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Effects on fertility

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Reference
Endpoint:
two-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study was performed accoding to the OECD 416 in compliance with GLP, with few deviations that were considered not to have compromised the validity or integrity of the study.
Qualifier:
according to
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
Deviations:
no
GLP compliance:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
oral: feed
Duration of treatment / exposure:
Exposure period: about 18 wk.
(F0 and F1) Premating exposure period (males): 10 wk.
Premating exposure period (females): 10 wk.
Duration of test: F0 pre-mating 10 wk, until F2 weaning.
Frequency of treatment:
Continuously
Remarks:
Doses / Concentrations:
1000, 2000 and 4000 ppm of test substance.
Basis:

No. of animals per sex per dose:
25
Control animals:
yes, concurrent vehicle
Parental animals: Observations and examinations:
Examination of F0 generation:
Clinical signs and mortality were checked daily. Food consumption and body weight were recorded at designated
intervals. Males and females were paired for a 2-wk period, until mating was obtained. The F0 females were allowed to deliver normally, and rear their progeny. Pregnancy and litter parameters were recorded.
During lactation, the pups (F1 generation) were observed daily for survival and clinical signs; body weight was
recorded at designated intervals; the sex-ratio was recorded. On Day 4 post-partum, the size of each litter was
adjusted to obtain eight pups per litter (four males and four females). Reflex development was assessed at designated
time-points.
Sperm parameters (parental animals):
Epididymal and testicular sperm parameters were evaluated for both F0 and F1 males.
Litter observations:
Examination of F1 generation:
On Day 22 post-partum, one male and one female pup per litter were selected to constitute the F1 generation, which
comprised 25 males and 25 females per group. The F1 animals were observed daily for clinical signs and mortality. Body
weight and food consumption were recorded once a week. Sexual development of both males and females was assessed.
Neurobehavioural tests were conducted at designated intervals to assess auditory and visual functions. Spontaneous
locomotor activity was also evaluated when the animals were between 7 and 8 wk old. After sexual maturity, F1 male and F1 female animals were
paired. The F1 females were allowed to deliver normally, and rear their progeny. Pregnancy and litter parameters were recorded.
During lactation, the pups (F2 generation) were observed daily for survival and clinical signs; body weight was recorded at designated intervals; the sex-ratio was recorded. On day 4 post-partum, the size of each litter was adjusted to obtain eight pups per litter (four males and four females).
Reflex development was assessed at designated time-points.
Postmortem examinations (parental animals):
Terminal examination of F0 and F1 animals:
After weaning of their respective progeny, F0 and F1 parent males and females were sacrificed. Designated organs were
weighed for F0 and F1 parents, as well as brain, spleen and thymus of one pup per sex per litter of each generation.
Epididymal and testicular sperm parameters were evaluated for both F0 and F1 males.
A macroscopic post-mortem examination was performed on all F0 and F1 parent males and females and on three pups per sex
and per litter of each F0 and F1 females killed at weaning. Any pups which died or were killed prematurely during the lactation period were also submitted for a macroscopic post-mortem examination.
Macroscopic lesions, reproductive organs, adrenals and pituitary glands were sampled in all parent animals. In all
pups, the macroscopic lesions were preserved. A microscopic examination was performed on macroscopic lesions,
reproductive organs, adrenals, and pituitary glands of all F0 and F1 parents of the control and high dose groups.
Particularly detailed histopathological examinations were performed for the ovaries and the testes.
Result: Not toxic to reproduction
F0 and F1 generations. At 4000 ppm (corresponding to approximately 123-208 mg/kg bw/d for F0 males and females and to 202-252 mg/kg bw/d for F1 males and females, respectively), a slightly to moderately lower mean food consumption and mean body weight gain were recorded during most of the dosing period in both parental males and females of the two generations and was associated with reduced liver weights. Necropsy of these animals (parents of both generations) revealed dilation of the cecum, colon or ileum in some animals (more marked in F0 parents). No effects were noted on sperm parameters or on histopathological examination of sexual organs. Slightly lower pup body weight was observed for each progeny and was associated, for the F2 generation pups, with a reduction in litter size (as a consequence of lower number of implantation sites of F1 parent females) and a delay in sexual development. Lower spleen weights were also noted for each progeny.
At 2000 ppm (corresponding to approximately 61-101 mg/kg bw/d for F0 males and females and 96-123 mg/kg bw/d for F1 males and females, respectively), a marginally to slightly lower mean food consumption and body weight gain were noted over all the dosing period for the males of the F0 generation and in both sexes for the F1 generation. Necropsy of parents of both generations revealed dilatation of the cecum in some animals of the F0 generation and in a single animal of the F1 generation. This was associated with lower liver weights in parental animals of both generations. No effects were noted on parental fertility as assessed by normal mating, gestation and delivery and, particularly, there were no effects on sperm parameters or at histopathological examination of sexual organs. Except for a marginally lower spleen weight of the progeny of each generation, no other effects were noted on their development.
At 500 ppm (corresponding to approximately 16-25 mg/kg bw/d for F0 males and females and 24-31 mg/kg bw/d for F1 males and females, respectively), a marginally to slightly lower mean food consumption and body weight gain were noted over all the dosing period for the males of the F0 generation and in both sexes for the F1 generation. This was associated in the F1 generation with lower liver weights of parental males and females. No effects were noted on mating, fertility, gestation, fecundity or delivery of either generation or on development of their progeny. As lower food consumption is known to occur due to palatability of compound. As no other substance related effects were seen than can be attributed to lower food intake, the level of 500 ppm test substance in the diet, corresponding to 16-25 mg/kg bw/d, should be regarded as NOAEL for parent and F1generation.

At 4000 ppm, number of implantation sites and litter size at birth were reduced. The progeny (F2) also showed lower pup weights. No effects were seen in F2 offspring at 2000 ppm regarding pup development and survival until weaning, and macroscopic examination after sacrifice at weaning. At the highest level of 4000 ppm pup weight gain was slightly lower during lactation, and upon necropsy dilatation of the caecum with faeces was observed in 4/25 males and 2/25 females. Therefore, 4000 ppm can be regarded as LOAEL, and 2000 ppm as NOAEL for F2.
Dose descriptor:
NOAEL
Effect level:
16 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: The effect level ranged from 16 to 25, due to lower body weight gains and reduced food consumption and/or necropsy findings at higher doses.
Dose descriptor:
NOAEL
Remarks:
Reproductive toxicity
Effect level:
61 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on the effect observed on mating, behaviour, fertility at the highest dose. The effective dose ranged from 61 to 101 mg/kg bw/day (nominal) (i.e., equivalent to 30.5 to 50.5 mg a.i./kg bw/d.
Result: Not toxic to reproduction
F0 and F1 generations. At 4000 ppm (corresponding to approximately 123-208 mg/kg bw/d for F0 males and females and to 202-252 mg/kg bw/d for F1 males and females, respectively), a slightly to moderately lower mean food consumption and mean body weight gain were recorded during most of the dosing period in both parental males and females of the two generations and was associated with reduced liver weights. Necropsy of these animals (parents of both generations) revealed dilation of the cecum, colon or ileum in some animals (more marked in F0 parents). No effects were noted on sperm parameters or on histopathological examination of sexual organs. Slightly lower pup body weight was observed for each progeny and was associated, for the F2 generation pups, with a reduction in litter size (as a consequence of lower number of implantation sites of F1 parent females) and a delay in sexual development. Lower spleen weights were also noted for each progeny. At 2000 ppm (corresponding to approximately 61-101 mg/kg bw/d for F0 males and females and 96-123 mg/kg bw/d for F1 males and females, respectively), a marginally to slightly lower mean food consumption and body weight gain were noted over all the dosing period for the males of the F0 generation and in both sexes for the F1 generation. Necropsy of parents of both generations revealed dilatation of the cecum in some animals of the F0 generation and in a single animal of the F1 generation. This was associated with lower liver weights in parental animals of both generations. No effects were noted on parental fertility as assessed by normal mating, gestation and delivery and, particularly, there were no effects on sperm parameters or at histopathological examination of sexual organs. Except for a marginally lower spleen weight of the progeny of each generation, no other effects were noted on their development. At 500 ppm (corresponding to approximately 16-25 mg/kg bw/d for F0 males and females and 24-31 mg/kg bw/d for F1 males and females, respectively), a marginally to slightly lower mean food consumption and body weight gain were noted over all the dosing period for the males of the F0 generation and in both sexes for the F1 generation. This was associated in the F1 generation with lower liver weights of parental males and females. No effects were noted on mating, fertility, gestation, fecundity or delivery of either generation or on development of their progeny. As lower food consumption is known to occur due to palatability of compound. As no other substance related effects were seen than can be attributed to lower food intake, the level of 500 ppm test substance in the diet, corresponding to 16-25 mg/kg bw/d, should be regarded as NOAEL for parent and F1generation. At 4000 ppm, number of implantation sites and litter size at birth were reduced. The progeny (F2) also showed lower pup weights. No effects were seen in F2 offspring at 2000 ppm regarding pup development and survival until weaning, and macroscopic examination after sacrifice at weaning. At the highest level of 4000 ppm pup weight gain was slightly lower during lactation, and upon necropsy dilatation of the caecum with faeces was observed in 4/25 males and 2/25 females. Therefore, 4000 ppm can be regarded as LOAEL, and 2000 ppm as NOAEL for F2.
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
24 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: The effect level ranged from 16 to 25, due to lower body weight gains and reduced food consumption and/or necropsy findings at higher doses.
Dose descriptor:
NOAEL
Remarks:
Reproductive toxicity
Generation:
F1
Effect level:
96 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on the effect observed on mating, behaviour, fertility at the highest dose. The effective dose ranged from 96 to 123 mg/kg bw/d (nominal) (i.e., equivalent to 48 to 61.5 mg a.i./kg bw/d
Reproductive effects observed:
not specified

The mean achieved dosages of the test substance for the dose-levels of 500, 2000 and 4000 ppm of test substance were as follows:
F0 generation
- males (Days 1 to 106): 16, 61 and 123 mg/kg bw/d, respectively,
- females: during premating period (Days 1 to 71): 19, 74 and 154 mg/kg bw/d, respectively,
    during pregnancy period (Days 0 to 20 p.c.): 18, 69 and 145 mg/kg bw/d, respectively,
    during lactation period (Days 1 to 21 p.p.): 37, 159 and 326 mg/kg bw/d, respectively.
F1 generation
- males (Days 1 to 120): 24, 96 and 202 mg/kg bw/d, respectively,
- females:
    during premating period (Days 1 to 64): 32, 127 and 269 mg/kg bw/d, respectively,
    during pregnancy period (Days 0 to 20 p.c.): 21, 83 and 164 mg/kg bw/d, respectively,
    during lactation period (Days 1 to 21 p.p.): 41, 162 and 323 mg/kg bw/d, respectively.

The actual intake of test substance for both males and females given 500, 2000 and 4000 ppm throughout the study is approximately
16-25, 61-101 and 123-208 mg/kg bw/d, respectively  for the F0 generation and 24-31, 96-123 and 202-252 mg/kg bw/d for the F1 generation.

Conclusions:
Under the experimental conditions of this study, the NOEL for parental toxicity is 500 ppm for the male and the female animals. The NOEL for mating behaviour, fertility and gestation of each generation and for development, growth and survival of each progeny is 2000 ppm (i.e., 61 to 101 mg/kg bw/day (nominal) (equivalent to 30.5 to 50.5 mg a.i./kg bw/d and 96 to 123 mg/kg bw/d (nominal) (equivalent to 48 to 61.5 mg a.i./kg bw/d for the F0 and F1 generation respectively).
Executive summary:

In a two-generation study, C12-16 ADBAC was administered in the diet to male and female Sprague Dawley rats at 0, 500 (i.e.,16-25 and 24-31 mg/kg bw/day or 8-12.5 and 12-15.5 mg a.i./kg bw/day in males and females); 2,000 (i.e., 61-101and 96-123 mg/kg bw/day or 30.5-50 and 48 to 61.5 mg a.i./kg bw/day in males and females) or 4,000 ppm (i.e., 123-208 and 202-252 mg/kg bw/day or 61-104 and 101-126 mg a.i./kg bw/day in males and females, before and through mating and gestation until the end of the lactation period in both F0 and F1 generations. At 2,000 ppm, F0 (males) and F1 parents showed marginally to slightly lower body weight gains and reduced food consumption. Necropsy of parents of both generations revealed dilatation of the caecum in some animals. This was associated with lower liver weights in parental animals of both generations. At 4,000 ppm, in F0 and F1 parents, number of implantation sites and litter size at birth were reduced. The progeny (F2) also showed lower pup weights. Pup weight gain was slightly lower during lactation. Upon necropsy, dilatation of the caecum with faeces was observed in 4/25 males and 2/25 females. Treatment with the test substance had no effect on mating, fertility and behavioural parameters in F0 and F1 parental Sprague-Dawley rats at treatment levels up to 2,000 ppm. No effect was recorded on litter parameters and on pre- and post-natal development of either generation at 2,000 ppm. Consequently, under the experimental conditions of this study, the NOEL for parental toxicity was 500 ppm for the male and the female animals. The NOEL for mating behaviour, fertility and gestation of each generation and for development, growth and survival of each progeny was 2,000 ppm.

Under the experimental conditions of this study, the NOEL for parental toxicity is 500 ppm for the male and the female animals. The NOEL for mating behaviour, fertility and gestation of each generation and for development, growth and survival of each progeny is 2000 ppm (i.e., 61 to 101 mg/kg bw/day (nominal) (equivalent to 30.5 to 50.5 mg a.i./kg bw/d and 96 to 123 mg/kg bw/d (nominal) (equivalent to 48 to 61.5 mg a.i./kg bw/d for the F0 and F1 generation respectively) (Foulon O, 2008).

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
30.5 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Information requirement for this tonnage band is sufficiently met with the available data.
Additional information

In a two-generation study, the read-across substance C12-16 ADBAC was administered in the diet to male and female Sprague Dawley rats at dose levels of 0, 500, 2,000, 4,000 ppm (purity 49.9%) i.e.:

  • 500 ppm = 16-25 and 24-31 mg/kg bw/day or 8-12.5 and 12-15.5 mg a.i./kg bw/day in males and females;
  • 2,000 ppm = 61-101 and 96-123 mg/kg bw/day or 30.5-50 and 48 to 61.5 mg a.i./kg bw/day in males and females
  • 4,000 ppm = 123-208 and 202-252 mg/kg bw/day or 61-104 and 101-126 mg a.i./kg bw/day in males and females.

Doses were administered before and throughout mating and gestation until the end of the lactation period in both F0 and F1 generations. At 2,000 ppm, F0 (males) and F1 parents showed marginally to slightly lower body weight gains and reduced food consumption. Necropsy of parents of both generations revealed dilatation of the caecum in some animals. This was associated with lower liver weights in parental animals of both generations. At 4,000 ppm, in F0 and F1 parents, number of implantation sites and litter size at birth were reduced. The progeny (F2) also showed lower pup weights. Pup weight gain was slightly lower during lactation. Upon necropsy, dilatation of the caecum with faeces was observed in 4/25 males and 2/25 females. Treatment with the test substance had no effect on mating, fertility and behavioural parameters in F0 and F1 parental Sprague-Dawley rats at treatment levels up to 2,000 ppm. No effect was recorded on litter parameters and on pre- and post-natal development of either generation at 2,000 ppm. Consequently, under the experimental conditions of this study, the NOEL for parental toxicity was 500 ppm for the male and the female animals. The NOEL for mating behaviour, fertility and gestation of each generation and for development, growth and survival of each progeny was 2,000 ppm (61 to 101 mg/kg bw/day (nominal) (equivalent to 30.5 to 50.5 mg a.i./kg bw/day and 96 to 123 mg/kg bw/day (nominal) (equivalent to 48 to 61.5 mg a.i./kg bw/day for the F0 and F1 generation respectively) (Foulon O, 2008).

In another study, the reproductive/developmental toxicity of the read-across substance C12-16 ADBAC in rats was evaluated. The test substance was orally administered to Sprague-Dawley CD rats (28/sex/group) at dose levels of 0, 300, 1,000 or 2,000 ppm test substance (equivalent to 0, 16-31, 51-102, and 100-188 mg/kg bw/day (males) and 0, 21-32, 67-106 and 139-198 mg/kg bw/day (females)) in the diet. There was one control group of 28 animals/sex. Following a 10 week pre-breed exposure period, the F0 rats were randomly paired within dose groups for a 3 week mating period to produce the F1 generation. Exposure continued through mating, gestation, parturition and lactation. At weaning, 28 F1 weanling/sex/group were randomly selected and exposed to the same dietary concentration of the test substance as their parents for 10 weeks. After their pre-breed exposure, F1 animals were paired to produce the F2 generation. The animals were observed twice daily and clinical findings, body weights and food consumption were recorded periodically. All F0 and F1 parental animals were necropsied and examined for gross lesions; selected reproductive tissues from the high dose and control groups were examined histologically as were other tissues with gross lesions. Ten F1 and F2 weanlings/sex/dose were randomly selected and necropsied and examined for gross lesions. F0 female body weights and food consumption were reduced at 2,000 ppm during the pre-breeding exposure period. For the pre-breeding period of the F1 parental animals, only slight reductions in body weight gain were observed for males in the high dose group. No other treatment-related effects were observed on any of the reproductive parameters. Based on the results of the study, it can be stated that, dietary administration of the test substance at dose levels of 0, 300, 1,000 and 2,000 ppm for two generations to Sprague-Dawley rats was well tolerated and no sign of reproductive toxicity was observed at any dose level. The NOAEL for both parental generation (P and F1) and offsprings (F1 and F2) was considered to be 1,000 ppm (in diet), equivalent to 51-102 or 41.3-83 mg a.i./kg bw/day in males and 67-106 mg/kg bw/day or 54-86 mg a.i./kg bw/day for female, respectively (Neeper-Bradley TL, 1990).


Short description of key information:
In the most recent two-generation reproduction study with the read-across substance C12-16 ADBAC, the NOEL for parental toxicity was 500 ppm for the male and the female animals (8-12.5 and 12-15.5 mg a.i./kg bw/day in males and females). The NOEL for mating behaviour, fertility and gestation of each generation and for development, growth and survival of each progeny was 2,000 ppm (61 to 101 mg/kg bw/day (nominal) or 30.5 to 50.5 mg a.i./kg bw/day and 96 to 123 mg/kg bw/day (nominal) or 48 to 61.5 mg a.i./kg bw/dayfor the F0 and F1 generation, respectively. Further, no reproductive effects were observed in another two-generation reproductive toxicity study conducted in rats up to 2,000 ppm.

Justification for selection of Effect on fertility via oral route:
Most recent, OECD guideline and GLP compliant study showing some reproductive toxicity at the highest dose while other two-generation study did not reveal any reproductive effect up to the highest tested dose.

Effects on developmental toxicity

Description of key information
A guideline prenatal developmental toxicity study conducted in rabbits revealed no treatment-related developmental effects up to the highest tested doses of 30 mg a.i./kg bw/day. However, due to some maternal effects (such as necropsy findings and reduced maternal body weight gain) at 10 mg a.i./kg bw/day and higher doses, the NOAEL for maternal toxicity was established at the lowest tested dose of 3 mg a.i./kg bw/day. In another developmental toxicity study conducted in rats, C12-16 ADBAC was found to produce some adverse effects in pregnant rats at 30 and 100 mg kg bw/day or, 24 and 81 mg a.i./kg bw/day ; however, no developmental effects were observed at any dose level. Hence, the NOAEL for maternal toxicity was 10 mg/kg bw/day (equivalent to 8.1 mg a.i./kg bw/day) and the NOAEL for developmental toxicity was 100 mg/kg bw/day (equivalent to 81 mg a.i./kg bw/day).
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study was performed accoding to the OECD guideline 414, in compliance with GLP with few deviations that were not considered to have compromised the validity or integrity of the study.
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
batch number is not presented for the vehicle (purified water) in the study report; autolysed foetuses were not sexed at the time of hysterectomy and head sections were archived in the same way as brain sections.
GLP compliance:
yes
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Route of administration:
oral: gavage
Duration of treatment / exposure:
Day 6 to 28 post coitum
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:
0, 3, 10 or 30 mg/kg bw/d
Basis:

No. of animals per sex per dose:
22 mated females per dose
Control animals:
yes, concurrent vehicle
Details on study design:
Sex: female
Duration of test: GD 6-28
Dose descriptor:
NOAEL
Effect level:
3 mg/kg bw/day
Based on:
act. ingr.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
30 mg/kg bw/day
Based on:
act. ingr.
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified

Result: The test substance is not teratogenic in rabbits.

Maternal effects:
At 30 mg/kg bw/d:
- three females died and two females were prematurely sacrificed for ethical reasons or abortion,
- the relevant clinical signs concerned the deceased females and two prematurely sacrificed females. No other clinical signs were noted in females from this group.
- body weight gain was transiently reduced (GD 9-12, -70% below the control, p<0.05) but returned to normal values thereafter,
- the necropsies revealed in 8/22 females: accentuated lobular pattern in the liver, pale liver, whitish areas and/or blackish deposits and/or edema in the stomach mucosa, reddish or brownish foci on the lungs, blackish contents in
the intestines, dilated intestines and dilated gall bladder,

At 10 mg/kg bw/d:
- there were no deaths. Reduction of maternal body weight gain and food consumption did not reach statistical significance,

- There were no relevant clinical signs except for two females with blood in the bedding on Days 22 and 23 post-coitum or absence of feces from Day 26 post-coitum
- the necropsies revealed in 5/22 females: dilated gall bladder, accentuated lobular pattern, 

- pale liver, brownish or reddish foci on the lungs, blackish deposit on the stomach mucosa,

At 3 mg/kg bw/d:
no signs of maternal toxicity,

Teratogenic / embryotoxic effects:
There were no effects on litter data parameters and no treatment-related findings upon external, visceral or skeletal observation in any of the dose groups.

Litter and foetal evaluation:
The fluctuations noted in the mean number of corpora lutea, implantation sites and post-implantation were slight and not
dose-related, they were consequently considered not to be treatment-related.
The fluctuations recorded for the mean number of resorptions (early or late) and the mean number of dead foetuses and
consequently for the percentages of post-implantation loss were also not considered to be treatment-related, as they
were minimal and not dose-related. The percentage of male foetuses was considered similar among the groups and the fetal body weight was unaffected by treatment.

External, soft tissue and skeletal observations in foetuses and final fetal assessment:
The occurrence of some external and soft tissue malformations throughout all treated groups, including the
controls, did not suggest any substance-related origin because of their low incidence, absence of dose-relationship
and/or statistical significance.
Concerning the skeletal observations, no relevant malformations was noted but the presence of a full supernumerary 13th pair of ribs (as a foetal variation), was markedly increased at 10 and 30 mg/kg bw/day. These differences
in foetal or litter incidence, which were within background data, were most probably due to a low control value. The
incidence of one other skeletal variation (unossified 5th sternebra) was significantly greater but in the low dose-group only.

Conclusion: Test substance is not teratogenic in rabbits.

LO(A)EL maternal toxic effects:
10 mg/kg bw/d, based on necropsy findings in 5/22 animals.
Incidence was increased to 8/22 at 30 mg/kg bw/d (dilated gallbladder 3/22, accentuated lobular pattern liver 3/22).
Foci (reddish/brownish) in the lung was also observed in 2 females, but also in view of findings in range finding study and
parallel study with comparable compound, this can be caused by inadvertent presence of substance into the airways and
not attributable to systemic toxicity. Incidence was not increased in the top-dose group. There is an indication of
lower body weight gain, correlating to a lower food consumption, but that was not statistical significant and in
the high-dose goup not different from the mid-dose group.
Blackish content in stomack and intestines is indicative of local corrosive effects of test substance.


NO(A)EL maternal toxic effects:
3 mg/kg bw/d. There seems to be a dose-response related increase in necropsy findings in stomach, intestine and liver.
Dilated gallbladder incidence was not increased in highest dose group compared to mid-dose.
LO(A)EL embryotoxic / teratogenic effects:
Based on the number of foetuses presenting malformations or variations and in the absence of a treatment-related
increase of such observation, the embryo-fetal development was not considered to be affected by treatment.
NO(A)EL embryotoxic / teratogenic effects:
30 mg/kg bw/d, being the highest tested dose.

Conclusions:
Under the condition of the study, the NOAEL for maternal toxicity was 3 mg a.i./kg bw/d while NOAEL embryo-foetal development was considered as 30 mg a.i./kg bw/d.
Executive summary:

A guideline equivalent developmental toxicity study was conducted in rabbits. C12-16 ADBAC was administered to pregnant rabbits by gavage from Day 6 to 28 post-coitum at the dose-levels of 3, 10 or 30 mg/kg bw/day of active substance. The dose of 30 mg/kg bw/day caused the death of three females, severe clinical condition or abortion in two other females and transient, lower maternal body weight gain. Necropsies revealed in 8/22 females accentuated lobular patterns in the liver, whitish areas and/or blackish deposits in the stomach mucosa and dilated intestines. At 10 mg/kg bw/day, relevant necropsy findings were noted in 5/22 females (dilated gall bladder, accentuated lobular pattern, pale liver, brownish or reddish foci on the lungs, blackish deposit on the stomach mucosa). No maternal toxicity or effects on litter data parameters or embryo-foetal development were noted at 3 mg/kg bw/day. Under the condition of the study, the NOAEL for maternal toxicity was 3 mg/kg bw/day while the NOAEL for embryo-foetal development was 30 mg/kg bw/day (Gaoua W, 2005).

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
30 mg/kg bw/day
Study duration:
subacute
Species:
rabbit
Quality of whole database:
A range finding study and two full studies conducted in rats and rabbits are available meeting the information requirement for this tonnage band.
Additional information

A guideline equivalent developmental toxicity study was conducted in rabbits. The read-across substance C12-16 ADBAC was administered to pregnant rabbits by gavage from Day 6 to 28 post-coitum at the dose-levels of 3, 10 or 30 mg/kg bw/day of active substance. The dose of 30 mg a.i./kg bw/day caused the death of three females, severe clinical condition or abortion in two other females and transient, lower maternal body weight gain. Necropsies revealed in 8/22 females accentuated lobular patterns in the liver, whitish areas and/or blackish deposits in the stomach mucosa and dilated intestines. At 10 mg/kg bw/day, relevant necropsy findings were noted in 5/22 females (dilated gall bladder, accentuated lobular pattern, pale liver, brownish or reddish foci on the lungs, blackish deposit on the stomach mucosa). No maternal toxicity or effects on litter data parameters or embryo-foetal development were noted at 3 mg/kg bw/day. Under the condition of the study, the NOAEL for maternal toxicity was 3 mg a.i./kg bw/day while the NOAEL for embryo-foetal development was 30 mg a.i./kg bw/day (Gaoua W, 2005).

A guideline equivalent study was carried out to assess the effects of the read-across substance C12-16 ADBAC on embryonic and foetal development in pregnant Sprague-Dawley CD rats. The test substance was administered to groups of 25 pregnant rats orally by gavage at dose levels of 0, 10, 30 and 100 mg/kg bw/day or 8.1, 24 and 81 mg a.i./kg bw/day , once daily from Day 6 to Day 15 of gestation inclusive. Control animals were treated with the vehicle (Milli-Q water). Clinical observations were made twice daily, and maternal body weights were measured on gestation Days 0, 6, 9, 12, 15, 18 and 21. Maternal food consumption was measured at 3 day intervals from Day 0 to Day 21. All surviving females were sacrificed on Day 21 and the foetuses were examined for visceral and skeletal variations and malformations. No mortality was observed during the study. Treatment-related clinical signs included perioral wetness and audible respiration in high dose group. Audible respiration was also observed in mid dose group. Food consumption was reduced between Days 6 to 9 in mid and high dose groups. There were no effects of treatment on gestational body weight and body weight gain and gravid uterine weight in any dose group. There were also no treatment-related differences in gestational parameters including total number of implantations, number of viable and nonviable implants between the control and the test groups. Further, there were no effects of treatment on fetal body weights per litter, or on the incidences of external, visceral and skeletal malformations and variations. Based on the results of this study, C12-16 ADBAC was found to produce some adverse effects in pregnant rats at 30 and 100 mg/kg bw/day, however, no developmental toxicity, including teratogenicity was observed at any of the dosages. The NOAEL for maternal toxicity was 10 mg/kg bw/day (equivalent to 8.1 mg a.i./kg bw/day) and the NOAEL for developmental toxicity was 100 mg/kg bw/day (equivalent to 81 mg a.i./kg bw/day) (Neeper-Bradley TL, 1992).


Justification for selection of Effect on developmental toxicity: via oral route:
Most recent, well conducted guideline compliant study with most conservative NOAEL.

Justification for classification or non-classification

The available data on the read-across substance C12-16 ADBAC demonstrates no effects on fertility or development. Therefore, C12-14 ADBAC is also not expected to be a reproductive toxicant and no classification is required according to DSD (67/548/EEC) and CLP (EC 1272/2008) criteria.