2-chloro-5-(trifluoromethyl)pyridine

Endpoint summary

Description of key information

In vitro tests showed CTF to penetrate rat and human skin only slowly, and so a low order of toxicity is anticipated by dermal contact. A standard acute inhalation test showed the LC50 to be 19 mg/l (190000 mg/m3) in the rat. In this study, the lung, liver and central nervous system all appeared to be target organs at high concentrations of CTF.

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no study available

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:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Equivalent to GLP guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

other: Alderley Park

Sex:

male/female

Duration of exposure:

4 h

Concentrations:

25.3, 16.07, 7.75 mg/l

No. of animals per sex per dose:

5

Control animals:

yes

Sex:

male/female

Dose descriptor:

LC50

Effect level:

ca. 19 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Mortality:

Within two days of exposure, six animals died in the 25.3 mg/l group and seven animals died in the 16.07 mg/l group. No deaths occurred in the 7.75 mg/l group.

Clinical signs:

other: During exposure and immediately afterwards, all test animals exhibited signs of CNS depression, irritation and at higher levels, convulsions. Excessive urination was noted in some animals. The severity and duration of these effects was dose related.

Body weight:

All test animals lost weight following exposure, but those that survived began to gain weight at about the middle of the observation period. The overall weight gain particularly of the females, tended to be less than that of the controls.

Gross pathology:

The weights of test animals’ lungs were expressed as a percentage of the last bodyweight before death. The males of the 25.3 mg/l group, all animals in 16.07mg/l group and the males in the 7.75 mg/l group all had significantly higher lung weights than controls.

Upon examination, most of the animals from the 25.3 and 16.07 mg/l groups had haemorrhagic lungs; many had abnormal livers and other visceral abnormalities. Some of these observations were carried out as soon after death as possible, autolysis of tissues may have influenced the results. The animals from the 7.75 mg/l group had lung lesions only and these were approximately equivalent to those seen on the control animals.

Table 1: Results of atmosphere analysis

Group	Atmospheric concentration (mg/l)
1	25.3 ± 1.84
2	16.07 ±0.19
3	7.75 ± 0.35

Interpretation of results:

harmful

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The four hour LC50 of 2-chloro-5-(trifluoromethyl) pyridine (CTF) in the rat is approximately 19 mg/l.

Executive summary:

The four hour LC50 of 2-chloro-5-(trifluoromethyl) pyridine (CTF) in the rat is approximately 19 mg/l. The lung, liver and central nervous system all appear to be target organs at high concentrations and deaths could have been caused by severe effects in one or more of these organs.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

19 000 mg/m³

Quality of whole database:

Satisfactory

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

GLP compliance:

yes

Test type:

other: percutaneous absorption

Limit test:

no

Results

After application to the skin membranes of CTF as a 2.5mg/ml solution in acetone (which was allowed to evaporate away) the mean rate of absorption of CTF through human epidermal membranes was:

0.0070 mg/cm2/hr (SEM ± 0.0011 : n=11)

When similarly applied to rat whole skin the mean rate of absorption was:

0.0062 mg/cm2/hr (SEM ± 0.00008 : n = 20)

When applied to separated rat epidermal membranes the mean rate of absorption of CTF was:

0.0053 mg/cm2/hr (SEM ± 0.00096 : n=7)

The mean damage ratio due to contact of CTF with the skin membranes was:

Human epidermal membranes: 4.25 (SEM ± 2.4 : n = 3)

Rat whole skin: 2.19 (SEM ± 0.12 : n = 4)

Separated rat epidermal membranes: 4.01 (SEM ± 0.87 : n = 7)

Contact with ethanol/water (50/50 v/v) alone produces a damage ratio of ~ 2.0

Conclusions:

2-chloro-5-(trifluoromethyl) pyridine (CTF) only penetrated both human and rat skin epidermal membranes slowly.

Executive summary:

2-chloro-5-(trifluoromethyl) pyridine (CTF) was applied in acetone (2.5mg/ml) to prepared human and rat epidermal membranes in glass diffusion cells. The mean in vitro percutaneous absorption rate of CTF was

0.0070mg/cm2/hr (SEM ± 0.011 : n = 11) through human skin

0.0053mg/cm2/hr (SEM ± 0.0096 : n = 11) through rat skin

These results indicate that CTF penetrated both these skin types slowly.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Additional information

The most pertinent routes for occupational exposure to 2-chloro-5-(trifluoromethyl) pyridine (CTF) are judged to be inhalation and dermal contact. In vitro tests showed CTF to penetrate rat and human skin only slowly, and so a low order of toxicity is anticipated by dermal contact. A standard acute inhalation test showed the LC50 to be 19 mg/l (190000 mg/m3) in the rat. In this study, the lung, liver and central nervous system all appeared to be target organs at high concentrations of CTF. In another acute toxicity test, which was commissioned as a dose finding study for subacute inhalation testing, the LC50 for the rat was determined to be in excess of 13.7 mg/l. An I.P study in the mouse showed the LD 50 for CTF to be 750 mg/kg/bw following a 7-day observation period.Overall, CTF is judged to be of moderate acute toxicity. The most pertinent result, the 4 hr LC50 of 19mg/l in the rat is supported by other available acute toxicity tests, and leads to a classification of Harmful by Inhalation.

Justification for classification or non-classification

CLP Regulation (EC) 1272/2008 states for vapours to be classified in Acute Toxicity Category 4 (Inhalation) that the LC50 must be in excess of 10.0 mg/l but less than or equal to 20 mg/l. The LC50 of CTF has been determined in the rat to be 19 mg/l. Therefore, CTF is self-classified according to CLP Regulation (EC) 1272/2008 as Acute Tox. Category 4, H332 (Harmful if inhaled).

Whilst there are no well-reported acute ingestion studies on CTF, Material Safety Data Sheets have generally quoted the oral LD50 in the rat to be approximately 2000mg/kg/b.w.leading to a classification as H302 (Harmful if swallowed) under CLP Regulation (EC) 1272/2008. This Harmful classification is leant support by a reported oral LD50 (rat) of 1520 mg/kg for a mixture of chlorofluoropicolines that included some 46% CTF. Overall, the weight of evidence suggests that a Harmful classification by the oral route is appropriate.

In two acute toxicity studies there is evidence of CNS effects persisting post exposure. The severity of these effects and duration appear to be dose related. In the supporting study (Bennett 2. 1982) only at the lowest exposure level of 2.0 mg/l were these effects noted to be absent immediately post exposure. This implies that CNS effects persisted post exposure at the next highest dose of 3.3 mg/l and, indeed, were reported as persisting until day 11 at the highest dose of 13.7 mg/l. In the main LC50 study (Bennett 1. 1982) the severity and duration of CNS effects was reported to be dose related and was seen at the lowest concentration tested at 7.75 mg/l. According to CLP Regulation (EC) 1272/2008 the guidance value for classification as STOT-SE Category 1 (inhalation, rat, vapour) is less than or equal to 10 mg/l/4hr. Therefore, based on the weight of available evidence it is justified to classify CTF as STOT-SE Category 1 by Inhalation, H370, Causes damage to organs (CNS).