Registration Dossier

Administrative data

Description of key information

Oral: The acute oral LD50 was determined to be 311 mg/kg bw in rats.
Dermal: The acute dermal LD50 was determined to be 178 mg/kg bw in rabbits.
Inhalation: No mortality was detected when rats were exposed to a saturated atmosphere of the test substance for 8 hours. The concentration of the test material in saturated atmosphere was calculated to be 14165 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
Study period:
1962
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Basic data are given
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: Carworth-Wistar
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 4 - 5 weeks
- Weight at study initiation: 90 - 120 grams
- Fasting period before study: no
- Rockland rat diet
Route of administration:
oral: gavage
Vehicle:
not specified
Doses:
The dosages were arranged in a logarithmic series differing by a factor of two.
No. of animals per sex per dose:
5
Control animals:
not specified
Details on study design:
14-day post observation period
Statistics:
Based upon mortalities during a 14-day observation period, the most probable LD50 value and its fiducial range are estimated by the method of Thompson* using the tables of Weil**.

*Thompson, W. R.: Use of Moving Averages and Interpolation to Estimate Median Effective Dose. Bacteriol. Rev. 11: 115 (June 1947).

**Weil, C. S.: Tables for Convenient Calculation of median-Effective Dose (LD50 or ED50) and Instruction in Their Use. Biometrics 8: 249 (Sep 1952)
Sex:
male
Dose descriptor:
LD50
Effect level:
311 mg/kg bw
Based on:
test mat.
95% CL:
>= 196 - <= 507
Mortality:
Only LD 50 value of 0.35 mL/kg bw (corr. to 311 mg/kg bw) was reported
Clinical signs:
no data
Body weight:
no data
Gross pathology:
no data
Other findings:
no data

Details of toxic effects not reported other than lethal dose value. Result in publication is given as 0.35 mL/kg. Density used by the registrant for conversion: 0.89 g/mL

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
311 mg/kg bw
Quality of whole database:
No GLP, but scientifically well documented studies

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
Study period:
1977
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable publication
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 433 draft (Acute Inhalation Toxicity: Fixed Concentration Procedure) (not officially approved)
GLP compliance:
no
Test type:
fixed concentration procedure
Limit test:
yes
Species:
rat
Strain:
not specified
Sex:
not specified
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
air
Analytical verification of test atmosphere concentrations:
not specified
Duration of exposure:
8 h
Concentrations:
Substantially saturated vapour atmospheres were generated dynamically.
Concentrations are not specified.
No. of animals per sex per dose:
Number: 6
Sex not specified.
Control animals:
not specified
Details on study design:
Concentrated vapour was generated in a gas washing bottle by passing died air at 2.5 L/min through a fritted glass disc immersed to a depth of at least 1-1/2 inches in the chemical which was delivered to rats in a 9L glass exposure chamber. Mean vapour concentration was calculated from the loss in weight of the liquid or estimated from the vapour pressure at the actual temperature of the chemical during aeration.
Preliminary study:
The saturated vapour, dynamically generated at 23 degree C is calculated to be equivalent to 4600 ppm.
Basis for the calculation was the vapour pressure of 4.66 hPa at 22.9 degree C as described in IUCLID section 4.
Based on a conversion factor for the vaporized test substance published by GESTIS* (1 ppm = 1 mL/m3 = 3.08 mg/m3), the inhaled concentration is calculated to be 14165 mg/m3.

*http://www.dguv.de/ifa/de/gestis/stoffdb/index.jsp
Sex:
not specified
Dose descriptor:
LC0
Effect level:
> 4 600 ppm
Based on:
test mat.
Exp. duration:
8 h
Remarks on result:
other: No mortality occurred in 6/6 rats exposed to a substantially saturated vapour, dynamically generated at 23 degree C. Based on conversion (1 ppm = 3.08 mg/m3), the inhaled concentration is equivalent to 14165 mg/m3.
Mortality:
None
Clinical signs:
Redness of extremities within 3 h.
Wet fur within 1.5 h.
Gross pathology:
No remarkable findings.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
14 165 mg/m³
Quality of whole database:
No GLP, but scientifically well documented studies

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:
1962
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Basic data are given
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
not specified
GLP compliance:
no
Test type:
other: Modified Draize test
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 2.5 - 3.5 kg

Type of coverage:
occlusive
Vehicle:
not specified
Details on dermal exposure:
The fur of the male albino New Zealand rabbits was removed from the entire trunk by clipping, and the dose is retained beneath an impervious plastic film.
The animals were immobilized during the 24-hours contact period, after which the film is removed and the rabbits are caged for the subsequent 14-Day observation period.
Duration of exposure:
24 h
Doses:
no data
No. of animals per sex per dose:
4 males
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
Statistics:
Based upon mortalities during a 14-day observation period, the most probable LD50 value and its fiducial range are estimated by the method of Thompson* using the tables of Weil**.

*Thompson, W. R.: Use of Moving Averages and Interpolation to Estimate Median Effective Dose. Bacteriol. Rev. 11: 115 (June 1947).

**Weil, C. S.: Tables for Convenient Calculation of median-Effective Dose (LD50 or ED50) and Instruction in Their Use. Biometrics 8: 249 (Sep 1952)
Sex:
male
Dose descriptor:
LD50
Effect level:
178 mg/kg bw
Based on:
test mat.
95% CL:
>= 0.13 - <= 0.24

Details of toxic effects not reported other than lethal dose value.

Result in publication is given as 0.2 mL/kg (0.15 - 0.27 mL/kg ).

Density used by the registrant for conversion: 0.89 g/mL

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
178 mg/kg bw
Quality of whole database:
No GLP, but scientifically well documented studies

Additional information

Oral:

The lowest LD50 was found in an acute oral toxicity study (Smyth, H.F. et al., 1962) where groups of five male Carworth-Wistar rats were exposed to Triethylenediamine by single oral doses (gastric intubation). Animals then were observed for 14 days. The identified LD50 value was 0.35 mL/kg bw, corresponding to 311 mg/kg bw (95% CL: >= 196 to <= 507 mg/kg). This study is classified as acceptable key study. The other available study results on oral acute toxicity reveal higher LD50 values:

- 500 mg/kg bw [Source: Encyclopaedia of Chemical Technology" (Spitz, R.D. , 1962)]

- 548 mg/kg bw (95% CL: >= 0.340 to <= 0.883 mg/kg bw), calculated from the published data of 0.616 mL/kg (95% CL: >= 0.382 to <= 0.992 mL/kg). [Source: NTIS/OTS (1991), also cited by Myers and Ballantyne (1997)]

- ca. 707 mg/kg bw (BASF, 1966).

Dermal:

In an acute dermal toxicity study (Smyth et al., 1962, also reported by RTECS, 2011) the penetration of rabbit skin by the test substance was examined in groups of four male albino New Zealand rabbits that were occlusively exposed for 24 hours and then observed for 14 days.

The identified LD50 value was 0.2 mL/kg bw, corresponding to 178 mg/kg bw.

This finding is supported by several studies (also under occlusive conditions) resulting in LD50 values of

- 356 mg/kg bw (95% confidence interval: equal/higher 218 and equal/lower 581 mg/kg bw), NTIS/OTS (1991), also reported by Myers and Ballantyne (1997), and

- ca. 200 mg/kg bw (BASF, 1979).

Inhalation:

In an acute inhalation toxicity study (NTIS/OTS, 1991), no mortality occurred in 6 rats exposed for 8h to a substantially saturated vapour, dynamicallly generated at 23 degree C (some skin irritation noted; 14 -day observation period).

Based on conversion (1 ppm = 3.08 mg/m3), the inhaled concentration is equivalent to 14165 mg/m3.

The same or identical results were reported by Myers and Ballantyne (1997) and Smyth et al. (1962).

Two further studies (BASF, 1966) support the findings in the key study: 12 rats were exposed by inhalation to a vapour-air mixture of the test substance at 20 degrees centigrade at 8300 mg/m3 for 1h and at 1950 mg/m3 for 8h exposure. In both studies, none of 12 animals died.

Other routes:

LD50 (i.p.) values of about 57 mg /kg bw (7 days post observation period) and about 53 mg /kg bw (14 days post observation period) were derived from an unpublished study in mouse (BASF, 1966).

A LD50 (i.p.) in mouse of 296 mg/kg bw is cited by RTECS. The original bibliographic source is Yakugaku Zasshi, a journal of pharmacy (1977).


Justification for selection of acute toxicity – oral endpoint
Most reliable study.

Justification for selection of acute toxicity – inhalation endpoint
Most reliable study.

Justification for selection of acute toxicity – dermal endpoint
Most reliable study

Justification for classification or non-classification

Acute oral toxicity

Based on a LD50 of 311 mg/kg bw, the test substance trimethylenediamine has to be classified Xn, R22 "Harmful if swallowed" according to Commission Directive 2001/59/EC and as acute oral cat. 4 (H302, "Harmful if swallowed") according to Regulation (EC) No 1272/2008 (CLP).

Acute inhalation toxicity

In an acute inhalation study the LC0 was found to be greater than 14165 mg/m3 for the test substance as no mortality occured at test conditions. Based on this data, trimethylenediamine is not liable for classification and labelling for inhalation toxicity according to Regulation (EC) No 1271/2008 (CLP) or Directive 67/548/EC (DSD) criteria.

Acute dermal toxicity

In an acute dermal toxicity study the LC50 was found to be 178 mg/kg bw. Based on this data, trimethylenediamine has to be classified T, R24 "Toxic in contact with the skin" according to Commission Directive 2001/59/EC and as acute dermal cat. 2 (H310, "Fatal in contact with skin") according to Regulation (EC) No 1272/2008 (CLP).