Registration Dossier

Administrative data

Description of key information

One available oral study with rats resulted in a combined LD50 value of 2152 mg/kg. Females appeared to be more sensitive as the LD50 was 1602 mg/kg for females. For males the LD50 was 2417 mg/kg.
The LC50 value via inhalation is over 5400 mg/m3 in rats.
The LD50 value after dermal exposure was higher than 2000 mg/kg bw in rabbits.
In humans, TAME caused slight acute toxic effects at concentrations of 15 (64 mg/m3) and 50 ppm (212 mg/m3).

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: GLP compliant, comparable to guideline study with acceptable restrictions.
Reference:
Composition 0
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles river
- Age at study initiation: 8-11 weeks
- Weight at study initiation: 200-350 gram
- Fasting period before study: overnight prior to dosing
- Housing: 5 per cage/per sex/per dose
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature: 68-76 degrees Fahrenheit
- Humidity (%): 40-70
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 1989-03-28 To: 1989-04-11
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
vehicle: none
exposure: by oral intubation via syringe and a No. 13 stainless steel straight, ball-tipped feeding needle

Doses:
2000, 2500 and 3000 mg/kg
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
The dose range was based on a range-finding study. Clinical observations were recorded at 1, 2, 4 and 6 hours after dosing and once daily for 14 days after dosing. Body weights were recorded on the day before dosing, the day of the dosing (day 0), day 7 and day 14 and at termination followed by a gross necropsy.
Statistics:
The body weights were analysed using standard deviations.
The LD50-value was calculated using the Litchfield-Wilcoxon method with equal weighing of the data points.
Sex:
male
Dose descriptor:
LD50
Effect level:
2 417 mg/kg bw
Sex:
female
Dose descriptor:
LD50
Effect level:
1 602 mg/kg bw
Sex:
male/female
Dose descriptor:
LD50
Effect level:
2 152 mg/kg bw
Mortality:
Four animals died in the 2000 mg/kg bw group, seven animals in the 2500 mg/kg bw group and eight animals in the 3000 mg/kg bw group. One animal was found dead on day 0 but this was thought to have resulted from a dosing error. The animal was replaced by another.
Clinical signs:
Clinical observations showed typical signs of sedation and included, for example, ataxia, emaciation, prostration, hypothermia, hypoactivity, dyspnoea,
hypopnea, wet and dry rales, both clear and red nasal and oral discharge, staining of the fur and piloerection and unthrifty coat. These observations were most prevalent during day 0 and day 1 in all groups. None of the surviving animals showed any observable abnormalities from day 2.
Body weight:
There was an increase in body weight over the initial values at the end of the study.
Gross pathology:
The animals that died showed in gross necropsy abnormalities of the gastro-intestinal tract and the urinary bladder, discolouration of the thymus, lungs and liver and staining of the fur. There was a single incident of enlarged heart atrium and one of dilated pelvis in both kidneys. Surviving animals had no observable abnormalities apart from a single incidence of dilated kidneys and one liver abnormality in the 2500 mg/kg bw group.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
2 152 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:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP compliant, comparable to guideline study with acceptable restrictions.
Reference:
Composition 0
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Test material information:
Composition 1
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles river Breeding lab. Inc., Portage, MI
- Weight at study initiation: 225-319 gram
- Housing: individually in stainless steel cages, exposure in 1m3 glass and stainless steel chambers (Unifab, Kalamazoo, MI)
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: approximately 3 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.5
- Humidity (%): 36.2
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
The animals were exposed for 4 hours to a test atmosphere generated from a single batch of the test article. The generation system consisted of a glass column packed with glass beads. The test article was delivered at a constant rate from a glass reservoir. Compressed air entered at the bottom of the glass bead column and test article entered approximately at the middle of the column. The resultant vapour entered the chamber supply air duct and was carried into the top of the chamber. The test article was completely vapourized with only a slight discolouration of the glass beads. The amount of residue on the beads was too small to measure.
The exposure was conducted in 1m3 glass and stainless steel chambers (Unifab, Kalamazoo, MI).

Analytical verification of test atmosphere concentrations:
yes
Remarks:
the test article vapour concentration was monitored by IR
Duration of exposure:
4 h
Concentrations:
5400 mg/m³
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
Five male and five female Sprague-Dawley rats were assigned to a single group, which was exposed in a 1 m3 exposure chamber to a mean TAME vapour concentration of 5,400 mg/m3 for 4 hours. The rats were clinically observed immediately after removal from the chamber, approximately 2 to 3 hours after the exposure and at least once per day during the 14-day post exposure observation period. Rats were weighed before the exposure, one week later and before necropsy.

Examinations performed: clinical observations, body weights, gross necropsy.
Statistics:
Statistical analyses were used to analyse the results: calculation of standard deviations.
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5 400 mg/m³ air
Exp. duration:
4 h
Mortality:
No mortality was observed.
Clinical signs:
In clinical observations, rales were seen in all rats immediately following the exposure. The rales were present in 7/10 animals about 2 hours after the exposure, but 3 ¼ hours later all rats appeared normal. Redness around the nose in 7/10 rats, salivation (1/10) and wet paws (1/10) were also observed during the study but were considered incidental and unrelated to treatment.
Body weight:
All rats gained weight during the study.
Gross pathology:
Necropsy revealed external haemorrhagic lung foci in the lungs in seven rats. However, mostly these foci were comparable in size and number to control rat foci, with the exception of one female rat that had numerous foci. One male that had a diffuse red area on its lungs. Six rats had enlarged mandibular lymph nodes.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
5 400 mg/m³

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:
1991
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP compliant, comparable to guideline study with acceptable restrictions
Reference:
Composition 0
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Test material information:
Composition 1
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Johnson Rabbit Ranch (Wilkinson, IN)
- Age at study initiation: 3-4 months
- Weight at study initiation: 3.16-3.30 kg
- Housing: individually
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23
- Humidity (%): 32
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: 240 cm2 (fur was clipped from the exposure sites)
- Type of wrap if used: application site (12.8 x 11.5) covered with surgical dressing and covered with plastic film

REMOVAL OF TEST SUBSTANCE
- Washing (if done): rinsed with light mineral oil
- Time after start of exposure: 24 hours
Duration of exposure:
24 h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5 male, 5 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: up to 14 days
- Frequency of observations and weighing: 0.5, 0.75, 2, 3, 4.25 and 6 hours after dosing and once a day for 14 days after removal of wrappings
- Examinations performed: clinical signs, skin abnormalities, body weights, gross necropsy.
Statistics:
Statistical analyses were used to analyse the results: calculation of standard deviations.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
No mortality occurred.
Clinical signs:
One rabbit was vocal immediately upon test article administration. All of the rabbits exhibited rapid respiration lasting 1-2 hours after dosing.
Body weight:
All rabbits gained weight during the study.
Gross pathology:
Gross necropsy findings were within normal limits in eight rabbits. One male had white areas on its liver, while a female had only one kidney which was enlarged; these conditions were not considered treatment related.
Other findings:
Dermal irritation (i.e., edema and erythema) was observed within the application site of all rabbits following removal of the wrappings, and eschar formation developed in all rabbits 2 to 7 days later. The scab formation in 3 rabbits sloughed off prematurely, probably as a result of grooming, and raw skin was exposed beneath. New and/or repaired skin was observed in six rabbits, while seven rabbits displayed superficial flaking at the application site. None of the rabbits completely recovered from all signs of dermal irritation before the end of the 14-day observation period.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw

Additional information

One acute toxicity (GLP-compliant, near-guideline) study with rats (Exxon Biomedical Sciences Inc., 1989) was available for assessment. The groups of 5 male and 5 female Sprague-Dawley rats were exposed by gavage to undiluted substance at 2000, 2500 and 3000 mg/kg bw. The combined LD50 value for male and female rats was determined to be 2152 mg/kg bw. Females appeared to be more sensitive than males, as the LD50 for females was 1602 mg/kg bw, compared to the LD50 of 2417 mg/kg bw for males. Clinical observations showed typical signs of sedation and included, for example, ataxia, emaciation, prostration, hypothermia, hypoactivity, dyspnoea, hypopnea, wet and dry rales, clear and red nasal and oral discharge, staining of the fur and piloerection. These observations were most prevalent during day 0 and day 1 in all groups. The animals that died showed abnormalities of the gastro-intestinal tract and the urinary bladder, discoloration of the thymus, lungs and liver and staining of the fur.

One acute inhalation toxicity (GLP-compliant, near-guideline) study with rats exposed to TAME was available for assessment (IIT Research Institute, 1991a). A single group of 5 male and 5 female Sprague-Dawley rats was exposed to TAME vapour at 5400 mg/m3 for 4 hours. None of the animals died. The LC50 value was determined to be > 5400 mg/m3. Regarding clinical observations, rales were seen in all rats immediately following the exposure. The rales were present in 7/10 animals about 2 hours after the exposure, but 3 ¼ hours later all rats appeared normal. Redness around the nose was noticed in 7/10 rats during the study. Necropsy revealed external haemorrhagic lung foci in the lungs in seven rats. However, mostly these foci were comparable in size and number to control rat foci, with the exception of one female rat that had numerous foci and one male that had a diffuse red area on its lungs. Six rats had enlarged mandibular lymph nodes.

 

One acute dermal toxicity study with rabbits, performed under GLP and according to a procedure comparable with OECD Guideline 402, was available for assessment (IIT Research Institute, 1991b). TAME was applied undiluted at a dose of 2000 mg/kg bw to the shaved backs of five male and five female New Zealand White rabbits. The test site was covered with an occlusive dressing. No deaths occurred during the study. The LD50 for TAME was estimated to be greater than 2000 mg/kg bw.

Dermal irritation (i.e. edema and erythema) was observed within the application site of all rabbits after the removal of the wrappings, and eschar formation developed in all rabbits 2 to 7 days later. The scab formation in 3 rabbits sloughed off prematurely probably as a result of grooming, and raw skin was exposed beneath. New and/or repaired skin was observed in six rabbits, while seven rabbits displayed superficial flaking at the application site. None of the rabbits completely recovered from all signs of dermal irritation before the end of the 14-day observation period.

Regarding the observed dermal irritation, given the occluded conditions used in this test, the skin irritation study with TAME (see section on skin irritation) is considered more relevant for drawing a conclusion on skin irritation.

In a volunteer study with six humans (men) per group (Pekari et al, 1997b), TAME caused only minor acute effects (exposure concentrations: 15 ppm (60 mg/m3) and 50 ppm (212 mg/m3)). The reporting on the effects is somewhat inconsistent and not very firm conclusions can be drawn from the study. Feelings characterised as heaviness of the head seemed to correlate inversely with increasing TAME concentration. Concentrations up to 50 ppm did not have an effect on reaction time, balance or mood during/after 4-hour exposure. In conclusion, 50 ppm (212 mg/m3)) is considered the NOAEC in this study.

Justification for classification or non-classification

Based on the oral LD50 value for female rats, TAME has to be classified according to the EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 for acute toxicity by the oral route as Cat. 4 - H302 (Harmful if swallowed). No classification for acute inhalation and dermal toxicity is warranted.