5-ethyl-1,3-dioxane-5-methanol

Endpoint summary

Description of key information

5 -ethyl-1,3 -dioxane-5 -methanol is of low acute oral toxicity: an acute oral LD50 > 2000 mg/kg bw is reported. No mortality or any effects were notied in an acute dermal toxicity study up to 2000 mg/kg. The acute dermal LD 0 >= 2000 mg/kg b.w. is reported based on this study. A waiver is proposed in accordance with Column 2 of Annex VIII of the REACH Regulation for acute inhalation toxicity on the basis that acute toxicity data are available for the oral route, and that inhalation is not predicted to be a significant route of exposure based on the physicochemical properties of the substance.

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

Study period:

24 June 1992 to 27 Aug 1992

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

not specified

Principles of method if other than guideline:

Not applicable.

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Specific details on test material used for the study:

Batch 9201; clear / colourless liquid

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
Source: Møllegaard Breeding Centre ApS, Ejby, DK-4623 Lille, Skensved
Age at study initiation: 6 - 7 weeks old
Weight at study initiation: 146 -163 g
Fasting period before study: Rats were fasted for approximately 18 hours prior to dosing
Housing: Housed in Macrolone type III cages (42 x 26 x 15cm), with 2 or 3 to a cage. Males and females were kept separated
Diet (e.g. ad libitum): Complete rodent diet "Altromin 1314" ad libitum
Water (e.g. ad libitum): Drinking water acidified with hydrochloric acid to pH 2.5 ad libitum
Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
Temperature (°C): 21 ± 3°C
Humidity (%): 55 ± 15%
Air changes (per hr): 10 times per hour
Photoperiod (hrs dark / hrs light): 12 hour photoperiod

IN-LIFE DATES: No information provided.

Route of administration:

oral: gavage

Vehicle:

other: Distilled water.

Details on oral exposure:

VEHICLE- Concentration in vehicle: 2000 mg/kg body weight. - Amount of vehicle (if gavage): No information provided. - Justification for choice of vehicle: No information provided. - Lot/batch no. (if required): No information provided. - Purity: No information provided. MAXIMUM DOSE VOLUME APPLIED: 10ml/kg body weight.DOSAGE PREPARATION (if unusual): No information provided. CLASS METHOD (if applicable)- Rationale for the selection of the starting dose: No information provided.

Doses:

2000 mg/kg body weight

No. of animals per sex per dose:

5 animals per sex per dose

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days - Frequency of observations and weighing: Bodyweights were recorded on Day 0, Day 7 and Day 14. Observations on clinical signs of toxicity were made 1, 2, 3 and 6 hours and daily thereafter from Day 1 to 14.- Necropsy of survivors performed: Any rats found dead during the 14 day observation period were subjected to a autopsy examination. All surviving rats were subjected to gross necropsy examination at the end of the 14 day observation period.- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: No information provided.

Statistics:

Not required

Preliminary study:

A dose-range finding study was conducted at a dose level of 2000 mg/kg bw

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

One female rat died during the treatment.

Clinical signs:

other:

Body weight:

other body weight observations

Remarks:

The surviving rats had a normal body weight gain during the study period.

Gross pathology:

Autopsy of the rat that died from the treatment revealed no pathological findings that could be attributed to the treatment. No gross pathological findings related to the treatment wee observed following autopsy of the surviving rats.

Interpretation of results:

Category 5 based on GHS criteria

Conclusions:

Under the conditions of this study, the oral LD50 of CTF was >2000 mg/kg bw.

Executive summary:

The acute oral toxicity of CTF in rats was determined according to the method recommended in OECD Guideline 401. CTF was administered orally by gavage to 5 male and 5 female Wistar rats at a concentration of 2000 mg/kg bw. The test animals were observed for a period of 14 days following exposure and observations were made at regular intervals, including observations on body weight, clinical signs and any clinical signs of toxicity. All test animals were subjected to a gross necropsy at termination on day 14. With only one female rat found dead during the course of the exposure, the oral LD50 was above 2000 mg CTF/kg body weight under the conditions of this study.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

A high quality modern GLP- and guideline-compliant study is available for this endpoint.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

10. Oct. 2022-09. Mar. 2023

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity: Fixed Dose Procedure)

Version / remarks:

adopted 09 October 2017

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Limit test:

no

Specific details on test material used for the study:

Cyclic trimethylolpropane formal (CTF)
chemical name 5-ethyl-1,3-dioxane-5-methanol
CAS number 5187-23-5, EC number 225-967-8
a clear, colourless liquid.
It was received on 21 September 2022 and stored at 15-25°C, under nitrogen, protected from light.

Species:

rat

Strain:

Wistar

Remarks:

Crl:WI(Han) strain

Sex:

female

Details on test animals or test system and environmental conditions:

Species Selection
The rat was selected because it is a rodent species recommended by various regulatory authorities. The rat has been found to be the most tractable species for the dosing procedures used in this type of study at this laboratory. The strain of rat was selected as it is widely used for this type of study and a literature base is available for comparative purposes.

Animal Specifications and Acclimatisation
Female (nulliparous, non-pregnant) Crl:WI(Han) strain rats were obtained from Charles River (UK) Ltd., Margate. All animals were given a clinical inspection for ill health on arrival and a sample was weighed.

The condition of the animals was assessed daily throughout the acclimatization period of 14 to 22 days. A clinical inspection was performed prior to study commencement to ensure the animals were suitable for the test procedures. Overtly healthy animals were arbitrarily allocated to the study at least one day before treatment commenced.

Animals were in a body weight range of 184 to 210 g on the day of dosing (Day 1). Based on information from the supplier the rats were approximately 8 to 10 weeks old on Day 1. Individual body weights were within ±20% of the mean weight of any previously dosed animals.

Housing

During the acclimatisation period, up to five rats of the same sex were accommodated in cages that conformed to the 'Code of Practice for the Housing and Care of Animals Bred, Supplied or Used for Scientific Purposes' (Home Office, London, 2014). From the day prior to dosing (Day-1), each rat was individually housed in a similar cage. After completion of the Day 3 observations animals allocated to the main study were returned to group housing.

Bedding was provided on a weekly basis to each cage by use of clean European softwood bedding (Datesand Ltd., Manchester, UK). The bedding had been analysed for specific contaminants and the results retained on file.
No contaminants were present in bedding at levels which might have interfered with achieving the objective of the study.

Water

Mains water was provided, ad libitum, via cage-mounted water bottles. The water had been periodically analysed for specific contaminants.
No contaminants were present in water at levels which might have interfered with achieving the objective of the study. Results are retained on file.

Diet
5LF2 EU Rodent Diet 14% (LabDiet, St Louis, USA) was freely available to the animals at all times. Each batch of diet had been analysed for specific constituents and contaminants by the manufacturer.
No contaminants were present in diet at levels which might have interfered with achieving the objective of the study. Results are retained on file.

Environment
The animal rooms were designed to permit a minimum of 15 air changes per hour.
The temperature and humidity ranges were 19 to 25°C and 40 to 70% respectively.
Daily recordings of maximum and minimum temperature and humidity were made.
Fluorescent lighting was controlled automatically to give a cycle of 12 hours light and 12 hours dark.

In order to enrich both the environment and the welfare of the animals, they were provided with wooden Aspen chew blocks, nesting materials and rodent retreats ( Wooden chew blocks were only provided for animal numbers 460 and 461 from the day of dosing. This deviation from protocol was considered not to have affected the integrity or outcome of the study as the absence of environmental enrichment does not affect the end points of the study). The nesting material was removed from the cages on the day of dosing and returned when the bandages were removed.

Animal Identification
A number written on the tail in indelible ink on the day before dosing individually identified the rats. A colour-coded card on each cage gave information including study number, group number, animal numbers and sex.

In-life Start Date: 11 October 2022
Experimental Completion Date: 16 November 2022

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
Electric clippers were used to remove all hair from the dorsum on the day before dosing. The dermal test site was an area of at least 10% of the total body surface on the clipped dorsum of the rat.

The test article was spread as uniformly as possible over the dermal test site. A dense gauze patch was placed over the treated skin and retained in place by an elasticated, open-weave, adhesive compression bandage. This was wrapped securely around the torso of the animal.

REMOVAL OF TEST SUBSTANCE
The dressing was removed approximately 24 hours after application. The dermal test site of each rat was lightly brushed clean of any solid residues and swabbed with water-moistened cotton wool before the animal was returned to the holding cage.

TEST MATERIAL
The test article was administered as supplied. The specific gravity was determined (1.106 g/mL) and used to calculate the appropriate dose volume for the required dose level. Individual dose volumes (mL) were calculated from the body weights of the rats on the morning of dosing (Day 1), the selected dose volume and the density of test article.

Duration of exposure:

24 hours

Doses:

Preliminary test:1000 and 2000 mg/kg
Main Study: 2000 mg/kg

No. of animals per sex per dose:

Preliminary test: one female per dose level
Main Study: 2 females per dose level

In total 4 animals used in this study.

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14 days

- Frequency of observations and weighing:
Clinical signs were recorded immediately post-dose, at approximately 15 and 30 minutes post-dose, hourly between 1 and 4 hours post-dose (inclusive), twice daily on Days 2, 3 and 4 and once daily from the fifth to last day of the observation period, Day 15*. *On day 15, the actual time was not recorded for the 15-minute post-dosing observation for animal number 458. This deviation from protocol was considered not to have affected the integrity or outcome of the study as sufficient observations were conducted.
All animals were examined at the beginning and end of the working day throughout the acclimatisation and study periods to ensure they were in good health.
Rats were weighed on Day-1 (day before dosing) and on Days 1, 4, 8 and 15.

-Dermal Reactions observation:
The condition of the dermal test site was recorded following removal of the dressing on Day 2, at approximately 24, 48 and 72 hours following removal of the dressing and once daily thereafter for the duration of the study period. Erythema and oedema were scored. See scoring scales in table 1 below.

- Necropsy of survivors performed: yes
Rats were killed on Day 15. Each animal was anaesthetised using isofluorane. Once a suitably deep plane of anaesthesia had been established, the animal was exsanguinated by the severing of major blood vessels. After exsanguination a full macroscopic necropsy was performed and all lesions were recorded.
The necropsy procedure included inspection of external surfaces and orifices, the dermal test site, all viscera and tissue within the abdominal, thoracic and cranial cavities, free-hand sectioning of the liver and kidneys and examination of representative sections of mucosal surfaces of the stomach and intestinal tract.
No tissue preservation or histopathological assessment of tissues was undertaken.

Statistics:

No statistic

Preliminary study:

The preliminary test was completed using one female per dose level in a sequential manner at dose levels of 1000 and 2000 mg/kg (The second animal was dosed 48 hours after the first animal). No treatment-related effects were seen in the preliminary test. Two animals were treated at 2000 mg/kg in the main study.

Key result

Sex:

female

Dose descriptor:

LD0

Effect level:

>= 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

not determinable due to absence of adverse toxic effects

Mortality:

There were no deaths in either the preliminary test or the main study.

Clinical signs:

other:

Body weight:

other body weight observations

Remarks:

All rats in the preliminary test and in the main study gained weight during the first and second weeks of the study. see details in Table 2 below.

Gross pathology:

No macroscopic changes were noted at necropsy of all animals from the preliminary test or the main study.

Other findings:

Dermal Reactions: There were no dermal reactions noted in either the preliminary test or in the main
study. See table 3 below.

Table 2 Individual Body Weights and Weekly Increments (preliminary test + main study).

Dose Level (mg/kg)	Animal Number	Body Weight (g) at:					Increment (g)
		Day‑1	Day 1	Day 4	Day 8	Day 15	Day 1 to 8	Day 8 to 15
1000	458	181	184	179	189	198	5	9
2000	459	182	185	178	187	207	2	20
	460	190	193	187	207	217	14	10
	461	210	210	199	218	234	8	16

 

Table 3 Dermal Reactions (preliminary test + main study).

Day (time after removal of dressing)	Dermal Reaction	Dose Level: 1000 mg/kg	Dose Level: 2000 mg/kg
		Animal No. 458	Animal No. 459	Animal No. 460	Animal No. 461
2	Erythema	0	0	0	0
	Oedema	0	0	0	0
	Other	-	-	-	-
3 (24 hours)	Erythema	0	0	0	0
	Oedema	0	0	0	0
	Other	-	-	-	-
4 (48 hours)	Erythema	0	0	0	0
	Oedema	0	0	0	0
	Other	-	-	-	-
5 (72 hours)	Erythema	0	0	0	0
	Oedema	0	0	0	0
	Other	-	-	-	-
6-15 (daily)	Erythema	0	0	0	0
	Oedema	0	0	0	0
	Other	-	-	-	-

Key:
- No other dermal changes apparent.

Interpretation of results:

GHS criteria not met

Conclusions:

The test article, Cyclic trimethylolpropane formal (CTF), was considered to have no significant acute toxic risk in respect of its acute dermal toxicity and did not meet the criteria for classification according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS, ninth revised edition, 2021).

Executive summary:

This study was conducted to determine the acute dermal toxicity of the test article, Cyclic trimethylolpropane formal (CTF), following a single (24 hour) semi-occluded topical application to the rat. The test article was applied as an undiluted liquid to the clipped dorsum of female
rats (Day 1). The sighting study commenced at a dose level of 1000 mg/kg. As this animal survived a further animal was treated at 2000 mg/kg. As this animal also survived, two further animals were treated at 2000 mg/kg. The treated areas of dorsum were covered by a semi-occlusive dressing for 24 hours. All four animals were killed on Day 15 and subsequently underwent a full necropsy. No animal died and there were no clinical signs of reaction to treatment. No overt dermal changes were noted at the test site. All rats achieved body weight gains during the first and second weeks of the study. No macroscopic changes were apparent at necropsy. The test article was considered to have no significant acute toxic risk in respect of its acute dermal toxicity and did not meet the criteria for classification according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS, ninth revised edition, 2021).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD0

Value:

>= 2 000 mg/kg bw

Quality of whole database:

A reliable GLP study according to OECD 402 guideline.

Additional information

Acute oral toxicity

The acute oral toxicity of 5 -ethyl-1,3 -dioxane-5 -methanol (CTF) in rats was determined according to OECD Test Guideline 401 (Dyring Jacobsen, 1992). CTF was administered orally by gavage to 5 male and 5 female Wistar rats at a concentration of 2000 mg/kg bw. Animals were observed for a period of 14 days following exposure and observations were made at regular intervals, including observations of body weight, clinical signs and any signs of toxicity. Only one female rat was found dead during the course of the exposure: no pathological findings attributable to treatment were observed. All test animals were subjected to a gross necropsy at termination on Day 14. No gross pathological findings were observed in treated animals. The oral LD50 was determined to be >2000 mg/kg bw under the conditions of this study.

 

Acute dermal toxicity 

No mortality or any effects were notied in a GLP acute dermal toxicity study in rat according to OECD TG 402 (Dreher, 2023) when dosed up to 2000 mg/kg. Based on this study, the acute dermal LD 0 is derminned as >= 2000 mg/kg b.w..

 

Acute inhalation toxicity 

A waiver is proposed for acute inhalation studies in accordance with Column 2 of Annex VIII of the REACH Regulation on the basis that acute toxicity data are available for the oral route. Inhalation is not predicted to be a significant route of exposure based on the physicochemical properties of the substance. The substance is a non-volatile liquid and the use pattern indicates that significant inhalation exposure is unlikely.

Justification for classification or non-classification

The oral LD50 of 5 -ethyl-1,3 -dioxane-5 -methanol in rats is > 2000 mg/kg bw. CTF is classified for acute oral toxicity in Category 5 according to GHS; classification for acute oral toxicity is not required under the CLP Regulation.