Registration Dossier

Administrative data

Description of key information

Based on effects on kidneys and forestomach, a No Observed Adverse Effect Level (NOAEL) for naphthalene-1,5-diol of 50 mg/kg/day was established (oral route, 90 days).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2004-06-24 to 2005-01-27
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Version / remarks:
September 1998
Deviations:
yes
Remarks:
The study integrity was not adversely affected by the deviations.
Qualifier:
according to
Guideline:
EU Method B.26 (Sub-Chronic Oral Toxicity Test: Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Version / remarks:
August 2001
Deviations:
yes
Remarks:
The study integrity was not adversely affected by the deviations.
Qualifier:
according to
Guideline:
EPA OPPTS 870.3100 (90-Day Oral Toxicity in Rodents)
Version / remarks:
August 1998
Deviations:
yes
Remarks:
The study integrity was not adversely affected by the deviations.
GLP compliance:
yes (incl. certificate)
Limit test:
no
Specific details on test material used for the study:
Test Substance Preparation
Vehicle: Propylene glycol, specific gravity 1.036
Rationale for vehicle: Based on trial formulations performed at NOTOX.
Stability in vehicle: At least 7 days in the refrigerator (determined at NOTOX).
Method: Formulations (w/w) were prepared daily within 4 hours prior to dosing, and were homogenised to visually acceptable levels. From day 36 onwards, formulations were prepared for dosing on the subsequent 6 or 7 days, except for days 42, 77 (group 2) and 92 when formulations were prepared on the day of dosing. Adjustment was made for specific gravity of the vehicle.
Storage conditions: Formulations prepared on the day of dosing were stored at ambient temperature. Formulations prepared for dosing on subsequent days were stored in the refrigerator.
Stability in vehicle Propylene glycol: at least 4 hours.
Species:
rat
Strain:
Wistar
Details on species / strain selection:
Rat: Wistar Crl:(WI) BR (outbred. SPF-Quality) Recognised by international guidelines as the recommended test system (e.g. EPA. FDA. OECD. EEC). Females were nulliparous and non-pregnant.
Sex:
male/female
Details on test animals and environmental conditions:
Test System
Rat: Wistar Crl:(WI) BR (outbred, SPF-Quality) Recognised by international guidelines as the recommended test system (e.g. EPA. FDA. OECD, EEC). Females were nulliparous and non-pregnant.
Source: Charles River Deutschland, Sulzfeld, Germany

Age at Start of Treatment
Approximately 6 weeks.

Number of animals
58 males, 58 females

Randomisation
By computer-generated random algorithm according to body weight, with all animals within ± 20% of the sex mean. A health inspection was performed prior to commencement of treatment to ensure that the animals were in a good state of health.

Identification
Earmark and tattoo

Animal Husbandry

Conditions
Animals were housed in a controlled environment, in which optimal conditions were considered to be approximately 15 air changes per hour, a temperature of 21.0 ± 3.0°C (actual range: 17.3
- 24.9°C), a relative humidity of 30-70% (actual range: 30 - 100%) and 12 hours artificial fluorescent light and 12 hours darkness per day. Temporary fluctuations from the ligh/dark cycle (with a maximum of 1 hour) occurred due to performance of functional observations in the room. Based on laboratory historical data, these fluctuations were considered not to have affected the study integrity.

Accommodation
Group housing of 4 animals per sex (main groups) or 5 animals per sex (recovery groups) in stainless steel suspended cages with wire mesh floors (55 x 34 x 21.5 cm height).
Acclimatisation period was at least 5 days before start of treatment under laboratory conditions. During activity monitoring, animals were individually housed overnight in Macrolon plastic cages (type Ill, height 15 cm.) with sterilised sawdust (Woody-Clean type 3/4, Tecnilab-BMI BV, Someren, The Netherlands) provided as bedding. Results of bedding analyses for contaminants are examined and archived.

Diet
Free access to standard pelleted laboratory animal diet (from Altromin (code VRF-1, Lage.Germany). Each batch is analysed for nutrients and contaminants are analysed on a regular basis. Results are examined and archived.

Water
Free access to tap water. Certificates of analysis (performed quarterly) were examined and archived.

Results of analysis for ingredients and/or contaminants of bedding, diet and water were assessed and did not reveal any findings that were considered to have affected study integrity.
Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on oral exposure:
A health inspection was performed prior to commencement of treatment to ensure that the animals were in a good state of health.

Method
Oral gavage, using a stainless steel stomach tube. Formulations were placed on a magnetic stirrer during dosing.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Chemical Analysis of Dose Preparations

Samples of formulations prepared for use on days 1, 36 and 85 were analysed to check homogeneity and/or accuracy of preparation (all concentrations). Stability in vehicle over 7 days in the refrigerator was also determined (highest and lowest concentration).

Day of preparation Group Analysis (type of sample)
1 acc (M)
3 acc+ hom (TMB) + stab(t=0) (TMB), stab(t=7), refrigerator (M)
4 acc (M)
36 1 acc(M)
2 acc+ hom (TMB)+ stab(t=0) (TMB), stab(t=7), refrigerator (M)
3 acc(M)
4 acc + hom (TMB) + stab(t=0) (TMB), stab(t=7), refrigerator (M)
85 1 acc(M)
2 acc + hom (TMB)
3 acc(M)
4 acc+ hom (TMB)
Duplicate samples were analysed
acc=accuracy, hom=homogeneity, stab=stability (days),
T=top, M=middle, B=bottom position of container

The analytical method used was based on the results of a separate project for the development and validation of the analytical method (NOTOX project 409567).
Duration of treatment / exposure:
At least 90 days.

Recovery
At least 28 days.
Frequency of treatment:
Frequency
Once daily for at least 90 days, 7 days per week, approximately the same time each day with a maximum of 4 hours difference between the earliest and latest dose. Animals were dosed up to the day prior to necropsy.
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
12 animals per sex and dose, 5 per sex in recovery groups
Control animals:
yes, concurrent vehicle
Details on study design:
Wistar rats were treated with 1,5-naphthalenediol for at least 90 days by oral gavage at dose levels up to 300 mg/kg bw/day, followed by a 28-day treatment-free recovery period.
Mortality and viability were checked at least twice daily.
Clinical observations were made in all animals once daily.
During week 12-13 of treatment functional observation tests were performed including hearing ability, pupillary, static righting and grip strength reflex test and motor activity test
Ophthalmoscopic examinations were conducted at pre-test with all animals and at week 13 with controls and the 300 mg/kg dose group.
Body weight and food consumption were monitored weekly.
blood samples were collected for clinical laboratory investigations immediately prior to scheduled post mortem examination and the common parameters were determined.
Positive control:
no
Observations and examinations performed and frequency:
Mortality / Viability
At least twice daily. Animals showing pain, distress or discomfort, which was considered not transient in nature or was likely to become more severe, were sacrificed for humane reasons based on OECD guidance document on humane endpoints (ENV/JM/MONO/ 2000/7). The time of death was recorded as precisely as possible.

Clinical signs
At least once daily, detailed clinical observations were made in all animals. Once prior to start of treatment and at weekly intervals during treatment (and also on days 9 and 20 of the recovery period), this was also performed outside the home cage in a standard arena. The time of onset, degree and duration were recorded.
All symptoms were recorded and graded according to fixed scales: Maximum grade 1: grade O = absent, grade 1 = present
Maximum grade 3 or 4: grade 1 = slight, grade 2 = moderate, grade 3 = severe, grade 4 = very severe

Functional Observations
During week 12-13 of treatment, the following tests were performed on all animals of the recovery groups and on all animals of the first cage of each main group allocation:
hearing ability pupillary reflex static righting reflex grip strength
motor activity test (recording period: 12 hours during overnight for individual animals, using a computerised monitoring system, Pearson Technical Services, Debenham, Stowmarket, England).
Based on the initial motor activity results, an additional motor activity measurement was performed in week 13 for animal nos. 26-29, 41-44, 96-99 and 111-114.

Ophthalmoscopic Examination (direct)
Following instillation of tropicamide solution (5 mg/ml), both eyes were examined by means of an ophthalmoscope (Heine Beta 200): at pretest : All animals at week 13 : Groups 1 and 4

Body weights
Weekly.

Food consumption
Weekly.

Water consumption
Subjective appraisal was maintained during the study, but no quantitative investigation introduced as no effect was suspected.
Sacrifice and pathology:
Clinical Laboratory Investigations
Blood sam pies were collected under iso-f1urane anaesthesia immediately prior to scheduled post mortem examination, between 7.00 and 10.30 a.m. The animals were fasted overnight (with a maximum of 20 hours) before blood sampling, but water was provided. Blood sampies were drawn from the retro-orbital sinus of aJl rats/sexigroup and coJlected into tubes prepared with EDTA for haematological parameters (0.5 ml), with citrate for cJotting tests (1.0 ml) and Liheparin
treated tubes for clinical biochemistry parameters (0.5 ml).

Necropsy
All animals surviving to the end of the observation period and all moribund animals were deeply anaesthetised using iso-flurane and subsequently exsanguinated. All animals assigned to the study were necropsied and descriptions of all macroscopic abnormalities recorded. Samples of the following tissues and organs were collected from all animals at necropsy and fixed in a neutral phosphate buffered 4% formaldehyde solution:
Identification marks: not processed Adrenal glands
Aorta
Brain
(cerebellum, mid-brain, cortex)
Caecum
Cervix
(Clitoral gland)
Colon
Duodenum
Epididymides
(Eyes with optic nerve and Harderian gland)
Female mammary gland area
(Femur including joint)
Heart
Ileum
Jejunum
Kidneys
(Larynx)
(Lacrimal gland, exorbital)
Liver
Lung, infused with formalin
Lymph nodes - mandibular, mesenteric
(Nasopharynx)
Oesophagus
Ovaries
Pancreas
Peyer's patches (jejunum, ileum) if detectable
Pituitary gland
(Preputial gland)
Prostate gland
Rectum
Salivary glands - mandibular, sublingual
Sciatic nerve
(Seminal vesicles) (Skeletal muscle) (Skin)
Spinal cord -cervical, midthoracic, lumbar Spleen
Sternum with bone marrow
Stomach
Testes
Thymus
Thyroid including parathyroid
(Tongue)
Trachea
Urinary bladder
Uterus
Vagina
All gross lesions
Tissues mentioned within brackets were not examined microscopically as there were no signs of toxicity or target organ involvement

Organ Weights
The following organ weights and terminal body weight were recorded from the surviving animals on the scheduled day of necropsy:
Adrenal glands
Brain
Epididymides
Heart
Kidneys
Liver
Ovaries
Spleen
Testes
Thymus
Uterus
Histotechnology
All organ and tissue sampies, as defined under Histopathology (following), were processed, embedded and cut at a thickness of 2-4 micrometers and stained with haematoxylin and eosin.

Histopathology
The following slides were examined bya pathologist:
all tissues and organs collected at the scheduled sacrifice from all animals of the control and the highest dose group;
all tissues and organs from all animals of all dose groups which died spontaneously or were sacrificed in extremis;
all gross lesions of all animals;
lungs, liver and kidneys of all animals (all dose groups).
Based on potentially treatment-related morphologie changes, the stomach was also examined from all rats of the intermediate dose groups and from recovery group animals. All abnormalities were described and included in the report. Tissues mentioned within brackets in the list of organs/tissues on page 14 (6.8.1. Necropsy) were not examined as there were no signs of toxicity or target organ involvement. An attempt was made to correlate gross observations with microscopic findings.
Statistics:
The following statistical methods were used to analyse the data:

- If the variables could be assumed to follow a normal distribution, the Dunnett-test1 (many-to­ one t-test) based on a pooled variance estimate was applied for the comparison of the treated groups and the control groups for each sex.
- The Steel-test2 (many-to-one rank test) was applied when the data could not be assumed to follow a normal distribution.
- The exact Fisher-test 3 was applied to frequency data.

All tests were two-sided and in all cases p < 0.05 was accepted as the lowest level of significance. Group means were calculated for continuous data and medians were calculated for discrete data (scores) in the summary tables. Test statistics were calculated on the basis of exact values for means and pooled variances. Individual values, means and standard deviations may have been rounded off before printing. Therefore, two groups may display the same printed means for a given parameter, yet display different test statistics values.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Purple urine was observed among all groups dosed with the test substance, which had resolved with discontinuation of treatment.

Other findings are occasionally noted in rats of this age and strain which are housed and treated under the conditions in this study. Also, the incidence of these observations was not related to the dose. Therefore, these were considered signs of no toxicological significance.
Mortality:
mortality observed, treatment-related
Description (incidence):
One high dose male (no. 62) was found dead on day 65, while another high dose male (no. 52) died at scheduled blood sampling. Three high dose females (nos. 122, 131 and 132) were found dead on days 60, 6, and 67 respectively.
One control female (no. 84) was killed moribund on day 86. Moribundity probably resulted from broken upper incisors, with consequent weight loss. All other rats survived the scheduled duration of the study.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Body weights and body weight gain of treated animals remained in the same range as controls over the study period.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
Food consumption before or after allowance for body weight was similar between treated and control animals throughout the study period.
Statistically significant changes in (relative) food intake during the study were considered to be incidental in nature and of no toxicological relevance
Ophthalmological findings:
no effects observed
Description (incidence and severity):
There were no ophthalmology findings at pretest and in week 13.
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Haematological parameters of treated rats were considered not to have been affected by treatment.
All statistically significant deviations from control mean showed no relationship to dose and were considered to be incidental in nature.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
The following statistically significant deviations in clinical biochemistry parameters that distinguished treated animals from control animals were considered to be related to treatment:
Increased bilirubin levels in females at 100 mg/kg/day and in males and females at 300 mg/kg/day (p<0.01);
Reduced urea levels in males at 100 and 300 mg/kg/day (p<0.05); Increased glucose levels in males and females at 300 mg/kg/day (p<0.05); Increased potassium levels in males at 300 mg/kg/day (p<0.01);
Increased total protein and albumin levels in females at 300 mg/kg/day (p<0.05 and p<0.01, respectively);
Reduced aspartate aminotransferase activity in females at 300 mg/kg/day (p<0.05). These changes had resolved at the end of the recovery period, whilst increased inorganic phosphate levels were recorded for high dose females (p<0.01).
The lower statistically significant inorganic phosphate level of males at 100 mg/kg/day occurred in the absence of a dose-related response, and was therefore not relevant in toxicological terms.
Behaviour (functional findings):
effects observed, non-treatment-related
Description (incidence and severity):
Hearing ability, pupillary reflex, static righting reflex and grip strength were normal in all animals.
Variations noted in motor activity data between treated and control animals occurred in the absence of a dose-related response and supportive clinical signs. Therefore, they were considered to be of no toxicological relevance
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
At the end of treatment, increased absolute kidney weights (p<0.05) and kidney to body weight ratios (p<0.01) were measured for high dose males (p<0.05). In addition, absolute liver weights were increased in high dose females (p<0.01), while liver to body weight ratios were increased in high dose males (p<0.05) and females (p<0.01). These deviations had resolved at the end of the recovery phase.
The lower, statistically significant, absolute brain weight of males at 100 mg/kg/day was considered to be of no toxicological relevance, since a relation to the dose was absent.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Black discolouration of the kidneys was recorded in all surviving animals at 300 mg/kg/day, and in 6/12 males at 100 mg/kg/day at the end of the treatment phase. Thickening of the limiting ridge of the stomach was noted in 8/12 males and 5/11 females at 300 mg/kg/day, 4/12 males at 100 mg/kg/day and 1/12 males at 50 mg/kg/day at the end of treatment. Thickening of the glandular mucosa was additionally noted in the high dose male that was found dead on day 65. At the end of the recovery phase, greenish discolouration of the kidneys was noted in 2/5 males and 1/5 females previously exposed to 300 mg/kg/day.
One female (no. 131) found dead on day 6 showed fluid in the thoracic cavity, which may possibly indicate a misgavage. The remainder of the macroscopic findings recorded are occasionally seen among (decadent) rats in these types of studies and occurred in the absence of a treatment-related distribution.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
The following microscopic findings were noted that distinguished treated from control animals at the end of treatment:
Brown/black tubular pigment in the kidneys (minimal to moderate degree) in 11/12 males and 8/11 females at 300 mg/kg/day and in 5/12 males at 100 mg/kg/day;
Increased severity of hyaline casts was seen in 6/12 males and 2/11 females at 300 mg/kg/day and in 2/12 males and 1/12 females at 100 mg/kg/day;
Increased severity (moderate) of corticomedullary basophilia in 5/12 males at 300 mg/kg/day;
Hyperplasia of the squamous epithelium of the limiting ridge in the stomach (minimal to moderate degree) in 11/12 males and 6/11 females at 300 mg/kg/day and in 3/12 males and 3/12 females at 100 mg/kg/day.
Following the recovery period brown/black tubular pigment in the kidneys was recorded in 2/5 males at 300 mg/kg/day (minimal to slight degree). One male at 300 mg/kg/day had a moderate degree of corticomedullary basophilia. In addition, a minimal or slight degree of squamous hyperplasia was recorded in 2/5 females at 300 mg/kg/day after the recovery period.
All other microscopic findings were within the range of background pathology encountered in Wistar rats of this age and strain and occurred at similar incidences and severity in both control and treated rats.
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
gross pathology
histopathology: non-neoplastic
Critical effects observed:
yes
Lowest effective dose / conc.:
100 mg/kg bw/day (actual dose received)
System:
urinary
Organ:
kidney
Treatment related:
yes
Relevant for humans:
yes
Conclusions:
Wistar rats were treated with naphthalene-1,5-diol for at least 90 consecutive days by oral gavage at dose levels up to 300 mg/kg/day, followed by a 28-day treatment-free recovery period.

Two males and three females at 300 mg/kg/day died during the treatment phase. Misgavage was considered the cause of death for one high dose male based on microscopic assessment and the other high dose male died during blood sampling. Fluid in the thoracic cavity of one high dose female may possibly indicate a misgavage. Although the cause of death was not established for the three high dose females, a relationship to treatment can not be excluded.

A purple discolouration of the urine was noted in all treatment groups, which resolved immediately after discontinuation of treatment. This effect was probably caused by the test substance and/or a test substance metabolite and was not regarded as adverse.

At the end of the treatment period, black discolouration of the kidneys was noted in most animals at 300 mg/kg/day and in six males at 100 mg/kg/day. The morphological correlate was brown/black tubular pigment, which was recorded in eleven males and eight females at 300 mg/kg/day, and in five males at 100 mg/kg/day. Following the recovery period, tubular pigment was still detected in two males previously dosed at 300 mg/kg/day, indicating that these changes had not completely resolved. The severity of hyaline casts was increased in six males and two females at 300 mg/kg/day and in two males and one female at 100 mg/kg/day.
Furthermore, the severity of corticomedullary basophilia was increased in five males at 300 mg/kg/day, and remained increased in one high dose male at the end of the recovery period. Higher kidney weights were recorded in males at 300 mg/kg/day, reflecting the above morphological changes.

In addition, a thickened limiting ridge in the stomach was noted in eight males and five females at 300 mg/kg/day, in four males at 100 mg/kg/day and in one male at 50 mg/kg/day at the end of the treatment period. The morphological correlate was hyperplasia of the squamous epithelium which was noted in eleven males and six females at 300 mg/kg/day, and in three animals of both sexes at 100 mg/kg/day. Following the recovery period, a minimal or slight degree of squamous hyperplasia was still recorded in two females at 300 mg/kg/day, indicating that the lesions had not completely resolved. The limiting ridge hyperplasia probably represented a

response to local irritation to test material residing in the forestomach, and is a commonly observed typical adaptive phenomenon in rodent studies4. This finding is regarded to be of no relevance to man.

Increased liver weights were recorded for males and females at 300 mg/kg/day at the end of treatment, which had resolved at the end of the recovery phase. However, no concurrent morphologic evidence of liver dysfunction was obtained.

The clinical biochemistry deviations noted at the end of the treatment period were probably secondary effects related to target organ toxicity. The higher glucose values at 300 mg/kg/day could reflect stress inflicted by the forestomach lesions. The higher total protein and albumin values recorded in females at 300 mg/kg/day may reflect dehydration. The higher potassium levels recorded in males at 300 mg/kg/day are consistent with impaired kidney function. The increased bilirubin levels in females at 100 mg/kg/day and in males and females at 300 mg/kg/day and reduced urea levels in males at 100 and 300 mg/kg/day may point to perturbations in liver function. The lower aspartate aminotransferase activity in females at 300 mg/kg/day was considered to be of no toxicological relevance. All of these changes had regressed by the end of the recovery period. The higher inorganic phosphate levels recorded for high dose females at the end of recovery were considered to be of uncertain significance in view of absence of evidence of kidney dysfunction at the end of recovery and absence of a similar finding at the end of treatment.

Based on effects on kidneys and forestomach, a No Observed Adverse Effect Level (NOAEL) for naphthalene-1,5-diol of 50 mg/kg/day was established.
Executive summary:

Repeated dose 90-Day oral toxicity study with naphthalene-1,5 -diol by daily gavage in the rat, followed by a 28-day recovery period.

Based on a 28-day range finding study (NOTOX Project 409556), the dose levels for this 90-day oral gavage study were selected to be 0, 50, 100 and 300 mg/kg/day.

The study was based on the following guidelines.

-       EC Directive 67/548/EEC, B Repeated Dose (90 days) Toxicity (oral), 2001.

-       OECD 408, Repeated Dose 90-day Oral Toxicity Study in Rodents, 1998.

-       EPA 712-C-98-199, 90-Day Oral Toxicity in Rodents, 1998.

The test substance was administered daily for at least 90 days by oral gavage to SPF-bred Wistar rats. One control group and three treated groups were tested, each consisting of 12 males and 12 females. An extra 5 animals per sex in the control and high dose group were allowed 28 days of recovery.

The following parameters were evaluated: clinical signs daily; functional observation tests; body weight and food consumption weekly; ophthalmoscopy at pretest and in week 13; clinical pathology and macroscopy at termination; organ weights and histopathology on a selection of tissues.

4.1 Discussion and Conclusion

Five high dose animals died during the treatment phase. Although the cause of death was not established for three high dose females, a relationship to treatment can not be excluded.

Purple discolouration of the urine as noted in all treatment groups was probably caused by the test substance and/or a test substance metabolite and was not regarded as adverse.

Necropsy findings at 300 and 100 mg/kg/day consisted of black discolouration of the kidneys (correlating to brown/black tubular pigment) and thickening of the limiting ridge in the stomach (correlating to hyperplasia of the squamous epithelium), the latter finding being regarded of no relevance to man. No microscopic correlate was found for the thickened limiting ridge in the stomach in a single male at 50 mg/kg/day. In addition, higher kidney weights were recorded in males at 300 mg/kg/day. Other histopathological lesions in the kidneys consisted of an increased severity of hyaline casts and corticomedullary basophilia at 300 and/or 100 mg/kg/day. Following recovery, renal tubular pigment, increased severity of renal corticomedullary basophilia and squamous hyperplasia of the stomach remained present only in a few high dose animals.

The clinical biochemistry deviations noted at the end of the treatment period were probably secondary effects related to target organ toxicity. These deviations included higher glucose,  total protein, albumin, potassium and bilirubin levels, and reduced urea levels at 300 mg/kg/day, and had regressed by the end of the recovery period. At 100 mg/kg/day, increased bilirubin and reduced urea levels were noted. The higher inorganic phosphate levels recorded for high dose females at the end of recovery were considered to be of uncertain significance in view of absence of evidence of kidney dysfunction at the end of recovery and absence of a similar finding at the end of treatment.

No concurrent morphologic evidence of liver dysfunction was obtained for the increased liver weights recorded for males and females at 300 mg/kg/day at the end of treatment.

Based on effects on kidneys and forestomach, a No Observed Adverse Effect Level (NOAEL) for naphthalene-1,5-diol of 50 mg/kg/day was established.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
50 mg/kg bw/day
Study duration:
subchronic
Species:
rat
System:
urinary
Organ:
kidney

Additional information

Justification for classification or non-classification