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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

A prenatal toxicity study is available.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because a pre-natal developmental toxicity study is available
Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available

Effects on developmental toxicity

Description of key information

The maternal NOEL of the 1-naphthol was 20 mg/kg bw/day because of a significant incidence of chromorhinorrhea, dilated pupils and lacrimation of some animals in the 100 mg/kg bw/day group. The developmental NOAEL was set at 400 mg/kg bw/day, the highest dose applied.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1998
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose:
reference to other study
Remarks:
The 1998 study is a Dose Range Finding study where the three doses are selected
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Test substance RE-1141.02 (equivalent to 1-naphthol) ; Batch 02 (crystal)
- Expiration date of the lot/batch: No Data
- Purity test date: No Data
- Purity Test : 99.7%

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temperature
- Stability under test conditions: Yes
- Solubility and stability of the test substance in the solvent/vehicle: Yes

TREATMENT OF TEST MATERIAL PRIOR TO TESTING No

FORM AS APPLIED IN THE TEST : liquid
Species:
rat
Strain:
Sprague-Dawley
Remarks:
CRL:CD(SD)BR VAF/Plus
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc, Portage, Michigan, USA
- Age at study initiation: 73 days
- Weight at study initiation: 224 - 267 g (female) and 513 - 872 g (male)
- Fasting period before study: No data
- Housing: individual
- Diet :ad libitum (certified rodent diet#5002 PMI Nutrition International, St Louis, Missouri, USA) and analyses were routinely performed by the feed supplier.
- Water: ad libitum (tap water -reverse osmosis membrane) and the processed water is analyzed twice annually.
- Acclimation period: Yes

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 to 26°C
- Humidity (%): 30% to 70%
- Air changes (per hr): ten changes per hour
- Photoperiod (hrs dark / hrs light): 12h light /12h dark
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
0.5%
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

VEHICLE
- Justification for use and choice of vehicle (if other than water): -
- Concentration in vehicle: 20, 100, 400 mg/kg/day
- Amount of vehicle (if gavage): 10 ml/kg bw adjusted daily on the basis of the individual body weight
- Lot no.: 32H0921
- Purity: No informaton of any potential contaminants (that would interfere with the results of this study.)
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
All levels (first and last preparation). All the conclusions indicate that the formulations were prepared correctly and are homogeneous.
Details on mating procedure:
- Impregnation procedure: cohoused
- M/F ratio per cage: 1/1
- Length of cohabitation: max 5 days
- Further matings after two unsuccessful attempts: No Data
- Verification of same strain and source of both sexes No data
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
10 days (DG 7 to DG 17)
Frequency of treatment:
Once daily on days 7 through 17 of presumed gestation
Duration of test:
Approximately 4 weeks
Dose / conc.:
20 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
400 mg/kg bw/day (nominal)
No. of animals per sex per dose:
25 per dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: on the basis of a dosage-range study
- Other:
The rats were intubated once daily at approximately the same time each day. The oral (gavage) route was selected for use because in comparison with the dietary route, the exact dosage can be accurately administered; and it allows the systemic toxic potential of the test article to be fully characterized.
All rats were sacrificed by carbon dioxide asphyxiation on DG 20
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice each day of the study. The rats were also examined for clinical observations of effects of the test article, abortions, premature deliveries and deaths before and approximately 30 minutes (± 10 minutes) after dosage (DGs 7 through 17) and once daily during the postdosage period (DGs 18 through 20)

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice each day of the study. The rats were also examined for clinical observations of effects of the test article, abortions, premature deliveries and deaths before and approximately 30 minutes (± 10 minutes) after dosage (DGs 7 through 17) and once daily during the postdosage period (DGs 18 through 20)

BODY WEIGHT: Yes
- Time schedule for examinations: recorded on D0 and daily during the dosage and post-dosage periods.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes (DG 0, 7, 10, 12, 15, 18 and 20)
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
- Time schedule for examinations: No data

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #20
- Organs examined: thoracic, abdominal and pelvic viscera
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes[all per litter]
- Soft tissue examinations: Yes: [half per litter]
- Skeletal examinations: Yes: [half per litter]
- Head examinations: No
Statistics:
Clinical observation and other proportion data were analyzed using the Variance Test for Homogeneity of the Binomial Distribution

Continuous data were analyzed using Bartlett's Test of Homogeneity of Variances and the Analysis of Variance when appropriate.when appropriate. If the Analysis of Variance was significant (p≤0.05), Dunnett's Test was used to identify the statistical significance of the individual groups. If the Analysis of Variance was not appropriate, the Kruskal-Wallis Test was used, when lessthan or equal to 75% ties were present. In cases where the Kruskal-Wallis Test was statistically significant (p≤0.05), Dunn's Method of Multiple Comparisons was used to identify the statistical significance of the individual groups. If there were greater than 75% ties, Fisher's Exact Test was used to analyze the data.

Count data obtained at Caesarean-sectioning of the dams were evaluated using the procedures described above for the Kruskal-Wallis Test
Historical control data:
Yes (june 1995 - June 1997) - 97 studies
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Statistically significant numbers of rats (p<0.01) in the 400 mg/kg bw/day dosage group had excess salivation, dilated pupils, decreased motor activity, ataxia, impaired righting reflex, lacrimation, lost righting reflex, lethargy, red, brown or orange perioral substance, urine stained abdominal fur, rales, chromorhinorrhea, twitches, body jerks and brown perinasal substance.
Additionally, dilated pupils, lacrimation, brown perioral substance and chromorhinorrhea occurred in one to five rats in the 100 mg/kg bw/day dosage group (p<0.05); the incidence of chromorhinorrhea was statistically significant.
All other adverse clinical signs were considered unrelatated to the test article.
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weight gains were significantly reduced for the entire dosage period (DG 7 to 18), the gestation period after the initiation of dosing (DG 7 to 20) and the entire gestation period (DG 0 to 20) in the 400 mg/kg bw/day group.
Maternal body weights were significantly reduced (p<0.05 or p<0.01) on DG 10 and 12 through 20, compared to the control group.

Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Absolute (g/day) and relative (g/kg/day) feed consumption values were significantly reduced (p≤0.05 or p≤0.01) on DGs 7 to 10, 10 to 12, 12 to 15 and 15 to 18 in the 400 mg/kg/day dosage group, as compared with the control group values. Significantly increased (p≤0.01) relative feed consumption values occurred in the 400 mg/kg/day dosage group during the postdosage period (DGs 18 to 20), rebound phenomena that commonly occur in these types of studies. Reflecting these events, the 400 mg/kg/day dosage group had significantly reduced (p≤0.01) absolute and relative feed consumption values for the entire dosage period (calculated as DGs 7 to 18), the entire period of gestation after the initiation of dosing (DGs 7 to 20), and the entire gestation period (DGs 0 to 20; absolute only). Feed consumption values were unaffected by the 100 mg/kg/day dosage of the test article.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not examined
Description (incidence and severity):
No gross lesions were identified at necropsy that was considered treatment related.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Number of abortions:
not examined
Pre- and post-implantation loss:
not examined
Total litter losses by resorption:
not examined
Early or late resorptions:
not examined
Dead fetuses:
not examined
Changes in pregnancy duration:
not examined
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not examined
Changes in number of pregnant:
not examined
Other effects:
not specified
Key result
Dose descriptor:
NOEL
Effect level:
ca. 20 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
clinical signs
Key result
Abnormalities:
not examined
Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
Average foetal body weights were reduced by 4% as compared to controls in the 400 mg/kg bw/day dosage group; these reductions were significant (p<0.05) for total and female foetal body weights.
This decrease in fetal weight, although within historical ranges of the Testing Facility, may have been treatment-related because there was evidence of maternal toxicity at this same dosage (significant decreases in maternal weight and feed consumption values).However, no other Caesarean-sectioning or litter parameters were affected by administration of the test article to the dams at dosages as high as 400 mg/kg/day. This includes a lack of typical changes in skeletal ossification that are indicative of developmental delay and which would have been expected to accompany significant fetal weight decrements.
Furthermore, the magnitude of the weight reduction is at the limit of statistical ascertainment for this endpoint on this study (typically 5%).
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined
Reduction in number of live offspring:
not examined
Changes in sex ratio:
not examined
Changes in litter size and weights:
not examined
Changes in postnatal survival:
not examined
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
A depressed eye bulge occurred in three 100 mg/kg/day dosage group fetuses from two litters (4954-10; 4971-6,-12). Visceral examination of these fetuses revealed associated microphthalmia of the left or right eye. The significant increase (p≤0.01) in the fetal incidence of this malformation was considered unrelated to the test article because: 1) it was not dosage-dependent; and 2) the litter incidence, the more relevant parameter(1), was not significant.
Skeletal malformations:
not examined
Visceral malformations:
not examined
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
The umbilical artery descended to the left of the urinary bladder in one control group fetus and four 100 mg/kg/day dosage group fetuses. The significant increases (p≤0.01) in the fetal and litter incidences of this alteration were considered unrelated to the test article because they were not dosage-dependent. No additional alterations occurred in these fetuses.
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 400 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
changes in litter size and weights
Key result
Abnormalities:
not examined
Key result
Developmental effects observed:
no

Summary of Fetal Alterations

In the 0 (Vehicle), 20, 100 and 400 mg/kg/day dosage groups, litters with fetuses with any alteration numbered 5 (21.7%), 3 (12.0%), 11 (44.0%) and 9 (36.0%), respectively. The numbers of fetuses with any alteration observed were 8 (2.4%), 3 (0.9%), 17 (4.6%)* and 14 (3.7%), and the percentages of fetuses per litter with any alterations were 2.64%, 1.57%, 4.43% and 3.76% in the four dosage groups, respectively. All fetal alterations were considered unrelated to the test article because the incidences: 1) were not dosage-dependent; and/or 2) were within the ranges observed historically at the Testing Facilitya. The statistically significant increase (p≤0.05) in fetuses with any alterations in the 100 mg/kg/day dosage group reflected the significantly increased (p≤0.01) number of fetuses and litters with umbilical artery descending to the left of the urinary bladder, the number of fetuses with microphthalmia and the number of fetuses with hypoplastic ribs.

* Significantly different from the vehicle control group value (p≤0.05).

Caesarean-Sectioning and Litter Observations summaries

Caesarean-sectioning observations were based on 23 (92%), 25 (100%), 25 (100%) and 25 (100%) pregnant rats with live litters in the four respective dosage groups. One litter in the 20 mg/kg/day dosage group (4939) consisted of only four conceptuses. Because such occurrences can abnormally skew the distribution of the data(19), statistical analyses were made without the values for this dam and litter.

Average fetal body weights were reduced by 4% as compared to controls in the 400 mg/kg/day dosage group; these reductions were significant (p≤0.05) for total and female fetal body weights. This decrease in fetal weight, although within historical ranges of the Testing Facilitya, may have been treatment-related because there was evidence of maternal toxicity at this same dosage (significant decreases in maternal weight and feed consumption values). However, no other Caesarean-sectioning or litter parameters were affected by administration of the test article to the dams at dosages as high as 400 mg/kg/day. This includes a lack of typical changes in skeletal ossification that are indicative of developmental delay and which would have been expected to accompany significant fetal weight decrements. Furthermore, the magnitude of the weight reduction, 4%, is at the limit of statistical ascertainment for this endpoint in this study (typically 5%). The litter averages for corpora lutea, implantations, litter sizes, live fetuses, early and late resorptions, percent resorbed conceptuses, and percent live male fetuses were comparable among the four dosage groups and did not significantly differ. No dam had a litter consisting of only resorbed conceptuses, and there were no dead fetuses; all placentae appeared normal.

Conclusions:
The maternal NOEL of 1-naphthol was 20 mg/kg bw/day because of a significant incidence of chromorhinorrhea, dilated pupils and lacrimation of some animals in the 100 mg/kg bw/day group. The developmental NOAEL was set at 400 mg/kg bw/day, the highest dose applied.
Executive summary:

Twenty-five pregnant female rats were assigned to each of four dosage groups. The test substance or aqueous 0.5% carboxymethylcellulose (control) was administered via gavage once daily on days 7 through 17 of presumed gestation. Vehicle and dosages of 20, 100, and 400 mg/kg bw/day were administered daily. Animals were observed for viability at least twice each day of the study. Body weights were recorded daily during the dosage and postdosage periods and feed consumption values were recorded. All rats were sacrificed by carbon dioxide asphyxiation on day 20, and a gross necropsy of the thoracic, abdominal and pelvic viscera was performed. The number of corpora lutea in each ovary was recorded. The uterus of each rat was examined for pregnancy, number and distribution of implantations, live and dead foetuses and early and late resorptions. Each foetus was identified, weighed and examined for sex and gross external alterations. Approximately one-half of the foetuses in each litter were examined for soft tissue alterations and the remaining foetuses in each litter examined for skeletal alterations.

Results: No deaths, abortions or premature deliveries occurred during this study. Statistically significant numbers of rats in the 400 mg/kg bw/day dosage group had excess salivation, dilated pupils, decreased motor activity, ataxia, impaired righting reflex, lacrimation, lost righting reflex, lethargy, red, brown or orange perioral substance, urine stained abdominal fur, rales, chromorhinorrhea, twitches, body jerks and brown perinasal substance. Additionally, dilated pupils, lacrimation, brown perioral substance and chromorhinorrhea occurred in one to five rats in the 100 mg/kg bw/day dosage group; the incidence of chromorhinorrhea was statistically significant. No gross lesions were identified at necropsy that was considered treatment related. Body weight gains and absolute and relative feed consumption values were significantly reduced for the entire dosage period in the 400 mg/kg bw/day group. Maternal body weights were significantly reduced compared to the control group. Average foetal body weights were reduced by 4% as compared to controls in the 400 mg/kg bw/day dosage group; these reductions were significant for total and female foetal body weights. No other Caesarean-sectioning or litter parameters were affected by exposure to the test substance to the dams at dosages as high as 400 mg/kg bw/day. (No typical changes in skeletal ossification those are indicative of developmental delay and which would have been expected to accompany significant foetal weight decrements). The slight foetal body weight reduction might be influenced by maternal toxicity.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
400 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Klimisch 1
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

On the basis of the data, the 1-naphthol is not classified.