j.2Irritation and corrosivity

j.2Irritation and corrosivity

j.2.1Skin

Campbell et al. (1975) examined the skin irritancy potential of MMT in groups of six male albino rabbits. MMT was applied under occlusion, as a neat solution (0.1 mL) to intact or abraded dorsal skin. The covering and test solution were removed after 24 hours. Skin reactions were assessed when the patch was removed (24 hrs) and 48 hours later (72 hrs) and were scored using an approach described by Campbell et al. (1975). Signs of erythema and oedema were confined to the test area and no eschar formation was observed (no further details provided). Campbell et al. concluded that MMT is not an irritant in intact skin and is a mild irritant in abraded skin.

The ability of MMT to induce skin irritation was assessed in intact and abraded skin of female New Zealand albino rabbits according to the method of Draize et al. (1944). In this study MMT (0.5 mL) was applied to groups of six rabbits under occlusion for 24 hours. MMT was found to cause well-defined erythema and slight oedema in both abraded and intact skin. Slight irritation was still present 72 hours post application. Mean irritation scores for erythema/eschar formation and oedema were 1.29 and 1.5 respectively, averaged over 24 and 72 hours (Ethyl Corporation 1976i; Hinderer 1979).

In acute lethality dermal studies, skin reactions were also noted. MMT (112-2000 mg/kg bw) was applied to intact and abraded rabbit skin under occlusion for 24 hours. At 24 hours post dosing, a slight to well-defined erythema and moderate oedema were noted in most animals. Skin irritation had generally cleared by day 3 in surviving rabbits. Each treatment group contained 4 rabbits (Ethyl Corporation 1975b, 1976f, 1976g).

Two poorly reported studies examining skin irritation were also identified. The first reported that undiluted MMT applied to the skin of rabbits for 24 hours caused no remarkable signs and a 6 hour exposure of 10% MMT in peanut oil to rat skin resulted in a mild transient irritation (Witherup et al Unknown date b). The second study found that a 24-hour exposure to Combustion Improver No. 2 Product (10% MMT in kerosene) caused erythema and oedema at 24 and 72 hours in rabbits (Witherup and Roell 1965).

j.2.2Eye

The ability of MMT to cause eye irritation was assessed also according to the grading method of Draize et al. (1944). In this study, MMT (0.1 ml) was applied to the conjunctival sac of the right eye of six Albino New Zealand rabbits. MMT resulted in mild conjunctival redness but no corneal effects. Mean Draize scores on day 1 of 0.83 and 0.17 for conjunctival redness and chemosis respectively were reported. A conjunctival discharge was observed in one animal on day 2 and one animal still showed minor conjunctival redness (score 1) on day 3. No effects were observed from day 4 onwards (no further details provided) (Ethyl Corporation 1976j; Hinderer 1979).

In an acute inhalation lethality study, rats receiving whole body exposure to MMT vapours (0.108-0.309 mg/L for 1 hr or 0.047-0.1 mg/L for 4 hrs) experienced eye irritation that lasted for a maximum of one day. Each treatment group contained 10 animals (Ethyl Corporation 1976h). Lacrimation and mild eye inflammation were observed also for up to 30 minutes post exposure in a similar on1 hour inhalation toxicity study of a product consisting of 62% MMT in petroleum distillate (Ethyl Corporation 1976a).

Two poorly reported studies examining eye irritation were also identified. In the first study, occasional mild injection of the vessels of the bulbar conjunctivae was observed in rabbit eyes that had been exposed to 10% MMT in kerosene (Witherup et al Unknown date b). In the second study, a 24-hour exposure to Combustion Improver No. 2 Product (10% MMT in kerosene) resulted in a mild hyperemia in the palpebrae in two of six New Zealand albino rabbits. Eyes were considered normal on days 2 and 3 (Witherup and Roell 1965).

j.3Sensitisation

j.4Repeated dose toxicity

At the lower dose of 0.0062 mg/L animals gained weight and none died. Many of the animals, including controls, died as a result of a chronic infectious disease (pneumonitis) and were not included in the analysis.

The viscera were examined for gross pathological changes and several tissues were examined for microscopic changes. The only findings noted in the report were that pathological changes resulting at high MMT concentrations were observed primarily in the liver and kidneys and at lower concentrations degenerative changes in the liver and kidneys occurred less consistently. The NOAEL for rats and mice was 0.0062 mg/L (6.2 mg/m³). Using the data of Gold et al (1984) as reference values for dose calculations, assuming a respiratory volume of 6 L/hour and a (male) body weight of 0.2 kg, this NOAEL corresponds to an intermittent dose of 1.3 mg/kg bw/day in rats.

Small groups of cats (1/dose), rabbits (1-4/dose), and guinea pigs (6-9/dose) were exposed to similar doses of MMT for 4 to 150 weeks. Very few animals died and none died at exposures at and below 0.017 mg/L MMT for 150 weeks. Two dogs were exposed to 0.012 mg/L MMT for 100 weeks and neither died. No MMT-dependent toxic effects were observed in cats, rabbits, guinea pigs or dogs. This is an unpublished study and no individual animal data or statistical analyses were reported (Witherup et al unknown date a).

Toxicity resulting from repeated dermal exposure to 0, 0.4, 2.4 or 16 g/L MMT (equivalent to 0, 0.8, 4.8 and 32 mg MMT/kg bw/day) in gasoline with and without tetraethyl lead (TEL) (~ 2 g/L) was assessed in Weanling CFW rats and male New Zealand White rabbits. Rats were exposed 5 days per week, for 25 weeks while rabbits were exposed 5 days per week, for 14 weeks. Repeated dermal contact with the gasoline solutions (2 mL/kg), regardless of whether they contained MMT with or without lead, resulted in severe and extensive skin injury in rabbits. Initial gasoline exposure caused a mild transient erythema, which developed into a mild oedema with continued exposure. The skin eventually became dry, hard, wrinkled with numerous fissures and ulcerations. At 4.8 and 32 mg MMT/kg bw/day, vacuolar degeneration of the liver and kidney was observed in some rabbits. Mild skin damage was seen in rats exposed to the gasoline solutions, regardless of whether they contained MMT with or without lead. No neurological irritation or significant effects on mortality, body weight, blood content (haemoglobin and leukocyte number), organ weight (heart, liver, lungs, kidneys, brain), or the viscera could be attributed to MMT. Five male and 5 female rats and 5 male rabbits were used per treatment. This is an unpublished report and individual animal data and scores and statistical analysis were not reported (Witherup et al unknown date c).