4-HEXYLRESORCINOL
First draft prepared by
Professor R. Walker
School of Biological Sciences, University of Surrey,
Guildford, Surrey, England
Explanation
Biological data
Biochemical aspects
Absorption, distribution, and excretion
Biotransformation
Toxicological studies
Acute toxicity studies
Short-term toxicity studies
Long-term toxicity/carcinogenicity studies
Reproductive toxicity studies
Special studies on teratogenicity
Special studies on genotoxicity
Special studies on delayed contact sensitization
Special studies on spermicidal activity
Observations in humans
Comments
Evaluation
References
1. EXPLANATION
This substance is used as a processing aid to prevent the
development of melanosis (black spot) in shrimps and related
crustacea, and was evaluated for this specific use only. It had not
been previously evaluated by the Committee.
4-Hexylresorcinol is applied as an aqueous solution at
concentrations of 50 mg/litre, resulting in residue levels in the
edible portion of crustacea of approximately 1 mg/kg. The estimated
intake of the compound resulting from this use was 1-8 µg per person
per day. Against this background, the Committee evaluated 4-hexyl-
resorcinol on the basis of previously established principles for
substances consumed in small amounts. The Committee was informed that
throat lozenges containing 2.4-4 mg per lozenge of 4-hexylresorcinol
for use as an oral antiseptic are available over the counter in some
countries (Gilman et al., 1985).
2. BIOLOGICAL DATA
2.1 Biochemical aspects
2.1.1. Absorption, distribution, and excretion
Dogs were given single doses of 1 or 3 g 4-hexylresorcinol
(equivalent to 100 or 300 mg/kg bw) as crystals in gelatin capsules or
as a solution in olive oil, and excretion monitored in urine and
faeces. After administration of 1 g crystalline compound, 29% of the
dose was detected in urine and 67% in faeces; when the dose was
increased to 3 g, 17% was excreted in urine and 73% in faeces. Urinary
excretion was rapid, mainly in the first 6 h, and levels were
virtually undetectable 12 h after the lower dose and 24-36 h following
the higher dose. When 4-hexylresorcinol was administered in olive oil,
a dose of 1 g resulted in 17% being excreted in urine and 76% in
faeces, while 10% was excreted in urine and 80% in faeces following a
dose of 3 g (Robbins, 1931).
When two men received doses of 1 g 4-hexylresorcinol, an average
of 18% of the dose was recovered in urine within the first 12 h;
thereafter the compound was not detected in urine samples. Faecal
excretion accounted for 64% of the dose (Robbins, 1935).
2.1.2. Biotransformation
It has been reported that 4-hexylresorcinol is excreted via the
urine mainly in the form of an ethereal sulfate conjugate (Goodman &
Gilman, 1970) but the origin of this secondary report is not
referenced.
2.2. Toxicological studies
2.2.1. Acute toxicity studies
The results of acute toxicity studies with 4-hexylresorcinol are
summarized in Table 1.
When 4-hexylresorcinol was administered to cats orally in alcohol
or olive oil, no pathological effects were observed at doses up to
60 mg/kg bw, but a dose of 260 mg/kg bw was lethal to all animals
(Maplestone & Chopra, 1934)
No deaths occurred in dogs given single doses of 88-140 mg/kg bw
(Christensen & Lynch, 1933)
Table 1: Acute toxicity studies with 4-hexylresorcinol
Animal Route LD50 Reference
mg/kg bw
Mouse s.c. (5% in olive oil) 750-1000 Dittmer, 1959
i.p. (5% in olive oil) 200
i.p. (1% aqueous emulsion) 300
Rat oral 550 Lamson et al., 1935;
Dittmer 1959
Guinea-pig oral 475 Anderson et al., 1931
Rabbit oral (10% in ethylene glycol) > 7501 Anderson et al., 1931
oral (solid in gelatin capsules) < 7502
1 6 animals; all survived
2 6 animals; all died
2.2.2. Short-term toxicity studies
2.2.2.1 Mice
In a range-finding study for subsequent short- and long-term
toxicity studies, groups of five B6C3F1 mice of each sex, 7-9 weeks
of age, were given 4-hexylresorcinol by gavage in corn oil at doses of
0 (vehicle control), 31, 63, 125,250 or 500 mg/kg bw daily for 12 days
(not including week-ends), i.e. 16 days overall. No dose-related
effects were observed (NTP, 1988).
In a 13-week study, 4-hexylresorcinol was administered by gavage
in corn oil, 5 days/week, to groups of 10 B6C3F1 mice of each sex,
starting at age 8-9 weeks. The dose levels administered were 0
(vehicle control), 63, 125, 250, 500 or 1000 mg/kg bw/day. Where
possible, animals dying during the course of the study were autopsied
and subjected to histological examination. At termination, detailed
histological examinations were performed on control animals and on all
animals in the two highest dose groups.
All male mice and 9/10 female mice in the 1000 mg/kg bw/day dose
group died during the first week of the study. No clinical signs were
reported. Final mean body weights were 6% and 5% lower than controls
(not significant) in males of the 250 and 500 mg/kg bw/day dose
groups; female body weights were comparable to controls. Mild to
moderate nephropathy was seen in 1/10 males at 63 mg/kg bw/day, 4/10
males and 1/10 females at 125 mg/kg bw/day, 8/10 males and 7/10
females at 250 mg/kg bw/day, and 7/10 males and 10/10 females at
500 mg/kg bw/day. A NOEL of 31 mg/kg bw/day was estimated in this
study by extrapolation from the dose-response data (NTP, 1988).
2.2.2.2 Rats
In a range-finding study for subsequent short- and long-term
toxicity studies, groups of five F344/N rats of each sex, 8 weeks of
age, were given 4-hexylresorcinol by gavage in corn oil at doses of 0
(vehicle control), 31, 63, 125, 250 or 500 mg/kg bw daily for 12 days
(not including week-ends), i.e. 16 days overall. No deaths occurred as
a result of treatment but final mean body weights of males in the top
two dose groups were 8% and 16% lower than that of the controls; body
weights of females were comparable. Rats receiving 500 mg/kg bw/day
were described as being hyperexcitable (NTP, 1988).
In a 13-week study, 4-hexylresorcinol was administered by gavage
in corn oil, 5 days/week, to groups of F344/N rats (10/sex), starting
at age 7 weeks. The dose levels administered were 0 (control), 63,
125, 250, 500 or 1000 mg/kg bw/day. Where possible, animals dying
during the course of the study were autopsied and subjected to
histological examination. At termination, detailed histological
examinations were performed on all animals of the control and two
highest dose groups.
All rats in the 1000 mg/kg bw/day dose group died during the
first week of the study. At termination, final mean body weights in
rats receiving 250 mg/kg bw/day were 22% and 9% lower than controls in
males and females, respectively. At 500 mg/kg bw/day, the decreases
were 38% and 16% for males and females, respectively. Clinical signs
seen during the study included nasal discharge, ocular irritation,
alopecia, diarrhoea and cachexia. At necropsy, reduction in size of
the seminal vesicles was reported in 4/10, 6/10 and 1/10 males in the
1000, 500 and 250 mg/kg bw/day groups, respectively. Hyposperma-
togenesis was seen microscopically in 4/10 animals in the highest dose
group and hypoplasia of the seminal vesicles was reported in 5/10 and
3/10 males in the 1000 mg/kg bw/day and 500 mg/kg bw/day groups,
respectively (presumably in the highest dose group these effect were
seen when the animals were autopsied after dying during week 1 but no
comparisons with controls were possible at that time and the animals
were only 7-8 weeks old). No histopathological lesions were identified
in rats given doses of 125 mg/kg bw/day or less (NTP, 1988).
2.2.3 Long-term toxicity/carcinogenicity studies
2.2.3.1 Mice
In a study of the potential carcinogenicity of spermicides,
groups of 20 female BALB/c mice were given intravaginal applications
of 0.1 ml of a 1% suspension of 4-hexylresorcinol in aqueous gum
tragacanth twice weekly for 31 weeks. During the observation period of
20 months, one mouse developed squamous carcinoma of the vagina
compared with none in the control group (Boyland et al., 1966).
A carcinogenicity study was conducted with B6C3F1 mice in which
groups of 50 mice of each sex were given 4-hexylresorcinol at dose
levels of 0 (vehicle control), 63 or 125 mg/kg bw/day by oral gavage
in corn oil (10 ml/kg bw), 5 days/week, for 102 weeks. The mice were
7-8 weeks of age when administration of the test compound commenced.
The animals were observed twice daily and body weights were recorded
weekly for 13 weeks and monthly thereafter. Necropsy was performed on
all animals at termination and, where possible, on those dying during
the study. Complete histological examinations were performed on all
mice of the control and high-dose groups; limited examinations were
conducted on the low-dose animals involving liver, kidneys, lungs,
bone, from both sexes, adrenal (males only) and pituitary and thyroid
(females only).
There was a treatment-related effect on body-weight gain. After
week 80, mean body weights of mate mice from the high- and low-dose
groups were 9-11% and 6-8% lower than controls; mean body weights of
low-dose females were 6-16% lower after week 67, and high-dose females
were 4-10% lower after week 88. No compound-related clinical signs
were noted and there was no significant differences in survival
between any group of either sex. Focal hyperplasia of the adrenal
medulla was observed with increased frequency in treated male mice and
phaeochromocytomas occurred with a positive trend but the incidences
of the latter were not significantly different from controls. The
incidences of carcinoma and of combined adenomas and carcinomas of the
Harderian gland were significantly greater in low-dose males than in
controls (Table 2). Treated females did not show an increased
incidence of proliferative changes in either adrenal or Harderian
glands. In contrast, in male mice, hepatocellular adenomas, carcinomas
or adenomas and carcinomas combined occurred with a negative trend,
being significantly lower with regard to hepatocellular adenomas in
the low-dose group, hepatocellular carcinomas in the high-dose, and
combined adenomas and carcinomas in treated males. Haemangiomas and
combined haemangiomas and haemangiosarcomas also occurred with lower
incidence in high-dose male and female mice, and the incidences of
alveolar/bronchiolar adenomas or carcinomas (combined) were lower in
the low-dose females than in controls. Based on these data, the
authors concluded that there was equivocal evidence of carcinogenic
activity of 4-hexylresorcinol in male mice but no evidence of
carcinogenic activity in female mice. Decreased incidences of two
tumour types were considered to be related to administration of
4-hexylresorcinol, namely hepatocellular neoplasms in male mice and
circulatory system tumours in mice of both sexes.
Non-proliferative pathological changes observed at termination
included nephropathy at increased incidences and severity in dosed
mice of both sexes (males: control, 39/50; low dose, 43/50; high dose
47/50; females: 7/50; 40/49; 47/50, respectively). The nephropathy
varied from mild focal tubular atrophy in the outer cortex to severe
atrophy with tubular cysts, tubular regeneration, dilatation of
the tubular lumen and Bowman's space and variable inflammatory
infiltration. Osteosclerosis was also reported at increased incidences
in high-dose males and females. A NOEL was not established for
nephropathy in female mice (NTP, 1988).
In a review and evaluation of the NTP study, it was concluded
that the proliferative changes in the adrenal medulla were unlikely to
be due to treatment with 4-hexylresorcinol since (a) undiagnosed
medullary hyperplasia was detected in 4 vehicle control animals, (b)
questionable diagnosis between focal hyperplasia and phaeochromocytoma
in some cases and (c) there were no observations supportive of
progression since the only malignant phaeochromocytoma occurred in the
low-dose group and bilateral lesions occurred primarily in the
low-dose group. It was also claimed that the statistically positive
trend in incidence of phaeochromocytomas was borderline and incidences
were within the historical control range (Sauer, 1990; ENVIRON, 1990).
With regard to the tumours of the Harderian gland, all 8 were
considered to be adenomas, compared to the diagnosis of 6 as
carcinomas by the study pathologists (Sauer, 1990).
2.2.3.2 Rats
A carcinogenicity study was conducted with F344/N rats in which
groups of 50 rats of each sex were given 4-hexylresorcinol at dose
levels of 0 (vehicle control), 63 or 125 mg/kg bw/day by oral gavage
in corn oil (10 ml/kg bw), 5 days/week, for 103 weeks. The rats were
6-7 weeks of age when administration of the test compound commenced.
The animals were observed twice daily and body weights were recorded
weekly for 13 weeks and monthly thereafter. Necropsy was performed on
all animals at termination and, where possible, those dying on test.
Complete histological examinations were performed on all rats of the
control and high-dose groups; limited examinations were conducted on
the low-dose animals involving liver, kidneys, lungs, spleen, from
both sexes, and adrenal, pancreas and thyroid from males only.
Table 2. Proliferative changes in adrenal and Harderian glands of
male mice treated with 4-hexylresorcinol (NTP, 1988)
Control 63 mg/kg bw/day 125 mg/kg
bw/day
Adrenal
Focal hyperplasia
overall rate 5/50 (10%) 16/50 (32%) 10/49
(20%)
Phaeochromocytoma1
overall rate 1/50 (2%) 2/50% (4%) 5/49 (10%)
adjusted rate 2.8% 4.7% 15.4%
Harderian gland
Adenoma
overall rate 0/50 (0%) 1/50 (2%) 1/50 (2%)
Carcinoma
overall rate 0/50 (0%) 4/50 (8%) 2/50 (4%)
adjusted rate 0.0% 13.5% 6.7%
Adenoma + Carcinoma2
overall rate 0/50 (0%) 4/50 (8%) 3/50 (6%)
adjusted rate 0.0% 13.5% 10.0%
1 Historical incidence of phaeochromocytomas or malignant
phaeochromocytomas (combined) in
NTP studies = 1 ± 2%
2 Historical incidence in NTP studies = 4 ± 3%
Mean body weights in high-dose males were 7-11% lower than
controls throughout the study; mean body weights of low-dose male and
treated females of both groups were similar to controls. No
compound-related clinical signs were noted and there no significant
differences in survival between any group of either sex although a
number of females (3 control, 8 low-dose and 14 high-dose) died during
the first year before they were at risk of developing tumours. The
tumour incidences did not provide evidence of carcinogenicity of
4-hexylresorcinol in rats. There was a marginal increase in the
adjusted rates of adenomas and of combined adenomas and carcinomas in
the anterior pituitary gland of female rats but this reflected the
early deaths in the high-dose group and was not considered by the
authors to be of biological significance since these tumours occur
commonly with a variable incidence in female F344/N rats. Two
astrocytomas and an oligodendroglioma were observed in 3 high-dose
males, a glioma in 1 low-dose male, and an oligodendroglioma in 1
control male. The high-dose incidence was not statistically
significantly different from controls and the neoplasms were detected
only by microscopic examination; these neoplasms were not considered
to be related to 4-hexylresorcinol administration. Negative trends
were observed with respect to incidences of mononuclear cell leukaemia
in male and female rats and of thyroid C-cell neoplasms in males; the
incidences of pancreatic islet cell adenomas, mammary gland fibromas
and endometrial stromal polyps were also reduced. No significant
treatment-related non-neoplastic changes were seen in rats of either
sex (NTP, 1988).
2.2.4 Reproductive toxicity studies
No data available
2.2.5 Special studies on teratogenicity
No data available.
2.2.6 Special studies on genotoxicity
The results of genotoxicity studies on 4-hexylresorcinol are
summarized in Table 3.
In a review classifying chemicals according to their structure,
mutagenicity and level of carcinogenicity, it was concluded that
4-hexylresorcinol did not have a structure that was classified as
"alerting" and was not mutagenic, however only data from the
Salmonella typhimurium assay were considered (Ashby et al., 1989).
2.2.7 Special studies on delayed contact sensitization
4-hexylresorcinol did not induce delayed contact sensitivity in
male Hartley strain guinea-pigs sensitized by the cutaneous route
(Baer et al. 1966).
2.2.8 Special studies on spermicidal activity
In an assay in which spermicidal activity was assayed by
titration against human spermatozoa using a cytoplasmic stripping
end-point, 4-hexylresorcinol was characterized as a potent spermicide
(Brotherton, 1977).
2.3 Observations in humans
The probable oral LD50 of 4-hexylresorcinol in humans has been
estimated to be between 500 and 5000 mg/kg bw (Gosselin et al.,
1984).
Table 3. Results of genotoxicity studies on 4-hexylresorcinol
Test system Test object Concentration of Results Reference
hexylresorcinol
Ames test S. typhimurium 0-30 µg/plate Negative1 Cortinas de Nava
TA98, TA100, et al,, 1983
TA1535, TA1537,
TA 1538
Ames test S. typhimurium 0.3-333 µg/plate Negative1,2 Mortelmans et al.,
TA98. TA100, 1986
TA1535, TA1537
E. coli E.coli W3110 pol 20-60 nmol/plate Positive1,4 Espinosa-Aguirre
pol A+/pol A+/p3478 pol A- 3000 µg/disc et al, 1987
A- assay
Mammalian cell Mouse L5178Y 1.25-40 µg/ml Negative1 National
mutation lymphoma cells Toxicology
(trifiuorothymidine Program, 1988
resistance)
Sister chromatid Chinese hamster 5-50 µg/ml Positive1,3 National
exchange ovary cells Toxicology
Program, 1988
Chromosomal Chinese hamster 5-50 µg/ml Negative1 National
aberrations ovary cells Toxicology
Program, 1988
1 with and without metabolic activation
2 toxicity at or above 100 µg/plate
3 negative in the presence of S9 mix
4 positive in disc diffusion and liquid suspension assays, negative in microsuspension assay
Adverse acute effects reported to occur following exposure to
high levels of 4-hexylresorcinol include irritation and erosion of
gastric and intestinal mucosa, respiratory mucosa, and skin (Gosselin
et al., 1984; Gilman et al., 1985; Hoover, 1975).
A patient with contact dermatitis following occupational exposure
reacted strongly to 4-hexylresorcinol in a patch test at 48 and 72
hours; 20 controls were all negative. The patient did not cross-react
with resorcinol (Burrows & Irvine, 1982).
In a study of cross-reactivity in patients with resorcinol-
induced dermatitis, 2 out of 8 subjects reacted positively to
4-hexylresorcinol in patch tests; a further 3 responded with one-degree
irritation and 2 were negative (Keil, 1962).
Negative reports have been published for teratogenic activity of
4-hexylresorcinol anthelmintic use (Heinonen et al., 1977, cited in
Schardein, 1985) but no details were available.
No specific epidemiological studies have been conducted to
investigate the relationship between 4-hexylresorcinol exposure and
carcinogenicity in humans but in relation to its use in antiseptic
mouthwashes, a retrospective study in women did not demonstrate an
association between daily mouthwash use and oral cancer
(Wynder et al., 1983).
3. COMMENTS
The Committee noted that toxicological information on this
substance was limited, but recent 13-week and 2-year carcinogenicity
studies in mice and rats were available. Nephrotoxicity was reported
in mice in both the 13-week and 2-year carcinogenicity studies, female
mice being affected at all dose levels. In the 2-year carcinogenicity
study in mice, the lowest dose tested, 63 mg/kg bw/day, caused a high
incidence of nephropathy. Nephrotoxicity was not reported in rats and
4-hexylresorcinol was not carcinogenic in either mice or rats.
4. EVALUATION
On the basis of the available data in animals, the Committee was
unable to establish a numerical ADI but concluded that the treatment
of crustaceans at concentrations of up to 50 mg/litre, resulting in
residue levels of approximately 1 mg/kg in the edible portion, was not
of toxicological concern.
The Committee emphasized that, for more extensive use or higher
levels of application, further toxicological data would be required,
including a long-term toxicity study in mice that establishes a clear
NOEL and the results of reproductive toxicity/teratogenicity studies.
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See Also:
Toxicological Abbreviations