Registration Dossier

Administrative data

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

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2005
Report date:
2005

Materials and methods

Test guideline
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

Test material

Constituent 1
Chemical structure
Reference substance name:
Resorcinol
EC Number:
203-585-2
EC Name:
Resorcinol
Cas Number:
108-46-3
Molecular formula:
C6H6O2
IUPAC Name:
benzene-1,3-diol

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female

Administration / exposure

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
Doses / concentrations
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.

Examinations

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.

Results and discussion

Results: P0 (first parental generation)

Effect levels (P0)

open allclose all
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

Results: P1 (second parental generation)

Effect levels (P1)

open allclose all
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

Results: F1 generation

Effect levels (F1)

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

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

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.

Applicant's summary and conclusion

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.