Reaction mass of propylidynetrimethanol and 2-ethylpropane-1,3-diol and 5-ethyl-1,3-dioxane-5-methanol

Endpoint summary

Description of key information

The available data from an acute oral toxicity study (according to OECD Guideline 423) with the target substance Polyol TD indicates that Polyol TD is of low toxicity. Based on the results and in accordance with OECD Guideline 423 the LD50 value was determined to be >2000 mg/kg bw. However, there are no studies available for the assessment of the dermal acute toxicity with the target substance. Therefore, data from an acute dermal toxicity study (equivalent to OECD Guideline 402) with the suitable read-across substance Trimethylolpropane (TMP) was used to assess the acute dermal toxicity. Based on the results, the dermal LD50 value was determined to be > 10000 mg/kg bw.

In both studies the LD50 values for the oral and dermal route are above the limit values of the relevant OECD guidelines. Thus, no classification for acute toxicity is warranted. For details and justification of read-across please refer to the report attached in section 13 of IUCLID.

In addition, a waiver is proposed for acute inhalation toxicity in accordance with Column 2 of Annex VIII of the REACH Regulation as acute toxicity data are available for the oral and dermal routes. Inhalation is also not predicted to be a significant route of exposure based on the physicochemical properties of the target 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:

2009-09-29 to 2010-02-03

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

December, 2001

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Batch number of test material: 3977901

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: stored at ambient temperature in the dark

OTHER SPECIFICS
- Test material form: clear liquid

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

The animals were female Sprague-Dawley Crl:CD(SD) rats. The animals were supplied by Charles River UK Ltd, Kent, UK, and were nulliparous and non-pregnant. The rats were aged 7-8 weeks old on arrival, and weighed 181-186 g. They were allowed to acclimatise to the laboratory conditions for at least 7 days prior to dosing. The rats were randomly assigned to treatment groups on arrival, and individuals were identified by ear punches.
The animals were housed in groups of 3 in polycarbonate cages (dimensions 61 x 43.5 x 24 cm) with stainless steel grid tops and solid bottoms. Wood shavings (supplied by Datesand, Manchester, UK) were used as bedding and wooden chew sticks (produced by Estap OÜ, Harjumaa, Estonia) were placed in each cage. The bedding and chew sticks were considered not to contain any additional substances in sufficient concentration to have had any influence on the outcome of the study. Certificates of analysis are included in the study data. Each cage was supplied with a water bottle and food hopper.
The environmental conditions in the room were recorded every 15 min. From animal arrival to the end of the observation period the daily average environmental temperature was recorded at approximately 21°C on each day and the relative humidity was within an approximate range of 38% to 72%. A 12 h light/dark cycle was in operation (light hours 0700 to 1900 h) with a minimum of 15 air changes per hour.
Rat and Mouse No. 1 Maintenance Diet (Special Diets Services Limited, PO BOX 705, Witham, Essex, CM8 3AD, UK) and water taken from the public supply (Scottish Water, Edinburgh, Midlothian, UK) were available ad libitum, except for a period of overnight food deprivation before dosing. Ad libitum feeding was resumed as soon as practicable after dosing. Each batch of diet is routinely analysed by the supplier for various nutritional components and chemical and microbiological contaminants. The quality of water supply is stipulated by legislation in Water Quality, Scotland, Regulations 2001 and certificates of analysis for dissolved materials, heavy metals, pesticide residues, pH, nitrates and nitrites are periodically provided. These analyses are based on water samples taken from these laboratories. The results of diet and water analyses did not provide evidence of contamination and so the outcome of the study was not prejudiced. Certificates relevant to the study are retained in the data.

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

The test substance was already in liquid form, therefore a vehicle was not used for dosing. The test substance was maintained on a magnetic stirring throughout dosing. The administered volume of test item was calculated on the basis of each individual animal’s body weight on the day of dosing. The dose volume was 1.87 mL/kg.

Doses:

2000 mg/kg

No. of animals per sex per dose:

6 females

Control animals:

no

Details on study design:

The initial dose level of 2000 mg/kg bw was selected by the Study Director for administration to 3 females (Group 1) following a review of the available test item information. This stated that the oral LD50 values for rats of 2 of the main components of the test item exceeded 2000 mg/kg. A dose volume of 1.87 mL/kg was used in order to account for the density of Polyol TD (1068 kg/m3). A second group (Group 2) also received 2000 mg/kg. Consequently, the study was completed with no further treatment being administered. The two groups were dosed at least 2 days apart.
The animals were observed for 14 days following dosing.
All animals were checked for viability early in the morning and again as late as possible on each day. All animals were examined for reaction to treatment on the day of dosing and once daily thereafter, until Day 15. The body weight of each individual animal was recorded before dosing on Day 1 and on Days 8 and 15.
All animals were subjected to a gross necropsy at the end of the observation period on Day 15. The necropsy consisted of an examination of the cranial, thoracic and abdominal organs and tissues in situ. Carcasses were discarded after this procedure. No lesions were recorded and therefore no tissues were collected.

Statistics:

No formal statistical analysis was conducted.

Preliminary study:

A preliminary study was not conducted.

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: No mortality at the limit dose

Mortality:

There were no unscheduled deaths during the observation period.

Clinical signs:

other: Adverse signs were restricted to salivation, which was observed in all animals at 5 min post dose. No other clinical signs were seen in any animal.

Gross pathology:

Macroscopic examination revealed no abnormalities.

Other findings:

No other findings were reported.

Interpretation of results:

GHS criteria not met

Conclusions:

Under the conditions of the study the median lethal oral dose level (the LD50) of Polyol TD in Sprague-Dawley rats was considered to exceed 2000 mg/kg bw.

Executive summary:

In an acute oral toxicity study, performed according to OECD TG 423 (acute toxic class method), two groups of 3 female nulliparous and non-pregnant Sprague-Dawley rats (7 to 8 weeks of age and 181 to 186 gram body weight) were given a single oral dose of Polyol TD (as supplied) at the limit dose level of 2000 mg/kg bw.

Animals were observed for signs of reaction to treatment at least 6 times on the day of dosing and once daily from Day 2 until the end of the observation period on Day 15. Body weights were recorded weekly and all animals were subjected to a gross necropsy.

There were no unscheduled deaths during the observation period. Adverse signs were restricted to salivation at 5 min post dose, which was observed in all animals. Body weight gain was considered to be acceptable for rats of this age and strain and there were no macroscopic abnormalities recorded at necropsy.

Under the conditions of the study the median lethal oral dose level (the LD₅₀) of Polyol TD in Sprague-Dawley rats was considered to exceed 2000 mg/kg bw. Applying the Globally Harmonised Classification System, Polyol TD can be classified as either Category 5 (LD50 >2000 to 5000 mg/kg) or as Unclassified in accordance with CLP Regulation 1272/2008.

This acute oral study is classified as acceptable. It does satisfy the guideline requirement for an acute oral study (OECD 423) in the rat.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 2 000 mg/kg bw

Quality of whole database:

GLP-compliant guideline study according to OECD 423 (acute toxic class method)

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

exposure considerations

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:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

For details and justification of read-across please refer to the report attached in section 13 of IUCLID.

Reason / purpose for cross-reference:

read-across source

Preliminary study:

No preliminary study was reported.

Sex:

male

Dose descriptor:

LD50

Effect level:

> 10 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: There were no mortalities during the 7 day post-exposure observation period

Mortality:

No mortalities occurred during the study.

Clinical signs:

other: All rabbits exhibited normal appearance and behaviour during the study, a very mild degree of dermal irritation was observed but disappeared the next day. No other signs were observed.

Gross pathology:

At autopsy, the kidneys of the majority of the rabbits at the three higher dose levels contained a hyperaemic zone at the cortico-medullary junction. Otherwise there were no abnormal findings.

Other findings:

Following removal of the dressings at the end of the exposure period, the abdomens and dressings of the 1.0 g/kg group showed no gross evidence of test material residue. The abdomens and dressings of the animals at the higher dose levels contained a small quantity of unabsorbed residue; the residue was slightly moist in the 10.0 g/kg group (the residue was dry in the remaining groups).
The single 24 hour application of trimethylolpropane produced a very mild degree of dermal irritation at each dose level tested. The irritation was characterised by a mild erythema at the end of the exposure period. The erythema subsided within 1 day, after which the exposed skin appeared normal.

The acute dermal LD₅₀ of trimethylolpropane is greater than 10000 mg/kg bw in male albino rabbits. The moving average method was used to estimate an LD₅₀ of 14.7 g/kg bw, however the relevance of this method is questionable in the absence of any mortality.

Interpretation of results:

GHS criteria not met

Conclusions:

The acute dermal LD50 of trimethylolpropane is greater than 10000 mg/kg in male albino rabbits.

Executive summary:

In an acute dermal toxicity study (similar to OECD 402), groups of 4 male albino rabbits were dermally exposed to trimethylolpropane which was moistened with distilled water and applied as a paste to the shaved, intact abdominal skin of the rabbits at doses of 1000, 2150, 4640 and 10000 mg/kg bw for 24 hours. Animals were then observed for 7 days.

The rabbits were observed daily for gross signs of dermal irritation and systemic toxicity, for a period of 7 days. At the end of the observation period, the animals were sacrificed and gross autopsies were performed. Body weights were measured at the start of the study and again at the time of sacrifice.

Dermal exposure resulted in a very mild degree of dermal irritation, that had subsided within 24 hours. There was no evidence of systemic toxicity, no mortalities occurred during the study, and there were no remarkable findings at gross necropsy. The acute dermal LD₅₀ of trimethylolpropane for male rabbits was therefore greater than 10000 mg/kg under the conditions of this study.

This information is used in a read-across approach in the assessment of the target substance. For justification of read-across please refer to the attached read-across report (see IUCLID section 13).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 10 000 mg/kg bw

Quality of whole database:

Read-across to an older proprietary study, which is considered scientifically acceptable and with a methodology comparable to current OECD guidelines.

Additional information

The acute oral toxicity of Polyol TD was investigated in a GLP study conducted according to OECD Guideline 423 (Robinson, 2010). Polyol TD was administered to two groups of three female Sprague-Dawley rats as a single dose of 2000 mg/kg bw. The animals were observed for signs of reaction to treatment for 14 days after administration. There were no unscheduled deaths during the observation period. Adverse signs were restricted to salivation at 5 min post dose, which was observed in all animals. Body weight gain was considered to be acceptable for rats of this age and strain and there were no macroscopic abnormalities recorded at necropsy. Under the conditions of the study the median lethal oral dose level (the LD50) of Polyol TD in Sprague-Dawley rats was considered to exceed 2000 mg/kg bw.

 

The acute dermal toxicity was assessed in a read-across approach with the source substance trimethylolpropane (TMP), which was administered to groups of 4 male albino rabbits (Elsea, 1956). The test material was moistened with distilled water and applied as a paste to the shaved, intact abdominal skin of the rabbits. Dose levels were 1.0, 2.15, 4.64 and 10.0 g/kg bw, the exposure period was 24 hours and the rabbits were observed for 7 days following exposure.

Dermal exposure resulted in a very mild degree of dermal irritation, that had subsided within 24 hours. There was no evidence of systemic toxicity, no mortalities occurred during the study, and there were no remarkable findings at gross necropsy. The acute dermal LD50 of trimethylolpropane is therefore greater than 10.0 g/kg bw in male rabbits.

 

No data are available for Polyol TD or CTF, however additional testing for acute dermal toxicity is not proposed. Based on the low acute oral toxicity of Polyol TD (with only minimal clinical signs seen at the limit dose of 2000 mg/kg bw), low acute dermal toxicity can also be predicted. Based on general theoretical considerations, dermal absorption of the individual components is likely to be less rapid and less extensive than oral absorption. Marked kinetic differences are unlikely, further indicating low dermal toxicity. This assumption is also confirmed by the very low acute dermal toxicity of the component TMP. It is therefore concluded that additional testing for acute dermal toxicity is not required scientifically and cannot be justified on grounds of animal welfare.

 

A waiver is proposed in accordance with Column 2 of Annex VIII of the REACH Regulation as acute toxicity data are available for the oral and dermal routes. Inhalation is also not predicted to be a significant route of exposure based on the physicochemical properties of the substance.

Justification for classification or non-classification

Based on the available information, Polyol TD (Reaction mass of 2-ethylpropane-1,3-diol and 5-ethyl-1,3-dioxane-5-methanol and propylidynetrimethanol; EC 904 -153 -2) does not meet the criteria for classification according to CLP Regulation (EC) No. 1272/2008.