4.19 Lindane (gamma-HCH) (T)

TOXICOLOGY

Lindane was evaluated toxicologically by the JMPR in 1963, 1965, 1966, 1970, 1971, 1973, 1977, and 1989. An ADI of 0-0.01 mg/kg bw was established in 1977. On the basis of additional data, the 1989 JMPR allocated an ADI of 0-0.008 mg/kg bw. An Environmental Health Criteria monograph on lindane has been published¹. Additional short-term studies on toxicity after dermal exposure, long-term toxicity and carcinogenicity, genotoxicity, and reproductive toxicity have become available and were evaluated at the present Meeting.

¹ WHO (1991) Lindane (Environmental Health Criteria 124), Geneva

In all of the studies in rats summarized below, the formation of hyaline droplets in the kidneys of males and the associated renal effects were male-specific and were characterized as so-called 'alpha_2m -globulin nephropathy'. This type of nephropathy is considered not to be relevant for humans. Therefore, in setting the NOAEL in rat studies these male-specific renal effects were not taken into account.

In a 13-week study of dermal toxicity (evaluated by the 1989 JMPR), rats were exposed to doses of 0, 10, 60, or 400 mg/kg bw per day. At the highest dose, clinical signs of neurological effects (convulsions) were observed. Other targets were the kidney of male animals, and the liver as demonstrated by changes in organ weight and histopathological changes. Since the male-specific renal effects were not taken into account, the NOAEL for dermal exposure was 10 mg/kg bw per day, on the basis of increased liver weight and histopathological changes in the liver.

In another 13-week study of dermal toxicity, rabbits were exposed to doses ) 0, 10, 60, or 400 mg/kg bw per day. At the highest dose, clinical neurological effects (convulsions) were observed. The NOAEL for dermal exposure was 10 mg/kg bw per day, on the basis of increased liver and adrenal weights and centrilobular hypertrophy of the liver.

In a two-year study of toxicity and carcinogenicity, rats were exposed to dietary concentrations of lindane of 0, 1, 10, 100, or 400 ppm. At the highest dose neurological effects (convulsions), reduced body-weight gain, decreased survival rates (also in males at 100 ppm), and changes in erythrocyte parameters were observed. Other changes seen at 400 ppm, and to a lesser extent at 100 ppm, were changes in weight and in the histological appearance of the liver and kidneys. The effects on the kidneys were confined to male rats with a slight increase in hyaline droplet formation that was also observed in male rats at 1 and 10 ppm. Since the male-specific renal effects were not taken into account, the NOAEL was 10 ppm, equal to 0.47 mg/kg bw per day, on the basis of a slight increase in mortality and effects on the liver. There was no evidence of carcinogenicity.

A two-generation study of reproductive toxicity in rats given lindane at dietary concentrations of 0, 1, 20, or 150 ppm did not indicate reproductive toxicity. The main effects found in progeny at 150 ppm were on weight gain, and decreased viability of pups was seen up to day 4 post-partum. In the pups of the second generation, there was a slight delay in tooth eruption and hair growth. Pups of the F₂ generation at 150 ppm that died before weaning showed increased incidences of hydronephrosis and hydroureter. The NOAEL for reproductive and developmental toxicity was 20 ppm, equivalent to 1 mg/kg bw per day. Histopathological effects in the kidneys were observed only in male parents at 20 and 150 ppm. Since the male-specific renal effects were not taken into account, the NOAEL for parental toxicity was 20 ppm, equivalent to 1 mg/kg bw per day, on the basis of effects on body-weight gain, liver effects, and increased kidney weights in animals of each sex.

Lindane did not induce chromosomal aberrations or unscheduled DNA synthesis in vitro.

Functional effects and histological changes in the immune system were induced by lindane (purity 97% or of unknown purity) in rats, mice, and rabbits. In rats and rabbits, effects were seen at doses equivalent to 1 mg/kg bw per day and above, but not in rats at 0.25 mg/kg bw per day. In mice exposed to doses of 0.012 mg/kg bw per day and above, an initial immunostimulation followed by immunosuppression was observed. It was noted, however, that the purity of the test material used in these studies was lower than that specified by current FAO specifications, namely >99% gamma-hexachlorocyclohexane.

The toxicological effects that are relevant for estimating hazard for humans are those on the liver and the central nervous system. In published studies, however, lindane of a purity of 97% or of unknown purity has been found to affect the immune system. As immunotoxic effects were observed at doses close to or even lower than the NOAEL found in the two-year study in rats, the Meeting concluded that additional data on immunotoxicity were required. Further, the Meeting recommended that when the new results become available, a full re-evaluation be performed to consider the validity of the studies that have been reviewed previously and to consider any new information that becomes available.

The Meeting established a temporary ADI at 0-0.001 mg/kg bw on the basis of the NOAEL of 0.5 mg/kg bw per day in the two-year study of toxicity and carcinogenicity in rats, using a safety factor of 500. Pending clarification of the immunotoxicity of lindane that meets

FAO specifications, this ADI provides a 10-fold margin of safety over the LOAEL of 0.012 mg/kg bw per day in a study of immunotoxicity in mice.

An addendum to the toxicological monograph was prepared.

TOXICOLOGICAL EVALUATION

(based on studies from this and earlier JMPR evaluations)

Levels that cause no toxic effect

Mouse:	300 ppm, equivalent to 15 mg/kg bw per day (26-week study of effects on the liver)
	50 ppm, equal to 7.8 mg/kg bw per day (80-week study of carcinogenicity)
	30 mg/kg bw per day (maternal and developmental toxicity in a study of developmental toxicity)
	<0.012 mg/kg bw per day (24-week study of immunotoxicity with 97% pure lindane)
Rat:	10 ppm, equal to 0.75 mg/kg bw per day (13-week study of toxicity)
	4 ppm, equal to 0.29 mg/kg bw per day (three-month study of toxicity, LOAEL= 20 ppm)
	10 ppm, equal to 0.5 mg/kg bw per day (two-year study of toxicity and carcinogenicity)
	20 ppm, equivalent to 1 mg/kg bw per day (two-generation study of reproductive toxicity)
	5 mg/kg bw per day (maternal toxicity in a study of developmental toxicity)
Dog:	50 ppm, equal to 1.6 mg/kg bw per day (two-year study of toxicity)
Rabbit:	<5 mg/kg bw per day (maternal toxicity in a study of developmental toxicity)

Estimate of temporary acceptable daily intake for humans

0-0.001 mg/kg bw

Studies without which the determination of an API is impracticable, to be provided by 2000

Confirmatory study of immunotoxicity in mice with lindane that meets the current FAO specification (³ 99% gamma-hexachlorocyclohexane).

Studies that would provide information useful for the continued evaluation of the compound Further observations in humans

Toxicological criteria for setting guidance values for dietary and non-dietary exposure to lindane

Human exposure	Relevant route, study type, species	Results, remarks
Short-term (1-7 days)	Oral, toxicity, dog	LD50 = 40 mg/kg bw
	Dermal, toxicity, rabbit	LD50 = 900 mg/kg bw
	Inhalation, 4 h, toxicity, rat	LC50 = 1600 mg/m3
	Skin, irritation, rabbit	Not irritating
	Eye, irritation, rabbit	Slightly irritating
	Skin, sensitization, guinea-pig	Not sensitizing
Medium-term (1-26 weeks)	Repeated inhalation, 90 days, toxicity, rat	NOAEL = 0.6 mg/m3 per day: clinical signs and increased cytochrome P450 enzymes
	Repeated dermal, 90 days, toxicity, rat/rabbit	NOAEL = 10 mg/kg bw per day: hepatic effects
	Repeated oral, 90 days, toxicity, rat	NOAEL = 0.75 mg/kg bw per day: changes in liver and kidney weight
	Repeated oral, developmental toxicity, rabbit	No NOAEL for maternal toxicity
		NOAEL = 10 mg/kg bw per day: fetuses with 13 ribs
	Repeated oral, reproductive toxicity, rat	NOAEL = 1 mg/kg bw per day: developmental toxicity and hepatic effects
Long-term (one-year)	Repeated oral, 2 years, toxicity/carcinogenicity, rat	NOAEL = 0.5 mg/kg bw per day: hepatic changes and decreased survival; no carcinogenicity.