2,6-xylidine

Endpoint summary

Description of key information

Acute oral toxicity
- Rat: LD50 = 840 - 1230 mg/kg bw [Jacobson et al., 1972; NTP, 1990; Vernot et al., 1977]

- Mouse: LD50 = 710 mg/kg bw [Vernot et al., 1977].

Acute Inhalation toxicity

- Rat: LC50 > 0.75 mg/L (Inhalation Hazard Test, 7h, saturated vapour) [BASF, 1982].

Acute Dermal toxicity

- No data available.

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: Basic data given, acceptable for assessment

Qualifier:

no guideline followed

Principles of method if other than guideline:

Single oral dose toxicity was determined by the method of Smyth et al . (1962).

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): 2,6-dimethylaniline
- no further data

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 200-300 g
- Diet Purina Formulab Chow 5008 ad libitum
- Water ad libitum

Route of administration:

oral: gavage

Vehicle:

not specified

Details on oral exposure:

no data

Doses:

no data

No. of animals per sex per dose:

no data

Control animals:

no

Details on study design:

no data

Statistics:

LD50 and its 95% confidence limits are estimated by the moving average technique (Thompson, 1947 ; Weil, 1952).
When fractional mortality was not noted, the LD50 value was listed without a confidence interval.
Occasionally enough data were obtained to use the probit method (Finney, 1971) for calculation.

Sex:

male

Dose descriptor:

LD50

Effect level:

1 230 mg/kg bw

95% CL:

>= 890 - <= 1 700

Mortality:

no data

Clinical signs:

other: no data

Gross pathology:

no data

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 230 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: Comparable to guideline (OECD 403, inhalation hazard test) with acceptable restrictions (partly limited documentation; post exposure observation period 7 days; low number of rats)

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

IHT, Inhalation hazard test

GLP compliance:

no

Test type:

other: IHT, Inhalation hazard test

Limit test:

yes

Specific details on test material used for the study:

- Name of test material (as cited in study report): 2,6-Dimethylanilin
- Physical state: brown liquid
- Analytical purity: no data
- Stability under test conditions: 6 months if oxygen is excluded

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Dr . K . Thomae GmbH, Biberach, D (SPF breed: SPF-Wistar/Chbb:THOM)
- Age at study initiation: 8 weeks
- Mean weight at study initiation: males 242 g(233-257 g); females 193 g (168-214g)
- Housing: 3 per cage
- Diet (e.g. ad libitum): Sniff R 10mm, Sniff, Soest, D
- Water (e.g. ad libitum): ca. 250 mL tap water/ cage*d
- Acclimation period: at least 5 d


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- 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:

Rats exposed for 7 h to a vapour saturated atmosphere.
Vapour was generated by bubbling 200 l/h dry air (no CO2) through the liquid substance column (volume ca. 50 ml) of about 5 cm above a fritted glass disc in a glass cylinder. The glass cylinder was heated in a water bath. The air pressure was 754 mm Hg. Temperature in the exposure chamber was 20°C.
The vapour saturation was calculated to be ca. 1.00 mg/L (at 20°C). Therefore, the test atmosphere has to be considered as vapour.

Analytical verification of test atmosphere concentrations:

no

Duration of exposure:

7 h

Concentrations:

0.75 mg/L (mean of 0.71 and 0.79 mg/L)

No. of animals per sex per dose:

6

Control animals:

no

Details on study design:

- Duration of observation period following administration: 11 days
- Frequency of observations and weighing: No weighing was done. Observation was several times at the day of exposure and presumably daily except on weekends and holidays.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs

Statistics:

not performed

Sex:

male/female

Dose descriptor:

other: inhalation hazard test

Effect level:

0.75 mg/L air

Exp. duration:

7 h

Remarks on result:

other: no mortality observed

Mortality:

No mortality observed

Clinical signs:

other: during exposure: salivation, aqueous eye secretion and muzzles wiping; after exposure: salivation, apathy, closed eyes and slight secretion of the nose; all effects reversible after 1d

Body weight:

not performed

Gross pathology:

Necropsy revealed no morphological changes 14 d after exposure.

Interpretation of results:

GHS criteria not met

Conclusions:

Inhalation of vapour saturated atmosphere of 2,6 -Xylidine for 7 hours in an inhalation hazard test did not cause mortality in rats.

Executive summary:

Study is comparable with the inhalation hazard test (IHT) described in the Annex of OECD Guideline 403 (adopted 1981) with acceptable restrictions (partly limited documentation; post exposure observation period 10 days). Rats were exposed for 7 h to a vapour saturated atmosphere (0.75 mg/L). 0/12 animals died after the 7 h exposure. Salivation, apathy, closed eyes and slight secretion of the nose were reversible within one day. There was no finding at necropsy at the termination of the study.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

750 mg/m³ air

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

There are only limited valid data available for the assessment of the acute toxicity of 2,6-xylidine.

 

Acute Toxicity: Oral

Data on acute toxicity from various studies are listed below.

Oral LD50 of 840-1230 mg/kg for 2,6-xylidine and of 2050 mg/kg for 2,6 xylidine hydrochloride have been determined for male rats. Cyanosis was observed in animals severely intoxicated with 2,6-xylidine, but methaemoglobinaemia did not appear so pronounced as to be the cause of death. An oral LD50 of 710 mg/kg has been determined for mice (NTP, 1990).

Table 1: Summarized data on Acute oral toxicity

Test animal	LD50 (mg/kg bw)	95% CI	Reference
mouse	710	520 - 960	Vernot et al., 1977
rat	1230	890 - 1700	Vernot et al., 1977
rat	840	640 - 1120	Jacobson et al. 1972
rat	1160	830 - 1630	NTP, 1990 (Mason)
rat	1270 (females) 1310 (males)	944 - 1520 (females) 1120 - 1520 (males)	NTP, 1990 (Litton)
rat	2042 (hydrochloride)	-	Lindstrom et al., 1969

In an acute acute toxicity study comparable to OECD guideline 401, groups of 5 male and 5 female F344/N received single doses of 310, 620, 1250, 2500 and 5000 mg/kg bw 2,6 -xylidine in corn oil by gavage. At doses of 310 and 620 mg/kg bw, all rats survived. All males and 3/5 females died at 1250 mg/kg bw and all rats died at doses of 2500 mg/kg bw and above.No LD50 value could be calculated for male rats. For female rats, a LD50 of 1160 mg/kg bw was determined. All rats were inactive after substance administration. Dyspnea and shallow breathing were observed atdoses of 1250 mg/kg bw and above. Necropsy revealedreddened renal medullae at 620 mg/kg and reddened gastric mucosa and thick, oily, opaque yellow fluid in the stomach and intestine at doses of 1250 mg/kg bw and above [NTP, 1990].

 

In another acute toxicity study comparable to OECD guideline 401, groups of 5 male and 5 female Charles River CD rats were exposed to doses of 215, 316, 681, 1000, 1470, 2150 and 3160 mg/kg bw. All rats survived doses of 681 mg/kg bw or less, and all males survived doses of 1000 mg/kg bw, whereas 4/5 females and males died at 1470 mg/kg bw, 4/5 females and all males died at 2150 mg/kg bw and all animals died at 3160 mg/kg bw. All animals dosed with 215 mg/kg bw showed reduced activity, prostration was observed in higher doses. Moreover, ptosis and watery discharge from the eyes was observed in animals dosed with 3160 mg/kg bw. Deceased animals had bright red lungs and pale livers and kidneys [NTP, 1990].

Vernot et. al (1977) published LD50 values of 710 and 1230 for mice and rats, respectively. Single oral dose toxicity was determined by the method of Smyth et al. (1962).

Jacobsen et al. (1972) investigated the acute oral toxicity of 2,6 -xylidine and other mono- and di-alkyl ring-substituted derivates of Aniline in male Sprague-Dawley (CD) rats. A LD50 value of 840 was stated for 2,6 -xylidine. The authors observed lethargy in treated animals, but otherwise no chraracteristic signs of toxicity. Cyanosis was detected in some animals. Necropsy revealed enlarged spleens and darkened organs in some animals. However, these findings were not clearly ascribed to 2,6 -xylidine but collectively mentioned for all tested substances without specification.

Lindstrom et al. (1969) published a LD50 value of 2042 mg/kg bw for male Osborne Mendel rats which received the hydrochloride of 2,6 -xylidine.

In cats, a single oral administration of 200 mg/kg bw 2,6 -xylidine caused moderate formation of methemoglobin (approx. 30%) after 4 hours accompanied by unspecific and reversible clinical signs (salivation, apathy, temporal feeding reluctance) and slight body weight reduction. Typical signs of methaemoglobin intoxification were missing (i.e. cyanosis) or were not reported (i.e. hypoxemia, formation of Heinz bodies) [BASF, 1982].

2,6-DMA also produced less than 3 % MHb after injection of 20 mg into the femur of male rats (Lindstrom et al., 1969). In cats which are known to be very susceptible to MHb-forming agents, a mean level of only 7.2 % was reached after i.v. administration of 0.25 mmol/kg 2,6-DMA (30.3 mg/kg). The potential of 2,6-DMA was very low compared to equimolar doses of other alkyl amines, e.g. aniline which caused 61.6 % MHb (SCOEL, 2009).

 

Acute Toxicity: Inhalation

In an inhalation hazard test, 6 rats were exposed to a saturated vapour of 2,6-xylidine (0.75 mg/l air) for 7 hours. At this concentration clinical signs observed included salivation, aqueous eye secretion and muzzles wiping during the exposure and salivation, apathy, closed eyes and slight secretion of the nose up to several hours after exposure; all effects reversible within 1 day. Mortalities did not occur and no pathological abnormalities were detected in post mortem necropsy [BASF, 1982].

 

Acute Toxicity: Dermal

Up to date there are no experimental data available concerning the acute dermal toxicity of 2,6-xylidine.

However, no deaths or systemic effects were reported in irritation studies with dermal application of 2,6 -xylidine.

 

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance is considered to be classified for acute oral toxicity Cat. 4 under Regulation (EC) No. 1272/2008, as amended for the fourteenth time in Regulation (EU) No 2017/776. Based on the available data, a classification for inhalation toxicity is not justified. No experimental data on acute dermal toxicity are available.

Furthermore, 2,6 -xylidine is included in Annex VI of Regulation (EC) No. 1272/2008 with the following legal classification:

• Acute toxicity - oral Cat. 4 (H302: harmful if swallowed)
• Acute toxicity - dermal Cat. 4 (H312: harmful in contact with skin)
• Acute toxicity - inhalation Cat 4 (H332: Harmful if inhaled)