Registration Dossier

Administrative data

Description of key information

The acute oral LD50 of trimethylol diallyl ether (TMPDE) in the rat is reported to be >2000 mg/kg bw .  The dermal LD50 of TMPDE in the rabbit was found to be >3000 mg/kg bw.  A waiver is proposed for acute inhalation toxicity.

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:
12 July to 4 August 1993
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Proprietary GLP guideline-compliant study
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Qualifier:
according to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
The animals were male and female Sprague-Dawley rats, supplied by Charles River (UK) Ltd., Kent. At the start of the main study the males weighed 150-169 g, and the females 140-170 g, and were approximately 5-8 weeks old. The animals were acclimatised for at least 5 days. Individuals were identified by indellible ink markings on the tail. Group selection was random.
The animals were housed in groups of five by sex in solid-floor polypropylene cages with sawdust bedding. With the exception of an overnight fast immediately before dosing and for approximately 2 hours after dosing, free access to mains drinking water and food (Rat and Mouse Expanded Diet No. 1, SDS Ltd., UK) was allowed throughout the study.
The animal room was maintained at a temperature of 19-23°C and relative humidity of 48-66%. The rate of air exchange was approximately 15 changes per hour and the lighting was controlled by a time switch to give 12 hours light and 12 hours darkness.
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
All animals were dosed once by gavage using a metal canula attached to a graduated syringe. The volume administered to each animal was calculated according to its fasted bodyweight at the tine of dosing. The dose volume was 2.10 ml/kg, and the specific gravity of the test substabce was 0.956.
Doses:
2000 mg/kg
No. of animals per sex per dose:
5 rats/sex/dose (main study).
Control animals:
no
Details on study design:
A range finding study with 1 male and 1 female rat was conducted. A single dose of 2000 mg/kg (dose volume 2.10 ml/kg) was adminsitered via gavage. The animals were observed for deaths or overt signs of toxicity 30 minutes, 1, 2 and 4 hours after dosing then once daily thereafter for 5 days. Individual bodyweights were recorded on the day of dosing to allow calculation of individual treatment volumes. No necropsies were performed.

In the main study, individual bodyweights were recorded prior to dosing on Day 0 and on Days 7 and 14. The animals were observed for deaths or overt signs of toxicity 30 minutes, 1, 2 and 4 hours after dosing then once daily thereafter for 14 days. At the end of the 14 day observation period the animals were killed annd subjected to gross pathological examination, consisting of an external examination and opening of the abdominal and thoracic cavities. THe appearance of any macropscopic abnormalities was recorded. No tissues were retained.
Statistics:
Statistical evaluation was not required.
Preliminary study:
There were no deaths, common signs of systemic toxicity noted were ataxia, hunched posture, lethargy, decreased respiratory rate and laboured respiration with an isolated incident of piloerection. The main study proceeded with a dose of 2000 mg/kg.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No deaths occurred during the study.
Clinical signs:
Signs of systemic toxicity noted were ataxia, hunched posture, lethargy, decreased respiratory rate and laboured respiration. Animals recovered one or two days after dosing.
Body weight:
All animals showed expected bodyweight gain during the study.
Gross pathology:
No abnormalities were noted at necropsy.
Other findings:
No other findings were reported.

The acute oral LD50 of the test substance was found to be greater than 2000 mg/kg bw.

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute oral LD50 was found to be greater than 2000 mg/kg bw.
Executive summary:

The acute oral toxicity of TMPDE (NEOALLYL T-20) was determined in male and female Sprague-Dawley rats, according to OECD method 404. Following a range-finding study, a group of five male and five female fasted rats were given a single oral dose of undiluted test substance at a dose level of 2000 mg/kg bw. The rats were observed for 14 days then killed for gross pathological examination.

No deaths occurred during the study. Common signs of toxicity noted were ataxia, hunched posture, lethargy, decreased respiratory rate and laboured respiration. Animals recovered one or two days after dosing. Bodyweight gain was normal throughout the study, and no abnormalities were noted at necropsy.

The acute oral LD50of TMPDE in the rat was found to be greater than 2000 mg/kg bw. No symbol and risk phrase are required according to EEC labelling regulations.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
Reliable, guildeline study in the rat

Acute toxicity: via inhalation route

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Older, non-GLP proprietary study.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
no
Remarks:
Older study, pre-GLP.
Test type:
standard acute method
Limit test:
yes
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
The animals were male and female young adult albino rabbits of the New Zealand strain. All rabbits were acclimated for at least 7 days prior to testing. During the acclimatisation period, the animals were examined with respect to their general health and suitability at test animals.
The rabbits were housed individually in suspended, wire-bottomed cages and maintained on a standard laboratory diet. Food and water were available ad libitum.
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
The test substance was applied to the backs of four rabbits at a dose level of 3000 mg/kg. The skin of the test site was abraded in half the rabbits (1 male and 1 female). The test site was covered by wrapping the trunk of the animal with impervious plastic sheeting, held in place with tape. Each rabbit was fitted with a lightweight flexible plastic collar throughout the obesrvation period (to prevent ingestion of the test material).
Duration of exposure:
24 hours
Doses:
3000 mg/kg
No. of animals per sex per dose:
2 rabbits/sex/dose
Control animals:
no
Details on study design:
Twenty four hours prior to the dermal applications, the backs of the rabbits were shaved free of hair with electric clippers. The shaved area on each animal was approximately 30% of the total body surface area.
At the end of the exposure period, the test sites were examined for local skin reactions. Observations for mortality, local skin reactions, and behavioural abnormalities were continued for a total of 14 days post-exposure. Initial and final body weights were recorded. A necropsy was conducted on all animals sacrificed at the end of the observation period.
Statistics:
A formal statistical analysis was not required.
Preliminary study:
No preliminary results.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 3 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no mortalities during the 14 day observation period.
Clinical signs:
No abnormal behavioural reactions were noted among any of the rabbits. 24 hours after application, the test sites showed pale red to red well-defined erythema and slight to mild oedema (area definable but not raised more than 1 mm). 7 days after application, pale red erythema remained with moderate desquamation. Mild desaquamation was still present after 14 days.
Body weight:
All rabbits gained weight during the study.
Gross pathology:
No abnormalities were detected at necropsy.
Other findings:
No other findings reported.

As no mortalities occurred, the LD50 can be considered to be greater than 3000 mg/kg.

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The LD50 of the test material was found to be greater than 3000 mg/kg bw under the conditions of this study.
Executive summary:

The acute dermal toxicity of trimethylopropane diallyl ether was evaluated in 2 male and 2 female New Zealand White rabbits. The undiluted test substance (3000 mg/kg bw) was applied to the shaved skin of the rabbits, and held in place under an occlusive plastic dressing for 24 hours. Two of the test sites (on 1 male and 1 female rabbit) were abraded, and two remained intact. The rabbits were observed for 14 days after the exposure period

.

There were no mortalities during the study, and all rabbits gained weight. There were no clinical signs of toxicity, although the test substance was noted to be slightly irritating to the skin at the application site. No abnormalities were detected at necropsy.

The acute dermal LD50 of TMPDE is therefore greater than 3000 mg/kg bw in rabbits.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
3 000 mg/kg bw
Quality of whole database:
Reliable, guildeline study in the rat

Additional information

The acute oral LD50 of trimethylol diallyl ether (TMPDE) in the rat is reported to be >2000 mg/kg bw (Driscoll, 1993). The dermal LD50 of TMPDE in the rabbit was found to be >3000 mg/kg bw (Kretchmar, 1973). A waiver is proposed for acute inhalation toxicity. The substance is demonstrated to be of low inherent toxicity by the oral and dermal routes; the susbtance is a non-volatile liquid and the use pattern indicates that significant inhalation exposure is unlikely. No additional testing is therefore warranted.

In two studies conducted by Bayer AG, the acute oral LD50 values of TMPDE in the rat are reported to be 4272 mg/kg bw (4.45 ml/kg bw) and 6500 mg/kg bw. Also, the acute dermal LD50 of TMPDE in the rabbit is reported to be > 15800 mg/kg bw (there were no mortalities at this dose level). Access to the original study reports is not available, the results were obtained from the IUCLID data set (2000) and are presented to support the data summarised above.


Justification for selection of acute toxicity – oral endpoint
Only one study available for this endpoint

Justification for selection of acute toxicity – dermal endpoint
Only one study available for this endpoint

Justification for classification or non-classification

No classification is proposed for acute toxicity, based on the available data, according to EEC Council Directive 79/831/EEC Annex VI, Part II (D) as described in Commission Directive 93/21/EEC or Regulation (EC) No 1272/2008. The substance is of low acute toxicity.