Registration Dossier

Administrative data

Description of key information

The key study and the key value for CSA for Oral toxicity was completed on rats. Several supporting studies at higher doses support the quoted LOAEL for Repeated Dose Oral Toxicity.


A waiver has been submitted for repeated dose dermal toxicity testing

Two repeat inhalation toxicity conducted by Davis on rats and beagles gave very similar conclusions with LOAEC levels of 12 mg/m3. LD100 values are also reported and differ for the two species, with a value of 22 mg/m3 quoted for rats and 12 mg/m3 for the dogs

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Principles of method if other than guideline:
No data on the exact method used is available
GLP compliance:
not specified
Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
Animals kept in cages. Test conditions: 22 degrees C, 50% relative humidity, 12 hours light, food and water ad libitum
5 Animals per group
Route of administration:
oral: gavage
Vehicle:
not specified
Duration of treatment / exposure:
13 Weeks
Frequency of treatment:
5 times per week
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
0.2 mg/kg bw/day (nominal)
Dose / conc.:
2 mg/kg bw/day (nominal)
No. of animals per sex per dose:
5 Animals per dose
Control animals:
yes, concurrent vehicle
Clinical signs:
not specified
Mortality:
not specified
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
At low dose and high dose, reduced body weight
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
At low dose and high dose, reduced feed intake
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Dry / Haematological: low dose - Amino laevulinicacid dehydrogenase high dose - not specified
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
excitability, irritability, tremors, coma
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
At low and high dose: brain lesions and spinal cord, eosinophilic inclusions in prox. Renal tubular
Dose descriptor:
LOAEL
Effect level:
0.2 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
body weight and weight gain
food consumption and compound intake
gross pathology
Critical effects observed:
not specified
Conclusions:
Repeat oral toxicity study carried out on groups of male rats, concluded that the first signs of toxicological effects due to TEL were observed at a dose rate of 0.2 mg/kg bw/d.
Executive summary:

Repeat oral toxicity study carried out on groups of male rats, concluded that the first signs of toxicological effects due to TEL were observed at a dose rate of 0.2 mg/kg bw/d.

An additional early study (21 weeks, oral, rats) by Schepers (1964b) supports the LOAEL identified in Franklin et al. (1987).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
0.2 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEC
12 mg/m³
Study duration:
subchronic
Species:
dog

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The key study chosen for repeated dose oral toxicity was the robust subchronic (13-week) toxicity study in rats, which identified a LOAEL of 0.2 mg/kg bw/day (Franklin et al. 1987). An additional early study (21 weeks, oral, rats) by Schepers (1964b) supports the LOAEL identified in Franklin et al. (1987). Although there is a 6 month study in rhesus monkeys (Heywood et al. 1979) that identified a NOAEL of 0.009 mg/kg bw/day, only this single low dose was administered for a limited portion of the animals lifetime (which is generally up to 20 years).

A testing waiver has been submitted for a repeated dose dermal toxicity test

Two repeat inhalation toxicity studies conducted on rats and beagles gave LOAEC levels of 22 mg/m3 for rats (Davies et al. 1963a) and 12 mg/m3 for dogs (Davies et al. 1963a). LD100 values are also reported and differ for the two species, with a value of 22 mg/m3 quoted for rats and 12 mg/m3 for the dogs. The values for dogs are used for the purposes of the CSA.


Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
It is proposed to waive this test. Exhaustive repeated dose testing has shown TEL to be highly toxic by all other routes with various species. The substance is classified as very toxic (T+) by ingestion, inhalation and absorption through the skin.

Justification for classification or non-classification

TEL is classified in Annex I of the EU DSD as R33 (Danger of cumulative effects) and as STOT Rep. Exp. 2 (H373: May cause damage to organs through prolonged or repeated exposure) according to EU CLP regulations.