0255 to 29,2 mg/L from 10 category members. When multiple values were available for the same chemical, their arithmetic mean (average) value was taken in prediction calculations. Category members are single chemicals or mixtures and are selected based on the profile of the target chemical. Only chemicals having experimental data are listed in the category.

 

The target chemical FALLS within the applicability domain of the model.

Reference 3

Endpoint:

adult fish: sub(lethal) effects

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1997

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 204 (Fish, Prolonged Toxicity Test: 14-day Study)

GLP compliance:

yes

Specific details on test material used for the study:

- Chemical name: 1,4-Butanediol
- CAS number: 110-63-4

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: The test substance was stored at room temperature in a light-shielded sample storage chamber.
- Stability and homogeneity of the test material in the vehicle/solvent under test conditions (e.g. in the exposure medium) and during storage: stable
- Stability in the medium, i.e. sensitivity of the test material to hydrolysis and/or photolysis: stable
- Solubility and stability of the test material in the solvent/vehicle and the exposure medium: stable

Analytical monitoring:

yes

Details on sampling:

- Concentrations: 50, 100 and 200 mg/L
- Sampling method: At the start of the test (day 0), and 7 days and 14 days later, 1.0 mL of test water was sampled from the test water tank and analyzed by gas chromatography.

Vehicle:

no

Details on test solutions:

PREPARATION AND APPLICATION OF TEST SOLUTION
- Method: Test substance was dissolved in distilled water to prepare the necessary amount of 10 wt% stock solution. The 10 wt% stock solution was added to dilution water to prepare the necessary amount of 1000 mg/L liquid to supply to the serial dilution device.
- Controls: A control group was established using dilution water only.

Test organisms (species):

Oryzias latipes

Details on test organisms:

TEST ORGANISM
- Common name: himedaka
- Strain: ME961205
- Source: Rokuotsu Fish Farm, December 5, 1997
- Length at study initiation: 1.80 cm (1.51 - 2.01 cm)
- Weight at study initiation: 0.096 g (0.0521-0.1447 g)
- Feeding during test: yes
- Food type: TetraMin
- Amount / Frequency: 2 % fish body weight/day


ACCLIMATION
- Acclimation period: at least 12 days.
- Acclimation conditions: under the same conditions (water quality, temperature, etc.) as the test conditions.
- Type and amount of food: TetraMin
- Health during acclimation: no mortalty was observed

Test type:

flow-through

Water media type:

freshwater

Limit test:

yes

Total exposure duration:

14 d

Post exposure observation period:

post exposure observation not performed

Hardness:

21.8 mg/L (calculated as CaCO3)

Test temperature:

24 ± 2 °C

pH:

6.8

Dissolved oxygen:

not specified

Salinity:

not applicable

Conductivity:

not specified

Details on test conditions:

TEST SYSTEM
- Test vessel: Thermostatic water tank
- Size of vessel: CL100
- Type: open
- Aeration: no active aeration
- Type of flow-through: serial dilution device using metering pump
- No. of organisms per vessel: 10
- No. of vessels per concentration: 1
- No. of vessels per control: 1


OTHER TEST CONDITIONS
- Adjustment of pH: no
- Photoperiod: Indoor light, 16 hours illumination/8 hours darkness


EFFECT PARAMETERS MEASURED: mortality, body length, body weight


RANGE-FINDING STUDY
- Results used to determine the conditions for the definitive study: From the results of the acute toxicity test, the 50% lethal concentration (LC50) after 96-hour exposure was > 100 mg/L, and the maximum 0% lethal concentration and minimum 100% lethal concentration were also >100 mg/L.

Key result

Duration:

14 d

Dose descriptor:

NOEC

Effect conc.:

> 100 mg/L

Nominal / measured:

nominal

Conc. based on:

test mat.

Basis for effect:

adult mortality

Remarks on result:

other:

Remarks:

analytically verified

Table 1. Measured concentrations of the test substance during the test procedure.

Nominal concentration (mg/L)	0 Day	7 Day	14 Day	Mean	Recovery Mean
Control	<20	<20	<20	-	-
100	93	97.2	87.2	92.5

 

Table 2. Fish Weight (g)

Nominal concentration (mg/L)	1	2	3	4	5	6	7	8	9	10	Mean
Control	0.1210	0.1114	0.1143	0.1181	0.1267	0.0557	0.1617	0.1353	0.0987	0.1230	0.1166
100	0.1114	0.1063	0.0646	0.1426	0.11563	0.0792	0.1113	0.1338	0.0930	0.0906	0.1048

 

Table 3. pH values during the test procedure

Nominal concentration (mg/L)	0 Day	1 Day	4 Day	6 Day	8 Day	11 Day	13 Day	14 Day
Control	7.1	6.9	6.9	6.7	6.6	7.0	6.5	6.6
100	7.1	6.9	6.8	6.8	6.6	6.9	6.6	6.7

 

Table 4. Dissolved Oxygen concentration during the test procedure

Nominal concentration (mg/L)	0 Day	1 Day	4 Day	6 Day	8 Day	11 Day	13 Day	14 Day
Control	8.24	7.22	7.69	7.73	7.46	7.71	8.01	8.26
100	7.90	7.34	7.26	7.24	7.18	7.48	7.44	7.58

Validity criteria fulfilled:

yes

Reference 4

Endpoint:

long-term toxicity to fish, other

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

1. SOFTWARE
QSAR Toolbox 4.4, Database version: 4.4

2. MODEL (incl. version number)
Trend analysis developed in QSAR Toolbox (see attached QSAR report in "Attached justification")

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
see attached QSAR report in "Attached justification"

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
see attached QSAR report in "Attached justification"

5. APPLICABILITY DOMAIN
see attached QSAR report in "Attached justification"

6. ADEQUACY OF THE RESULT
- The model is scientifically valid (see attached QSAR report in "Attached justification").
- The model estimates the toxicity to aquatic organisms: Long-term toxicity to aquatic invertebrates (NOEC); this data can be used to support the assessment regarding the toxicity of a substance to
aquatic organisms (see attached QSAR report in "Attached justification").

Qualifier:

no guideline followed

Principles of method if other than guideline:

- Principle of test:
Estimation method for NOEC; Mortality; Pimephales promelas; 32 d;
Data gap filling method: Trend analysis

Report based on:
- "Guidance document on the validation of (quantitative) structure-activity relationships models" OECD, September 2007
- "Guidance on information requirements and chemical safety assessment / Chapter R.6: QSAR and grouping of chemicals" ECHA, May 2008

The Toolbox has multiple functionalities to perform a number of operations:
- identify analogues for a chemical, retrieve experimental results available for those analogues and fill data gaps by read-across or trend analysis
- categorize large inventories of chemicals according to mechanisms or mode of action
- fill data gaps for any chemical by using the library QSAR models
- evaluate the robustness of a potential analogue for read-across
- evaluate the appropriateness of a (Q)SAR model for filling a data gap for a particular target chemical
- build QSAR models

Analytical monitoring:

no

Vehicle:

no

Test organisms (species):

Pimephales promelas

Test type:

not specified

Water media type:

freshwater

Limit test:

no

Total exposure duration:

32 d

Key result

Duration:

28 d

Dose descriptor:

NOEC

Effect conc.:

261 mg/L

Nominal / measured:

nominal

Conc. based on:

test mat.

Basis for effect:

adult mortality

Remarks on result:

other: The substance is within the applicability domain of the model.

Summary:

Toxicity of the target chemical (261mg/L) is predicted from category members using Trend analysis based on 16 values wiithin the range of 0,0063 to 129 mg/L from 10 category members. When multiple values were available for the same chemical, their arithmetic mean (average) value was taken in prediction calculations. Category members are single chemicals or mixtures and are selected based on the profile of the target chemical. Only chemicals having experimental data are listed in the category.

 

The target chemical FALLS within the applicability domain of the model.

Description of key information

Based on a GLP-compliant prolonged toxicity test according to OECD TG 204 with medaka fish (Oryzias latipes) the long-term NOEC for 1,4-Butanediol was determined to be > 100 mg/L. This conclusion is supported by results derived from valid (Q)SAR models falling into their applicability domain.

Key value for chemical safety assessment

Fresh water fish

Fresh water fish

Dose descriptor:

NOEC

Effect concentration:

> 100 mg/L

Additional information

Experimental data on the long-term toxicity of 1,4-Butanedion on fish is available from one Prolonged Toxicity Test according to OECD TG 204. The key result is supported by long-term results derived from valid (Q)SAR models falling into their applicability domain. The available information is discussed in a weight of evidence approach.

 

Existing information of a valid and GLP-compliant Prolonged Toxicity Test with 1,4-Butanediol are publicly available (NITE, 1997). In this study, 10 medaka fish (Oryzias latipes, strain ME961205) were exposed for 14 days to the limit test item concentration of 100 mg/L (nominal) using a flow-through system (serial dilution device with metering pump). Fish were acclimatized for at least 12 days at the same conditions as for the test. During the acclimatisation period no mortality was observed. The test substance was dissolved in distilled water to prepare a 10 wt% stock solution. The 10 wt% stock solution was added to dilution water to prepare the necessary amount of 1000 mg/L liquid to supply to the serial dilution device. A negative control group (10 fish, 1 replicate) was established using dilution water only. The nominal limit concentration was analytically verified using a GC_FID method. Samples of test water were taken at the start of the test (day 0), and 7 days and 14 days later. As a result, no toxic effects were detected at this limit concentration. Therefore, the 14-day NOEC (mortality) of 1,4-Butanediol was determined to be > 100 mg/L (based on nominal concentration). All validity criteria of the applied guideline were fulfilled. The vailidity criteria of the guideline were fulfilled. The study is thus regarded valid and acceptable for hazard assessment under Regulation (EC) 1907/2006 (REACH).

 

In addition long-term data from valid (Q)SAR models falling into their applicability domain were generated. Using ECOSAR the chronic toxicity to fish was calculated for the chemical class "Neutral Organic SAR (Baseline Toxicity) to be 30d ChV = 557.3 mg/L. In a trend analysis based on a dataset for several freshwater fish species (Cyprinodon variegatus, Danio rerio, Fundulus heteroclitus, Jordanella floridae, Oncorhynchus mykiss, Oryzias latipes) as implemented in OECD QSAR Toolbox, the 28-d NOEC for growth and mortality was estimated to be 94.2 and 261 mg/L, respectively (BASF SE, 2021).

 

 

Conclusion

The Prolonged Toxicity Test with the registration substance 1,4-Butanediol was carried out in compliance with the internationally agreed guideline OECD TG 204 and GLP principles. All validity criteria of the guideline were fulfilled; the data is hence considered reliable and acceptable for assessment. In this test no effects on mortality, weight and growth were detected at the limit concentration of 100 mg/L. The 14-day NOEC was therefore determined to be > 100 mg/L. This result  is supported by chronic effect values derived from valid (Q)SAR models falling into their applicability domain. The estimated long-term effect values range between 94.2 and 557.3 mg/L with a geometric mean of 239 mg/L. The available experimental and in silico data do not indicate a potential for long-term toxicity on fish.

In conclusion, the long-term NOEC for 1,4-Butanediol is considered to be > 100 mg/L based on the results of the OECD TG 204 with medaka fish (Oryzias latipes) as the most relevant and reliable information.

 

 

NON-SUBMISSION JUSTIFICATION

Additional studies on long-term toxicity of 1,4-Butanediol on fish does not need to be conducted for the reasons of adaptation rules of section 1 Annex XI (scientifically not necessary).

 

Long-term toxicity testing on fish is an information requirement under Section 9.1.6 of Annex IX to Regulation (EC) 1907/2006 (REACH). In accordance with the ECHA draft decision on Butane-1,4-diol (dated 16 August 2021) and the ECHA Guidance on Information Requirements and Chemical Safety Assessment Chapter R.7b: Endpoint specific guidance Version 4.0 (June 2017, currently being reviewed), the Fish, Early-life Stage Toxicity Test (test method OECD TG 210) is the most appropriate test method with sub-lethal effects to sensitive life-stages (juveniles, eggs, larvae) as the major endpoints examined.

 

Reliable data on long-term toxic effects to fish is available from a publicly available Prolonged Toxicity Test (NITE, 1997; see above). The test revealed a 14-day NOEC of 1,4-Butanediol was determined to be > 100 mg/L (based on nominal concentration). The estimated long-term effect values range between 94.2 and 557.3 mg/L with a geometric mean of 239 mg/L, which is by a factor of 100 higher than the threshold concentration of 1 mg/L for classification for aquatic long-term toxicity given in table 4.1.0(b)(ii) of Regulation 1272/2008 (CLP). The NOEC determined in the Prolonged Toxicity Test (NITE, 1997) is also consistent with the key result for short-term toxicity to freshwater fish: in an Acute Toxicity Test according to OECD TG 203 the 96-hour LC50 was 30 g/L, which is clearly above the set threshold concentration for chronic toxicity of 100 mg/L given in table 4.1.0(iii) of the same regulation.

 

It should be noted that although the method according to OECD TG 204 examines lethal effects to fish over a long exposure duration, it does not completely cover all endpoints provided in the Fish Early Life Stage Test (OECD TG 210) like sublethal effects at sensitive developmental stages. Notwithstanding, the Prolonged Toxicity Test (OECD TG 204) achieves a high level of significance for chronic toxic effects such as mortality. Sublethal effects are anyhow not expected since there are no indications for developmental toxicity of 1,4-Butanediol from valid experimental studies with other vertebrates (for details please refer to IUCLID section 7.8.2). In a Combined Repeat Dose and Reproductive/Developmental Screening Test according to OECD TG 422 no adverse effects on the development of rats were observed (see IUCLID section 7.8.1). Moreover, a long-term Reproduction Test with Daphnia magna revealed a 21-day NOEC of > 85 mg/L (arith. mean measured) underlining the absence of reproductive effects to aquatic organisms. In sum, existing data sufficiently demonstrate that the substance is not long-term toxic to aquatic invertebrates as well as vertebrates, and additional long-term testing with fish is unlikely to contribute to scientific knowledge. Additional experimental information concerning long-term toxicity on fish is therefore waived.

 

This approach also complies with the ECHA integrated testing strategy (ITS) which stipulates that the long-term toxicity testing on aquatic invertebrates (Daphnia) should be conducted first and results of this test should be considered together with other information as part of the chemical safety assessment to identify whether further long-term testing on fish is needed. This ensures that the Daphnia study is undertaken first to ensure no vertebrate animals are unnecessarily tested. Based on the long-term results from the Reproduction Test with Daphnia magna (see above), and following the ITS, further long-term tests with fish are regarded scientifically not necessary.

 

Furthermore, in Regulation (EC) 1907/2006, Annex IX Column 2 it is laid down that chronic tests on fish shall be proposed by the registrant if the chemical safety assessment indicates the need to investigate further the effects on fish. According to Annex I of this regulation, the chemical safety assessment triggers further action when the substance or the preparation meets the criteria for classification as dangerous according to Regulation (EC) 1272/2008 (CLP), or is assessed to be a PBT or vPvB. The substance is nontoxic to the environment and neither classified for aquatic short-term (acute), nor aquatic long-term (chronic) toxicity in accordance with Regulation (EC) 1272/2008 (CLP), as amended for the seventeenth time in Regulation (EU) 2021/849. Further, the substance is regarded to be not PBT/vPvB since it was determined to be readily biodegradable, has a very low Log Pow of - 0.88 and does not fulfil the criteria for T-properties. An environmental risk assessment is therefore not needed and, consequently, the intrinsic properties of the substance do not indicate the need to investigate further the effects on fish.

 

The above points lead to the conclusion that the criteria of section 1 in Annex XI to REACH are met, which justifies the adaptation of the information requirements. Therefore, and considering animal welfare reasons, additional studies on long-term toxicity to fish are neither scientifically, nor from a regulatory point of view justified.

 

This is also in line with the rule of information requirement adaptation as stated in Annex IX Section 9.1 column 2. Further testing does not appear to be scientifically appropriate.