Naphthalene

Direct observations: clinical cases, poisoning incidents and other

Administrative data

Endpoint:

direct observations: clinical cases, poisoning incidents and other

Type of information:

other: case report

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Peer-reviewed assessment report

Data source

Reference

Reference Type:

review article or handbook

Title:

Unnamed

Year:

2003

Materials and methods

Study type:

other: review on clinical cases of poisoning

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Clinical observations

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Naphthalene

EC Number:

202-049-5

EC Name:

Naphthalene

Cas Number:

91-20-3

Molecular formula:

C10H8

IUPAC Name:

naphthalene

Method

Type of population:

general

Route of exposure:

oral

Reason of exposure:

other: accidential or intentional

Exposure assessment:

estimated

Results and discussion

Clinical signs:

see below

Results of examinations:

--

Effectivity of medical treatment:

blood transfusion

Outcome of incidence:

There is no information on the effects of naphthalene following acute inhalation or dermal exposure in humans.
Acute oral exposure to naphthalene causes haemolytic anaemia, which may be fatal. Individuals deficient in G-6-PD are more susceptible to the effects of naphthalene.

Any other information on results incl. tables

Excerpt from RAR, ECB 3003

Summary of single exposure studies: Haemolytic anaemia

There is no information on the effects of naphthalene following acute inhalation or dermal exposure in humans.

Acute oral exposure to naphthalene causes haemolytic anaemia, which may be fatal. Individuals deficient in G-6-PD are more susceptible to the effects of naphthalene.

The first signs of toxicity are usually seen within 2 days. There is little quantitative information available, although severe haemolytic anaemia, which may have proved lethal in the absence of clinical intervention, was reported in a female who had ingested approximately 6 g naphthalene. An in vitro study backed up by an in vivo study in rabbits has demonstrated that the anaemia is caused by the naphthalene metabolite,1-naphthol.

Naphthalene is of low toxicity in rats, with mice being more sensitive. However, studies in animal models (mainly rats, mice and rabbits) have indicated that the toxic effects of naphthalene seen in these species are different from those in humans. Of the species studied, only dogs (in a poorly conducted study) demonstrated naphthalene-induced haemolytic anaemia. Rabbits showed signs of haemolytic anaemia with 1-naphthol but not with naphthalene. It appears that rodents are not suitable animal models for the acutely toxic human health effects of naphthalene in relation to haemolytic anaemia.

Thus, while the LD50 results from the rat suggest relatively low acute toxicity in this species, the available information in humans indicates significant toxicity. Very severe haemolytic anaemia occurred in one case report (of a 16 year old female) at an estimated single oral dose of approximately 6 g. It is possible that this represents a lethal dose, given that a number of blood transfusions were required.[ECB 2003, p. 143/144].

There are a great many case reports in the literature of acute haemolytic anaemia produced by naphthalene. The signs and symptoms of haemolytic anaemia associated with naphthalene exposure are well described (e.g. Gosselin et al., 1984, Mack, 1989).

The first signs and symptoms of toxicity are usually dark urine, pallor, abdominal pain, fever, nausea, vomiting and diarrhoea. On clinical examination the liver and spleen were enlarged. Haematological effects are fragmentation of red blood cells with anisocytosis and poikilocytosis, jaundice, anaemia with a reduction in haemoglobin levels and haematocrit values and resulting reticulocytosis and leucocytosis. More severe reactions also include Heinz body formation, haemoglobinuria and mild methaemoglobinaemia. In young children deaths have occurred due to kernicterus (a severe neural condition associated with high levels of bilirubin in the blood). In older children and adults renal failure may occur. Liver damage has also been described, but as a rare occurrence.

Individuals who are deficient in G-6-PD are particularly sensitive to haemolytic anaemia produced by naphthalene (Gosselin et al., 1984). This deficiency is genetically determined and occurs more often in males. The defect results in an inability by the red blood cell to maintain a balance between reduced and oxidised glutathione which in turn results in an increased susceptibility to oxidative attack by exogenous chemicals. It seems probable that the oxidative attack, following exposure to naphthalene, can occur following redox cycling of the naphthalene metabolites 1-naphthol and the quinone. The deficiency is known to be more common in Blacks,

Greeks, Italians, Sephardic Jews, Orientals and Filipinos.[HSE/UK 2003, p. 141/142]

Applicant's summary and conclusion

Conclusions:

In humans, the occurrence of haemolytic anaemia has been reported in at least 30 individuals, typically following single or repeated oral intake of naphthalene mothballs but also following inhalation and dermal exposure to naphthalene from clothing. In some cases (particularly neonates) the naphthalene-induced haemolytic anaemia proved fatal, although it is not possible to determine the doses involved from the reports available. Overall, due to a lack of quantitative information on the exposures producing haemolytic anaemia in humans, the nature of the dose-response relationship cannot be identified.
Furthermore, it is apparent that individuals who are deficient in the enzyme glucose-6-phosphate dehydrogenase are more susceptible to the haemolytic effects of naphthalene than are the general population, and as the enzyme status of the individuals was not always given in the case reports this adds further uncertainty to the assessment of risk for this endpoint.