2-hydroxy-2-methylpropionitrile

Endpoint summary

Description of key information

Data for acute oral, dermal and inhalation toxicity are available. The substance is  very toxic by all these exposure routes which is reflected in the legally binding harmonised classification as given in REGULATION (EC) No 1272/2008 Annex VI Table 3.1 (GHS): 
Acute tox 2*       H330 (oral)
Acute tox 1         H310 (dermal)
(Acute tox 2*       H300 (inhalation, vapour)) Based on the actual data this classification in annex VI, EU GHS, is too low. Data indicate the following:
Acute tox 1        H300 (inhalation, vapour)
and Table 3.2 (Annex I of Directive 67/548/EEC): 
T+; R26/27/28

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion

Dose descriptor:

LD50

Value:

17 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Dose descriptor:

discriminating conc.

Value:

223 mg/m³ air

Acute toxicity: via dermal route

Endpoint conclusion

Dose descriptor:

LD50

Value:

16 mg/kg bw

Additional information

2-hydroxy-2-methylproanenitril has been the subject of an assessment report of the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC report, JACC No. 53, Volume I, 2007; in the following cited as ECETOC). Furthermore Acute Exposure Guideline Levels (AEGLs) have been established by AEGL-Committee (US-NAC, Acetone Cyanohydrin, Interim Acute Exposure Guideline Levels (AEGLs), Interim final draft, 2005; in the following cited as AEGL). In these reports 2-hydroxy-2-methylproanenitril is designated as acetone cyanohydrin (ACH). Data for acute oral, dermal and inhalation toxicity are available.

Acute toxicity oral:

One key study has been identified, Smith et al 1962. In this acute oral toxicity study groups of five male Carworth Wistar rats (four to five weeks old, weight: 90 to 120 g) were given a single oral dose of 2-hydroxy-2-methylproanenitrile (a.i. and % dilution unstated) in a suitable vehicle. The dosages were arranged in a logarithmic series differing by the factor of two. Animals were then observed for 14 days.

Oral LD₅₀ Males = 17 mg/kg bw (11 – 26 mg/kg bw 95% C.I.)

Supporting data are available from literature and IUCLID 4 database, which fit very well with the observations of this study. Data reported from AEGL committee are presented in the following table. The same data are reported in the ECETOC report.

Summary of oral LD50 data for acetone cyanohydrin
Species	LD50 (mg/kg)	References
Rat	17	Smyth et al., 1962
Rat	13.3	Shkodich, 1966
Rat	17.8	Marhold, 1972
Mouse	14	Marhold, 1972
Mouse	15	Hamblin, 1953
Mouse	2.9	Shkodich, 1966
Guinea pig	9	Shkodich, 1966
Rabbit	13.5	Shkodich, 1966

Acute toxicity inhalation:

Only one study from literature could be selected as reliable. This is in compliance with ECETOC and AEGL. “The AEGL Committee found that hardly any data exist on inhalation for ACH. They relied on a range-finding study of Smyth et al (1962)” (quotation from ECETOC). The study was described in the AEGL as follows:

“Smyth et al. (1962) exposed groups of 6 albino rats to acetone cyanohydrin vapors that were produced by passing a 2.5-l/min-air stream through a fritted glass disc immersed in 50 ml acetone cyanohydrin. Doses were logarithmically distributed, differing by a factor of two (doses were not stated explicitly). The observation period was 14 days. After exposure for 4 hours, 2/6 rats were killed at 62.5ppm and 6/6 rats were killed at 125 ppm. The maximum time rats could be exposed to saturated vapor (about 1300 ppm) without producing any deaths was 5 minutes. No other signs of toxicity were reported.”

Concentration(mg/m³) (ppm)	Exposure time (h)	Number of deaths/exposed	Observation period (d)
62.5 (221)	4	2/6	14
125 (442)	4	6/6	14

Acute toxicity dermal:

The study of Carreon has been identified as reliable from available literature in compliance with ECETOC.

In this acute dermal toxicity study equivalent to OECD TG 402 (1981), 3 groups of New Zealand White rabbits (2 males and 2 females per dose level) were dermally exposed to 2-hydroxy-2-methylpropionitrile (10 % aq.) for 24 hours at doses of 6, 25, 40 mg/kg bw. Animals then were observed for 14 days.

Dermal LD₅₀ Combined = 16 mg/kg bw (95% C.I. 8 - 28).

Lethargy (at 6, 25, 40 mg/kg bw), labored breathing (at 25 and 40 mg/kg bw), and convulsions (at 25 mg/kg bw) were clinical signs of toxicity observed after treatment. There were no treatment related necropsy findings. Slight (4/5 animals) to moderate (1/5 animals) redness, slight swelling in 3/5 animals, and slight necrosis in 1/5 animals were found after 24 hours post treatment in the surviving animals.

One additional study has been identified by ECETOC as follows:

Skin condition	LD50 (mg/kgbw)	Reference
Intact	16.0	Carreon et al, 1981
Intact	850	Sterner and Chibanguza, 1980
Abraded	150	Sterner and Chibanguza, 1980

Discussion:

“Commercial and technical grade ACH are stabilised by the addition of 0.01% sulphuric or phosphoric acid. Stabilised ACH will exert a significant vapour pressure, primarily due to the presence of more volatile HCN, at room temperature. Under physiological conditions, acid-stabilised ACH will be buffered by the intracellular buffering capacity resulting in its rapid and quantitative decomposition to HCN and acetone. Hence, ACH will exhibit the combined characteristics of HCN and acetone (Frank et al, 2002)" (quotation from ECETOC).

"On a molar basis, there is no significant difference in acute toxicity between HCN, or its alkali salts, and ACH. This is consistent with the molar decomposition of ACH into acetone and HCN (US-NAC, 2000a,b)” (quotation from ECETOC).

"All cyanides ingested will be present, at the physiological pH of the stomach, as HCN. The HCN will be absorbed in the blood via the stomach wall and in the intestines. Before the blood enters the systemic circulation it has to pass the liver with a relatively high content of the enzyme rhodanese. A considerable part of cyanide is detoxified in the liver. This is apparent from comparison of the oral LD₅₀ value for rabbits (0.092 mmol/kgbw) with those obtained by intravenous (i.v.) injection or inhalation for 5 minutes (0.022 or 0.019 mmol/kgbw, respectively) (Ballantyne, 1987a), indicating a first-pass effect via ingestion" (quotation from ECETOC).

“The difference between the two dermal LD₅₀ values reported for ACH is remarkable since both studies were carried out according to the OECD 402 protocol, the only apparent difference being that Sterner and Chibanguza (1980) clipped the hair of only 150 cm² on the back, whereas – Carrion et al (1981) clipped the hair from the full trunk of the rabbits. This suggests that the area of skin contact and integrity of the skin areas very important in case of ACH. Abrasion of the skin enhances the dose rate and increases the toxicity of ACH” (quotation from ECETOC).

"In the humid air and the moist mucosa of the respiratory tract, acetone cyanohydrin decomposes to yield its molar equivalent in hydrogen cyanide and acetone. This reaction is a result of the physical chemistry of acetone cyanohydrin (Stewart and Fontana, 1940) and it is not known to be enzyme catalyzed in animals or humans (DECOS, 1995; Kaplita and Smith, 1986)" (quotation from AEGL).

"In mammals, cyanide is rapidly absorbed in the form of HCN following oral, dermal or inhalation exposure. Cyanides are very toxic by all routes of entry. The mechanism of toxicity is by inhibition of oxygen utilisation by tissues; the most sensitive organs are those with the greatest oxygen demand such as brain, heart and testes. In humans, the acute lethal dose is approximately 1.5 mg/kgbw following oral uptake. The acute inhalation toxicity is a function of the body weight and the time of exposure. Using probit analysis of the acute inhalation data in different species, a human LC₅₀ value of 202 mg/m³ (180 ppm) and an LC₀₁ of 88 mg/m³ (78 ppm) were derived, both following 60 minutes of exposure. The lethal dose by the dermal route will depend upon the area of skin exposed. A dose of approximately 100 mg/kgbw is lethal even if only a small area of skin is contacted. Acutely toxic levels might also be achieved following eye contact" (quotation from ECETOC).

Justification for classification or non-classification

Legally binding harmonised classification as given in REGULATION (EC) No 1272/2008 Annex VI Table 3.1 (GHS):

Acute tox. 2*       H330

Acute tox. 1        H310

Acute tox. 2*       H300

and Table 3.2 (Annex I of Directive 67/548/EEC):

T+; R26/27/28