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Effects on fertility

Link to relevant study records
Reference
Endpoint:
two-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline and GLP study
Qualifier:
according to guideline
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
Version / remarks:
; Other: EPA OPPTS 870.3800
Deviations:
yes
Remarks:
: Minor study deviations were noted however these deviations did not adversly effect the quality or integrity of the data or the study outcome.
GLP compliance:
yes
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Route of administration:
oral: drinking water
Details on mating procedure:
Male: F0: 70 days, F1: 70 days beginning at weaning
Female: F0: 70 days, F1: 70 days beginning at weaning
Duration of treatment / exposure:
70 days prior to mating and throughout mating, gestation and lactation
Frequency of treatment:
Continuous
Details on study schedule:
Duration of test: 18 months

No. of generation studies: 2
Remarks:
Doses / Concentrations:
0, 120, 360, 1000 and 3000 mg/l
Basis:

No. of animals per sex per dose:
30/sex/group
Control animals:
yes, concurrent no treatment
Details on study design:
Four groups of male and female Crl:CD SD rats (30/sex/group) were administered resorcinol in drinking water for at least 70 consecutive days prior
to mating.  Exposure levels were 0, 120, 360, 1000 and 3000 mg/L for the F0 and F1 generations.  The concurrent control group (30/sex/group)
received reversed osmosis purified municipal water.  The test article was administered to the offspring selected to become the F1 parental generation following weaning (post natal day 21).  The F0 and F1 males continued to receive the test article throughout the mating and through the day of
euthanasia. The F0 and F1 females continued to receive the test article throughout mating, gestation, lactation and through the day of euthanasia.
Statistics:
All statistical tests were performed using appropriate computing devices or programs.

Reproductive indices:
Study was conducted to evaluate the potential adverse effects of resorcinol on the reproductive capabilities, including gonadal function, estrous
cyclicity, mating behaviour, conception, gestation, parturition, lactation and weaning of the F0 and F1 generations.
Offspring viability indices:
Study was conducted to evaluate the potential adverse effects of resorcinol on the F1 and F2 neonatal survival, growth and development.
Dose descriptor:
NOAEL
Effect level:
3 000 mg/L drinking water
Sex:
male/female
Basis for effect level:
other: no adverse effects observed in highest dose tested
Dose descriptor:
NOEL
Effect level:
1 000 mg/L drinking water
Sex:
male/female
Basis for effect level:
water consumption and compound intake
Dose descriptor:
NOAEL
Effect level:
3 000 mg/L drinking water
Sex:
male/female
Basis for effect level:
other: no adverse effects observed in highest dose tested
Dose descriptor:
NOEL
Effect level:
1 000 mg/L drinking water
Sex:
male/female
Basis for effect level:
water consumption and compound intake
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
3 000 mg/L drinking water
Sex:
male/female
Basis for effect level:
other: no adverse effects observed in highest dose tested
Reproductive effects observed:
not specified

RM-Freetext:

Although not indicated by the study author, we have concluded that the overall systemic NOEL for males and females is 1000 mg/L based on reduced body weight at 3000 mg/L.

RS-Freetext:

No effects on any of the reproductive parameters

When expressed on a body weight basis (average F0 and F1 animals), the water concentrations corresponded to: approximately 0, 11, 31, 86 and 223 mg/kg/day for males over the entire generation; 16, 48, 126 and 304 mg/kg/day for females during premating and gestation; and 28, 85, 225, and 660 mg/kg/day for females during lactation, respectively.  In offspring (the F1 generation only), the water concentrations corresponded to approximately 0,11,33,93 and 245 mg/kg/day in males while in females 0, 16, 41, 126 and 295 mg/kg/day.

There were no F0 or F1 parental test article-related deaths or clinical findings during the weekly detailed physical examinations. Reproductive performance (estrous cycles, mating and fertility indices, number of days between pairing and coitus, and gestation length) and parturition in the F0 and F1 animals were unaffected by the test article.
  Spermatogenic endpoints (mean testicular and epididymal sperm numbers and sperm production rate, motility, progressive motility and morphology) in the F0 and F1 males were unaffected by the test article. No test article-related effects were observed on F1 and F2 pup survival or the general physical condition of the pups during the pre-weaning period. No test article-related macroscopic findings, organ weight or adverse microscopic target-organ effects were observed in the F0 or F1 parental animals. In addition, no test article-related macroscopic findings or effects on organ weights were noted in the F1 or F2 pups at the scheduled necropsies; no test article-related macroscopic findings were noted for found dead F1 or F2 pups. No effects of the test article were observed on the mean days of acquisition of balanopreputial separation and vaginal patency in the F1 pups.

Decreased (not statistically significant) mean cumulative body weight gains were noted in the 3000 mg/L group F0 males during study days 0-70 (pre-mating period) and study days 0-126 (entire generation). While weekly mean body weight gain differences from the control group were only statistically significant during study days 91-98, the reduced mean cumulative body weight gains in the 3000 mg/L group males corresponded to decreased water consumption and were considered test article-related. Mean body weights were unaffected in the 3000 mg/L group males; differences from the control group were slight and not statistically significant.

A decreased (not statistically significant) mean cumulative body weight gain was noted in the 3000 mg/L group F0 females during study days 0-70 (pre-mating period).
There were no clear trends in the weekly mean body weight gains for these females; however, mean body weights were reduced in these females from study days 56 through 70 (prior to mating; 5.1% to 6.3%) and after the end of lactation on study day 126 (6.3%). Only the reduction on study day 126 was statistically significant (p0.01). The decreased mean body weights and cumulative body weight gain in this group corresponded to decreased water consumption and were considered test article-related. There were no effects on mean body weights or body weight gains in the 120, 360 and 1000 mg/L groups. Differences from the control group were slight, did not occur in an exposure-related manner and/or were not statistically significant.

Decreased mean water consumption was noted for the 3000 mg/L group F0 and F1 parental animals during the pre-mating period (females) or the entire generation (males) and for the F1 pups gang-housed by litter from PND 21-28. Water consumption was also often decreased in the 1000 mg/L group males and females, although the decreases were less severe and the onset was later than in the 3000 mg/L group. Mean water consumption in the 1000 mg/L group was consistently reduced compared to the control group beginning on study days 21-24; however, slight decreases were also noted inconsistently earlier in the pre-mating period. The decreased water consumption in the 1000 mg/L group continued through the first week of gestation while the decreased water consumption in the 3000 mg/L group females continued throughout gestation and lactation. The test article-related decreases in water consumption were not considered an adverse change due to the lack of associated effects on food intake and food utilization.

Hormone Analysis:
No statistically significant test article-related changes in the mean concentrations of T3, T4 or TSH were noted in the F0 or F1 parental animals or in the F1 or F2 pups selected for analysis (PND 4 or PND 21). The higher TSH values noted in the F0 males at the scheduled necropsy were not considered test article-related in the absence of effects on T3 or T4, organ weights or adverse macroscopic or microscopic findings. Test article-related decreased colloid within the thyroid glands of the 3000 mg/L F0 males was not considered adverse due to the lack of associated functional effects.

Conclusions:
Decreased mean water consumption was noted for the 1000 mg/L (F0 generation only) and 3000 mg/L group F0 and F1 parental animals due to the
poor palatability of water containing the two highest concentrations of Resorcinol. The test article-related decreases in water consumption were not
considered adverse even in the 3000 mg/L group because of the lack of associated effects on food intake and food utilization, which indicated that
homeostasis was uncompromised.

Test article-related reductions in mean body weights and/or body weight gains were observed in both parental generations in the 3000 mg/L group. However, there was no evidence of cumulative effects on mean body weights or body weight gains when evaluated across two generations, nor was
there evidence of gender-related effects or of enhanced sensitivity of females to the test article during gestation and lactation.

Decreased mean cumulative body weight gains were noted in the 3000 mg/L F0 group during the premating period (females) and the entire
generation (males). While no definite trends were apparent in weekly mean body weight gains for these animals, mean body weights were reduced in
the F0 females prior to mating (up to 6.3%), during gestation (up to 5.5%) and throughout lactation (up to 8.4%). Mean body weights were unaffected inthe 3000 mg/L group F0 males. A decreased mean cumulative body weight gain was also noted for the 3000 mg/L group F1 males for the entire
generation, corresponding to decreased (up to 7.1%) mean body weights throughout the generation.

There were no clear effects on mean body weight gains in the 3000 mg/L group F1 females; however, mean body weights were decreased in these
females during lactation (up to 6.1%) and after the lactation period ended (up to 7.0%). These reductions were most likely due to poor palatability of
the drinking water containing 3000 mg Resorcinol/L as evidenced by the correspondingly reduced water consumption recorded for these animals.
Decreased water consumption was noted in F0 and F1 males and females at 3000 mg/L and, to a lesser extent, in F0 males and females at an
exposure level of 1000 mg/L during the pre-mating period. However, there were no effects on mean body weights or body weight gains in the 120,
360 and 1000 mg/L group F0 and F1 males and females. During gestation and lactation, water consumption was decreased in both the F0 and F1
females in the 3000 mg/L group. Water consumption remained decreased for these females after the end of the lactation period. In addition, water
consumption was reduced at an exposure level of 3000 mg/L in the F1 generation during the week following weaning (PND 21-28) when the animals were housed by litter. The test article-related decreases in water consumption were not considered adverse due to the lack of associated effects on
food intake and food utilization, which indicated that homeostasis was uncompromised.

The NOAEL is considered to be 3000 mg Resorcinol/L for parental systemic and offspring toxicity (ca. Average F0 and F1 generation 223 mg/kg/day (males), 304 mg/kg/day (females(premating and gestation)), 660 mg/kg/day (females(lactation)) (F1 generation (males) 245 mg/kg/day and
(females) 295 mg/kg/day, while the NOEL is 1000 mg Resorcinol/L (ca. 86 mg/kg/day (males), 126 mg/kg/day (females(premating and gestation),
and 225 mg/kg/day (females(lactation)) (F1 generation (males) 93 mg/kg/day and (females) 126 mg/kg/day.

Although Resorcinol was known to be readily absorbed and eliminated, blood Resorcinol levels could be detected in some animals in the 3000 mg/L
group. Decreased colloid in the thyroid histopathology, although a non-adverse effect in this study, was observed only in the 3000 mg/L group F0
males. Therefore, the effects of Resorcinol have been appropriately evaluated in this study.
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
233 mg/kg bw/day
Species:
rat
Quality of whole database:
The one study available is a Guideline and GLP two-generation reproduction study.
Effect on fertility: via dermal route
Quality of whole database:
Two rat studies are available; one (the key study) was conducted to GLP and OECD Guidelines, and the other is similar to a guideline study. The one rabbit study available was conducted according to the version of the OECD Guideline that was available at the time, with some variations. A further rabbit study is available that was conducted using a compound that is metabolised to resorcinol.
Additional information

In an OECD TG 416 study, Sprague Dawley rats (30/sex/group) were exposed to resorcinol via drinking water for at least 70 days prior to mating (WIL, 2005).  Water concentrations were 0, 120, 360, 1000 and 3000 mg/L for the F0 and F1 generations. When expressed on a body weight basis (average F0 and F1 animals), the water concentrations corresponded to approximately:  0, 11, 31, 86 and 233 mg/kg/day for males over the entire generation; 0, 16, 48, 126 and 304 mg/kg/day for females during premating and gestation; and 0, 28, 85, 225 and 660 mg/kg/day for females during lactation, respectively.  In offspring, these concentrations corresponded to approximately:  0, 11, 33, 93 and 245 mg/kg/day in males; and 0, 16, 41, 126 and 295 mg/kg/day in females. A peer review of the microscopic thyroid evaluation was conducted. (See Section 3.1.9 for specifics on the thyroid evaluation.) Reproductive parameters evaluated included gonadal function, estrous cyclicity, mating behavior, conception, gestation, parturition, lactation and weaning of the F0 and F1 generations and F1 and F2 neonatal survival, growth and development.  Reproductive performance and spermatogenic endpoints were unaffected by resorcinol.  No test article related effects were observed on F1 and F2 pup survival, macroscopic findings or effects on organ weights.  Decreases in water consumption are indicated to be due to the poor palatability of the water containing the two highest concentrations of resorcinol.  The NOAEL is considered to be 3000 mg/L for parental systemic and offspring toxicity (ca. 233 mg/kg/day (males), 304 mg/kg/day (females (premating and gestation)), and 660 mg/kg/day (females (lactation)) while the NOEL is 1000 mg resorcinol/L for decreases in water consumption (ca. 86 mg/kg/day (males), 126 mg/kg/day (females (premating and gestation)) and 225 mg/kg/day (females (lactation)).  The NOAEL for reproductive toxicity (fertility and development) is 3000 mg/L which corresponds to 245 mg/kg bw (males) and 295 mg/kg bw (females) in the F1 generation. 


Short description of key information:
Resorcinol was not a reproductive toxicant and did not cause reproductive effects in the rat when administered in drinking water.

Effects on developmental toxicity

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Principles of method if other than guideline:
Study was designed to comply with OECD 414 dated Jan. 22, 2001.
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Route of administration:
oral: gavage
Vehicle:
other: purified water
Duration of treatment / exposure:
6-19 days of gestation
Frequency of treatment:
Daily
Duration of test:
20 days
No. of animals per sex per dose:
24 per group
Control animals:
yes, concurrent vehicle
Details on study design:
A total of 96 pregnant Sprague-Dawley female rats were allocated to four groups (24 per group). Three groups were administered with the test item,
Resorcinol (A011), by gavage once daily from day 6 to day 19 of gestation, inclusive, at the dose-level of 40, 80 or 250 mg/kg/day. One group of
females was only administered with the vehicle, purified water, at the same constant dose volume of 5 mL/kg; individual volumes were adjusted
according to the most recently recorded body weight.
Maternal examinations:
The females were sacrificed on day 20 of gestation and subjected to a macroscopic examination.
Fetal examinations:
The numbers of corpora lutea, implantations and live fetuses were recorded. The fetuses were removed from the uterus, weighed, sexed and
externally examined. Half of the fetuses underwent soft tissue examination while the remaining fetuses received a skeletal examination.
Statistics:
Statistical analysis:  Mean values were compared by one-way analysis of variance and the Dunnett test (mean values being considered as normally
distributed and variances being considered as homogeneous). Percentage values were compared by the Fisher exact probability test.
Details on maternal toxic effects:
Details on maternal toxic effects:
Maternal body weight and food consumption: At 250 mg/kg/day, the net body weight change was significantly lower (p>0.05%, -19%) than the
control group value. There were no other treatment effects on maternal body weight, body weight gain or food consumption.

Macroscopic post-mortem examination: No findings recorded at maternal necropsy were considered to be treatment-related.

Pregnancy data: All the group mean numbers of implantations and live fetuses and the extent of pre- and post-implantation losses were comparable with the controls.
Dose descriptor:
NOAEL
Effect level:
80 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified

Mortalities and clinical observations: No premature deaths occurred during the study and no clinical observations were considered to be treatment-related.

Fetal data: 

In the treated groups, the mean numbers of corpora lutea, implantation sites, live fetuses, resorptions (early and late) were similar to the control group values.

The mean male and female fetus weights were significantly greater at 250 mg/kg/day, when compared to the controls. This observation was considered to be the consequence of the low control group values (outside the range of the last version of Historical Control Data 3.8 g - 4.5 g, and within the range of the control group values during the period where this study was conducted: 3.6 g - 3.9 g), rather than, an effect of the treatment. The probability to mask an effect in fetal body weights resulting from the low control group value was evaluated but was considered to be with a
very low probability according to the homogeneity of individual fetal body weights, the absence of a dose-related trend in fetal body weights or the good general ossification of the skeletons. The percentage of male fetuses was similar to controls for all groups. As a result, it was concluded
that there were no effects of treatment on fetal body weight.

Fetal abnormalities:
 

No external, soft tissue or skeletal malformations or variations were considered to be treatment-related.

There was a significantly increase in the incidence of fetuses with an incompletely ossified interparietal at 40 and 80 mg/kg/day, when compared to controls (p0.05 and p0.01, respectively). The incidence of incompletely ossified parietals was also significantly greater at 80 mg/kg/day, when compared to controls (p0.05). In the absence of any effects at 250 mg/kg/day these observations were not considered to be treatment-related.

There was a significantly greater incidence of incompletely ossified 5th sternebra at 250 mg/kg/day, when compared to controls (p0.01). The thoraco-lumbar region is known to be particularly labile in the rat and, in the absence of other variations or malformations, this observation was not
considered to be treatment-related.

No fetal malformations or variants were considered to be related to treatment.

Conclusions:
The maternal No Observed Adverse Effect Level (NOAEL) of Resorcinol (A011) administered by oral route (gavage) to pregnant female rats was
considered to be 80 mg/kg/day based on statistically significant body weight changes and the developmental NOAEL was considered to be
250 mg/kg/day (highest dose tested).
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
250 mg/kg bw/day
Species:
rat
Additional information

In an OECD TG 414 study, female Sprague Dawley rats (24/group) were exposed to resorcinol via oral bolus dosing (gavage) from day 6 to day 19 of gestation at 0, 40, 80 or 250 mg/kg bw/day  (CIT, 2004).  At 250 mg/kg/day, the net body weight change was significantly lower (p>0.05%, -19%) than the control group value. There were no other treatment effects on maternal body weight, body weight gain or food consumption. No findings recorded at maternal necropsy were considered to be treatment-related.  All the group mean numbers of implantations and live fetuses and the extent of pre- and post-implantation losses were comparable with the controls.   In the treated group the mean number of corpora lutea, implantation sites, live fetuses and resorptions (early and late) were similar to control group values.  In foetus, no external, soft tissue or skeletal malformations or variations were considered to be treatment related.  The mean male and female fetus weights were significantly greater at 250 mg/kg bw/day when compared to the controls.  However, this observation was considered to be the consequence of the low control group values that were outside the range when compared with historical control data. Further evaluations were conducted in which it was concluded that there were no effects of treatment on fetal body weights.  There was a significant increase in the incidence of fetuses with an incompletely ossified interparietal at 40 and 80 mg/kg bw/day when compared to controls.  The incidence of incompletely ossified parietals was also significantly greater at 80 mg/kg bw/day, when compared to controls.  In the absence of any effects at 250 mg/kg bw/day these observations were not considered to be treatment-related.  There was a significantly greater incidence of incompletely ossified 5thsternebra at 250 mg/kg bw/day when compared to the controls.  The thoraco-lumbar region is known to be particularly labile in the rat and in the absence of other variations or malformations and, in the absence of other variations or malformations, this observation was not considered to be treatment-related. Resorcinol was not a developmental toxicant in this study.  The maternal and development NOAELs are 80 and 250 mg/kg bw/day (highest dose tested), respectively.  Teratogenicity was not detected.

Ten to thirteen Female Sprague Dawley rats were administered resorcinol by gavage at doses of 0, 125, 250 and 500 mg/kg bw/day during days 6 – 15 of gestation (DiNardo et al., 1985).  Study methods were similar to standard guideline studies.  Although a reduction of mean maternal weight gains occurred at days 0-6, 6-16 and 16-20, they were not statistically significant at the high doses.    No additional significant differences were observed in the incidence of fetuses with gross, visceral or skeletal anomalies, the foetal weights and resorption rates are not modified or any of the other parameters investigated.  Teratogenicity was not observed up to 500 mg/kg bw day.  The maternal and developmental NOAEL is 500 mg/kg bw day (highest dose tested).

In a teratogenicity study, mated New Zealand white rabbits (18 -26 animals/dose) were administered resorcinol at doses of 0 (vehicle), 0 (positive control, vitamin A), 25, 50 or 100 mg/kg bw/day on days 6 -18 of gestation. Animals were kept until day 28 when they were necropsied and examined. No treatment related deaths or clinical or macroscopic effects occurred in any dose groups. Maternal bodyweight gain was reduced in the top dose group compared to controls. Pregnancy incidence and number of implantations were not affected by treatment with resorcinol. Post-implantation loss was slightly higher than controls in the bottom 2 dose groups. However, these losses were within historical controls and therefore are not considered to be an effect of treatment. The mean number of foetuses per doe and the sex distribution was comparable to controls. Litter and foetal weights were comparable for all dose groups. There were no foetal defects related to treatment with resorcinol. The positive control has slight effects on the foetal weight and teratogenic effects. A maternal NOAEL of 50 mg/kg bw/day can be derived for this study based on reduced bodyweight gain at the top dose. A developmental NOAEL of 100 mg/kg bw/day can be derived based on no observed effects on foetal development. The study was undertaken before the current version of the OECD 414 (2001) guidelines were available, however it is in-line with the previous version of the OECD 414 (1981). Lack of clear effects on maternal animals (only bodyweight gain was reduced in the top dose group) and reduced number of foetuses examined may have affected the sensitivity of the study. However, the results of this study are in-line with other studies on rabbit and rat species.

In a developmental toxicity study, resorcinol bis-diphenylphosphate (RDP; a compound for which resorcinol is known to be one of the major urinary metabolites) was administered to pregnant female New Zealand White rabbits (27/dose) at dose levels of 0, 50, 200 or 1000 mg/kg bw/day from days 6 through 28 of gestation. No biologically significant adverse effects were observed, and NOAELs of 1000 mg/kg bw/day (the highest dose tested) were identified for both maternal and developmental toxicity.

Justification for classification or non-classification

Based on the above studies, resorcinol was not a developmental toxicant and did not cause reproductive effects in the rat and rabbit when administered by gavage.

Additional information