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EC number: 701-357-1 | CAS number: -
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Key value for chemical safety assessment
- Toxic effect type:
- concentration-driven
Effects on fertility
Description of key information
The available two-generation reproductive toxicity studies with the read across substance in rats, indicate no concern for reproductive toxicity for the test substance. Further, due to the absence of specific reproductive toxicity and the fact that the observed effects in parents relate to general toxicity which are secondary to local effects, the parental NOAELs (16 mg/kg bw/day) were not considered to be relevant to the determination of a systemic DNELs.
Link to relevant study records
- Endpoint:
- two-generation reproductive toxicity
- Type of information:
- read-across based on grouping of substances (category approach)
- Adequacy of study:
- key study
- Study period:
- 2008
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study with acceptable restrictions
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Route of administration:
- oral: feed
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- - Exposure period: about 18 wk.
P0 and P1:
Premating exposure period (males): 10 wk.
Premating exposure period (females): 10 wk.
- Duration of test: P0 pre-mating 10 wk, until F2 weaning. - Frequency of treatment:
- Continuously
- Details on study schedule:
- Groups of 25 male and 25 female Sprague-Dawley rats were administered the test substance (purity 49.9%) at levels of 0, 500, 2000 or 4000 ppm in their diet over a period of 10 wk before mating, 2 wk during mating, and until after weaning of the pups (total period 18 wk). From every litter one or two pups were selected to again obtain 25 animals per sex and dose group for the F1 generation. These animals were similarly treated as the parent (P1) animals throughout premating, mating, pregnancy until sacrifice, after weaning of F2 progeny.
- Remarks:
- Doses / Concentrations: 0, 500, 2000 or 4000 ppm (equivalent to 250, 1000 and 2000 a.i. ppm) of test substance
- Remarks:
- F0 generation - 16-25, 61-101, 123-208 mg/kg bw/day (equivalent to 8-13, 31-51, 62-104 mg a.i./kg bw/day); F1 generation - 24-34, 96-123, 202-252 mg/kg bw/day (equivalent to 12-17, 48-62, 101-126 mg a.i./kg bw/day)
- No. of animals per sex per dose:
- 25
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- For details, kindly refer to the attached background material section of the IUCLID.
- Parental animals: Observations and examinations:
- - Examination of P0 and P1 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 P1 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 P0 and P1 males.
- Litter observations:
- Examination of F1/P1 generation:
- On Day 22 post-partum, one male and one female pup per litter were selected to constitute the F1/P1 generation, which comprised 25 males and 25 females per group. The F1/P1 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 P0 and P1 animals:
- After weaning of their respective progeny, P0 and P1 parent males and females were sacrificed. Designated organs were weighed for P0 and P1 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 P0 and P1 males.
- A macroscopic post-mortem examination was performed on all P0 and P1 parent males and females. 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. A microscopic examination was performed on macroscopic lesions, reproductive organs, adrenals, and pituitary glands of all P0 and P1 parents of the control and high dose groups.
- Particularly detailed histopathological examinations were performed for the ovaries and the testes. - Postmortem examinations (offspring):
- - A macroscopic post-mortem examination was performed on three pups per sex and per litter of each P0 and P1 (F1 and F2 generation) 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. In all pups, the macroscopic lesions were preserved.
- Statistics:
- For details, kindly refer to the attached background material section of the IUCLID.
- Reproductive indices:
- For details, kindly refer to the attached background material section of the IUCLID.
- Offspring viability indices:
- For details, kindly refer to the attached background material section of the IUCLID.
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- - At 2000 ppm, a slightly lower mean body weight gain was recorded during most of the dosing period in both parental males and females (and was associated with reduced liver weights).
- At 1000 and 250 ppm, a marginally to slightly lower body weight gain was noted over all the dosing period for the males. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- - At 2000 ppm, a slightly to moderately lower mean food consumption was recorded during most of the dosing period in both parental males and females.
- At 1000 and 250 ppm, a marginally to slightly lower mean food consumption was noted over all the dosing period for the males. - Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- - At 2000 and 1000 ppm, no effects were noted at histopathological examination of sexual organs.
- Histopathological findings: neoplastic:
- not examined
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- no effects observed
- Description (incidence and severity):
- - At 2000 and 1000 ppm, no effects were noted on sperm parameters.
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- - At 2000 ppm, slightly lower pup body weight was observed (with lower spleen weights).
- At 1000 ppm, no effects were observed on parental fertility as assessed by normal mating, gestation and delivery.
- At 250 ppm, no effects were noted on mating, fertility, gestation, fecundity or delivery of either generation or on development of their progeny. - Key result
- Dose descriptor:
- NOAEL
- Remarks:
- systemic toxicity
- Effect level:
- ca. 250 ppm
- Based on:
- act. ingr.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- food consumption and compound intake
- organ weights and organ / body weight ratios
- gross pathology
- Remarks on result:
- other: equivalent to 16-25 mg/kg bw/day (8-12.5 mg a.i./kg bw/day)
- Key result
- Dose descriptor:
- NOEL
- Remarks:
- reproductive toxicity
- Effect level:
- ca. 1 000 ppm
- Based on:
- act. ingr.
- Sex:
- male/female
- Basis for effect level:
- other: absence of adverse effects on mating behaviour, fertility and gestation of each generation
- Remarks on result:
- other: equivalent to 61-101 mg/kg bw/day (30.5-50.5 mg a.i./kg bw/day)
- Key result
- Critical effects observed:
- no
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- - At 2000 ppm, a slightly to moderately lower mean body weight gain was recorded during most of the dosing period in both parental males and females (and was associated with reduced liver weights).
- At 1000 ppm, a marginally to slightly lower mean body weight gain was noted.
- At 250 ppm, a marginally to slightly lower mean body weight gain was observed in both sexes. This was associated with lower liver weights of parental males and females. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- - At 2000 ppm, a slightly to moderately lower mean food consumption was recorded during most of the dosing period in both parental males and females.
- At 1000 and 250 ppm, a marginally to slightly lower mean food consumption was noted over all the dosing period in both sexes. - Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- - At 2000 ppm, reduced liver weights were observed.
- At 1000 and 250 ppm, lower liver weights in parental animals were recorded. - Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- - At 2000 ppm, necropsy of these animals revealed dilation of the cecum, colon or ileum in some animals (more marked in F0 parents).
- At 1000 ppm, necropsy of parents revealed dilatation of the cecum in a single animal. - Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- - At 2000 and 1000 ppm, no effects were noted at histopathological examination of sexual organs.
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- See under Any other information on results incl. tables for details on results.
- Reproductive function: sperm measures:
- no effects observed
- Description (incidence and severity):
- - At 2000 and 1000 ppm, no effects were noted on sperm parameters.
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- - At 2000 ppm, 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 P1 females) and a delay in sexual development. Lower spleen weights were also noted for each progeny.
- At 1000 ppm, no effects were noted on parental fertility as assessed by normal mating, gestation and delivery.
- At 250 ppm, no effects were noted on mating, fertility, gestation, fecundity or delivery and development of their progeny. - Key result
- Dose descriptor:
- NOAEL
- Remarks:
- systemic toxicity
- Effect level:
- ca. 250 ppm
- Based on:
- act. ingr.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- food consumption and compound intake
- organ weights and organ / body weight ratios
- gross pathology
- Remarks on result:
- other: equivalent to 24-31 mg/kg bw/day (12-15.5 mg a.i./kg bw/day)
- Key result
- Dose descriptor:
- NOEL
- Remarks:
- reproductive toxicity
- Effect level:
- ca. 1 000 ppm
- Based on:
- act. ingr.
- Sex:
- male/female
- Basis for effect level:
- other: absence of adverse effects on mating behaviour, fertility and gestation of each generation
- Remarks on result:
- other: corresponding to 96-123 mg/kg bw/day (48-61.5 mg a.i./kg bw/day)
- Key result
- Critical effects observed:
- no
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- mortality observed, treatment-related
- Description (incidence and severity):
- - At 2000 ppm, the litter size at birth was reduced.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- - At 2000 ppm, slightly reduced pup body weight was observed. Pup weight gain was also slightly lower during lactation.
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Sexual maturation:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- - At 2000 ppm, lower spleen weights were noted.
- At 1000 ppm, except for a marginally lower spleen weight of the progeny, no other effects were noted on their development. - Gross pathological findings:
- no effects observed
- Histopathological findings:
- no effects observed
- Behaviour (functional findings):
- not examined
- Developmental immunotoxicity:
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- general toxicity
- Generation:
- F1
- Effect level:
- ca. 250 ppm
- Based on:
- act. ingr.
- Sex:
- male/female
- Basis for effect level:
- other: a marginally to slightly lower mean food consumption and body weight gain and liver weights
- Remarks on result:
- other: corresponding to 24-31 mg/kg bw/day (12-15.5 mg a.i./kg bw/day)
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- developmental toxicity
- Generation:
- F1
- Effect level:
- ca. 1 000 ppm
- Based on:
- act. ingr.
- Sex:
- male/female
- Basis for effect level:
- other: mean age of preputial separation and vaginal opening was delayed due to reduced food intake
- Remarks on result:
- other: corresponding to 96-123 mg/kg bw/day (48-61.5 mg a.i./kg bw/day)
- Key result
- Critical effects observed:
- no
- Clinical signs:
- not examined
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- mortality observed, treatment-related
- Description (incidence and severity):
- - At 2000 ppm, the litter size at birth were reduced (as a consequence of lower number of implantation sites of F1 parent females).
- At 1000 ppm, no effects were seen in F2 offspring regarding pup survival until weaning. - Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- - At 2000 ppm, slightly lower pup body weight was observed. The pup weight gain was slightly reduced during lactation,
- At 1000 ppm, no effects were seen regarding pup development. - Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Sexual maturation:
- effects observed, treatment-related
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- - At 2000 ppm, lower spleen weights were noted.
- At 1000 ppm, except for a marginally lower spleen weight, no other effects were noted on their development. - Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- At 2000 ppm, dilatation of the caecum with faeces was observed in 4/25 males and 2/25 females.
At 1000 ppm, no effects were seen regarding pup development and after sacrifice at weaning. - Histopathological findings:
- not examined
- Behaviour (functional findings):
- not examined
- Developmental immunotoxicity:
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- general / developmental toxicity
- Generation:
- F2
- Effect level:
- 1 000 ppm
- Based on:
- act. ingr.
- Sex:
- male/female
- Basis for effect level:
- mortality
- other: based on lower pup weights, lower pup weight gain during lactation, and upon necropsy dilatation of the cecum with feces was observed in 4/25 males and 2/25 females
- Remarks on result:
- other: corresponding to 96-123 mg/kg bw/day (48-61.5 mg a.i./kg bw/day)
- Key result
- Critical effects observed:
- no
- Key result
- Reproductive effects observed:
- no
- Conclusions:
- Based on the results of the read across study, the NOAELs for parental, reproductive and development toxicity were established at 250, 2000 and 1000 ppm respectively.
- Executive summary:
A two-generation study was conducted to determine the toxicity to reproduction of the read across substance, C12 -16 ADBAC (49.9% active in water) according to OECD Guideline 416, in compliance with GLP. In this study, the substance was administered in the diet to male and female Sprague-Dawley rats at dose levels of 0, 250, 1000 and 2000 ppm (i.e., equivalent to 0, 16-25, 61-101 and 123- 208 mg a.i./kg bw/day, respectively for the F0 generation and 24-31, 96-123 and 202-252 mg a.i./kg bw/day for the F1 generation respectively). Doses were administered before and throughout mating and gestation until the end of the lactation period in both F0 and F1 generations.
At 2000 ppm, 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 dilatation 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 1000 ppm, P0 (males) and P1 (both sexes) showed 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 250 ppm (corresponding to approximately 16-25 mg a.i./kg bw/day for F0 males and females and 24-31 mg a.i./kg bw/day 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.
The lower food intake, which was most pronounced in period of start of intake as well in F0 as in F1 animals, indicated that the intake was influenced by palatability of the compound and not by a toxic mechanism. At 250 ppm, the small effects on body weight, body weight changes and absolute and relative organ weights were considered to be resulting from reduced food intake. Similar was the case for the 1000 ppm group. As this was not considered to be an adverse toxic effect from exposure to the read across substance, 250 ppm was considered to be the NOAEL for parental systemic toxicity. The NAOEL for mating behaviour, fertility and gestation of each generation was considered to be 2000 ppm. The marginally lower absolute and body weight-related spleen weight of the F2 progeny at 1000 ppm was also considered to be indirectly caused by the lower food intake of F1 parents, and therefore was not considered to be an adverse toxic effect from exposure to the read across substance. Therefore, the NOAEL for development, growth and survival of each progeny was considered to be at 1000 ppm. Under the conditions of the study, the NOAELs for parental, reproductive and development toxicity were established at 250, 2000 and 1000 ppm respectively (Foulon, 2008).
- Endpoint:
- two-generation reproductive toxicity
- Type of information:
- read-across based on grouping of substances (category approach)
- Adequacy of study:
- key study
- Study period:
- 1990
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study
- Remarks:
- KL2 due to RA
- Qualifier:
- according to guideline
- Guideline:
- EPA OPP 83-4 (Reproduction and Fertility Effects)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Test animals
- Source: Sprague-Dawley CD rats were obtained from Charles River Breeding Laboratories, Kingston, NY, USA
- Age at study initiation: Six weeks
- Weight at study initiation: 212.2-213.4 g (males); 148.3-150.2 g (females)
- Housing: Individually in stainless steel, wire mesh cages (22.5x15.5x18.0 cm; mating cages 22.5x31.0x18.0 cm)
- Diet: Certified Ground Rodent Chow # 5002 (Ralstor Purina Co., St. Louis, MO), ad libitum
- Water: Tap water, ad libitum. Water was provided by an automatic watering system with demand control valves mounted on each cage rack.
- Acclimation period: Two weeks
Environmental conditions
- Temperature: 66-73°F
- Humidity: 40-60% - Route of administration:
- oral: feed
- Vehicle:
- other: Certified Ground Rodent Chow # 5002
- Details on exposure:
- Diet preparation: A concentrated premix was prepared by direct addition of the test substance to ground chow and mixing for approximately an hour. Test diets were prepared by appropriate dilutions of the concentrated premix or higher diet concentrations.
- Rate of preparation of diet (frequency): Fresh diet was prepared weekly.
- Mixing appropriate amounts with (Type of food): Certified Ground Rodent Chow # 5002
- Storage temperature of food: Diets were stored in polyethylene containers at room temperature. - Details on mating procedure:
- - M/F ratio per cage: 1:1
- Mating procedure: After pre-breeding exposure the animals were mated on the basis of one male to one female selected randomly within each dose group for a period of 21d to produce F1 generation.
- Proof of pregnancy: Copulation plug and/or vaginal sperm as Day 0 of gestation.
- After the first 7d of the mating period females of unsuccessfully mated pairs were placed with males of other unmated pairs within the same dose group; after an additional 7d, unsuccessfully mated pairs were similarly exchanged again for a period of 7d or until successful mating had occurred, whichever came first, allowing for a total of 21d to mate.
- After successful mating each pregnant female was caged: Pregnant females were housed individually. On Day 20 of gestation each pregnant female was transferred to a shoe-box cage. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Experimental diets were analyzed for stability, homogeneity and concentration of test substance using high pressure liquid chromatography.
- Homogeneity study indicated that the distribution of the test substance in the test diet was uniform.
- Stability study indicated that the dosed feed was stable for at least 14d when stored in open glass feed jars at room temperature. Dosed feed was stable for at least 21d when stored in closed polyethylene containers at room temperature.
- Concentration verification analyses of the dosed feed indicated that the mean concentrations of the test substance in the diet for the 300, 1000 and 2000 ppm dosage levels were 95.3-109.0% of nominal for 300 ppm, 95.6-107.9% of nominal for 1000 ppm and 94.7-108.0% of nominal for 2000 ppm. - Duration of treatment / exposure:
- P0 generation: 19 weeks (from 1st prebreed dose to last F0 sacrifice)
F1 generation: 25 weeks (from 1st F1 wean to last F1 sacrifice)
F2 generation: Until weaning - Frequency of treatment:
- Daily
- Details on study schedule:
- - P1 parental animals not mated until 17-18 weeks after selection from the F1 litters.
- Selection of parents from F1 generation when pups were 28d old.
- Number of P1 generation animals selected: 28 males and 28 females - Remarks:
- Doses / Concentrations:
0, 300, 1000 or 2000 ppm test substance (i.e., 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)).
Basis: nominal in diet - No. of animals per sex per dose:
- 28
- Control animals:
- yes, plain diet
- Details on study design:
- - Rationale for animal assignment: Animals were randomly distributed based on body weight
- Animal identification: By ear tags - Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily
CLINICAL SIGNS: Yes
- Time schedule: Once daily for overt clinical signs.
BODY WEIGHT: Yes
- Time schedule for examinations: Weekly during prebreed and mating for both sexes. For females on gestational Day 0, 6, 15, and 20 and on postnatal Day 0, 7, 14, and 21.
FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- Time schedule: Weekly during prebreed for both sexes. For females in 3- or 4-day intervals throughout gestation and to postnatal Day 14.
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
WATER CONSUMPTION AND COMPOUND INTAKE: No - Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: Yes, maximum of 8 pups/litter (4/sex/litter as nearly as possible). Excess pups were subjected to detailed external examination and then sacrificed.
PARAMETERS EXAMINED
The following parameters were examined in F1 and F2 offspring: Live/Still births on the day of birth (postnatal Day 0), survival indices at Days 0, 4, 7 and 14 after birth and weaning, weight on postnatal Day 1, 4, 7, 14, and at weaning (Day 21), and physical abnormalities for all pups at birth and throughout the pre-weaning period.
GROSS EXAMINATION OF DEAD PUPS: The thoracic and abdominal organs from pups which died after Day 4 were preserved for subsequent histopathological examination. - Postmortem examinations (parental animals):
- SACRIFICE: Yes
- How many animals: All animals
- Necropsy method: Animals were anesthetized with methoxyflurane and exsanguinated by severing the brachial vessel.
GROSS NECROPSY: Yes
- How many animals: All animals sacrificed in F0 and F1 parental animals
- Gross necropsy consisted of: Vagina, uterus, ovaries, gross lesions, testes, epididymis, seminal vesicles and prostrate.
HISTOPATHOLOGY : Yes
- How many animals: All animals of control and high dose groups sacrificed in P0 and P1 parental animals
- Tissues evaluated: Vagina, uterus, ovaries, gross lesions, testes, epididymis, seminal vesicles and prostrate and any tissues or organs showing gross alterations from the low and mid dose groups - Postmortem examinations (offspring):
- SACRIFICE
- The F1 offsprings not selected as parental animals and all F2 offsprings were sacrificed at 7d of age.
GROSS NECROPSY
- Examination for gross lesions was performed on any pup appearing abnormal or dying on test and for ten randomly selected F1 and F2 weanlings/sex/group. - Statistics:
- - The results of the quantitative continuous variables (e.g., body weights, food consumption, etc.) were compared between the three treatment groups and one control group using Levene’s test for equal variances, analysis of variance and (pooled or separate variance) t-test.
- Non-parametric data were statistically evaluated using the Kruskall-Wallis test followed by the Mann-Whitney U test for pairwise comparisons when appropriate.
- Frequency data were compared using the Fisher’s exact test. - Reproductive indices:
- Mating index, fertility index and gestational index were determined.
- Offspring viability indices:
- Live birth index, 4-d survival index, 7-d survival index, 14-d survival index, 21-d survival index and lactation index
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No significant signs of toxicity during the pre-breed, mating, gestation or lactation periods at any dose for either generation were observed.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- - During the 10-week pre-breed exposure, F0 males exhibited no reduction in body weight. During the same period, F0 females at 2000 ppm exhibited reduction in body weight during Weeks 5, 6, 9 and 10 of pre-breed treatment. Body weight gain was also reduced at 2000 ppm for one week (Week 8-9) during the pre-breed period.
- On lactation Day 21 mean body weight of F0 dams at 2000 ppm exhibited a significant increase. Increased lactation body weight gain was observed at 2000 ppm throughout lactation. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- - Food consumption in the F0 females at 2000 ppm was reduced for the first four exposure weeks. Food consumption in F0 males was significantly reduced at 2000 ppm for the first week of treatment only.
- At F0 breed to produce F1 litters, food consumption during gestation and lactation was unaltered by treatment. - Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- effects observed, treatment-related
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- Mating index, fertility index and gestational index
No treatment-related effects on any reproductive parameters were observed at any dose; NOEL (parental) = 1000 ppm - Key result
- Dose descriptor:
- NOAEL
- Remarks:
- systemic toxicity
- Effect level:
- 1 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- food consumption and compound intake
- Remarks on result:
- other: i.e., equivalent to 51-102 mg/kg bw/day (or 41-83 mg a.i./kg bw/day) in males and 67-106 mg/kg bw/day (or 54-86 mg a.i./kg bw/day) in females
- Key result
- Dose descriptor:
- NOEL
- Remarks:
- reproductive toxicity
- Effect level:
- 2 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no reproductive toxicity observed
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Remarks:
- i.e., equivalent to 100-188 mg/kg bw/day (or 81-152 mg a.i./kg bw/day) in males and 139-198 mg/kg bw/day (or 113-161 mg a.i./kg bw/day) in females
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 1 000 ppm
- System:
- other: body weight and food consumption
- Treatment related:
- yes
- Dose response relationship:
- yes
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No significant signs of toxicity during the pre-breed, mating, gestation or lactation periods at any dose for either generation were observed.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- At 2000 ppm, only slight reduction were observed in males and females
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not examined
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- Mating index, fertility index and gestational index
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- systemic toxicity
- Effect level:
- 1 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- Remarks on result:
- other: i.e., equivalent to 51-102 mg/kg bw/day (or 41-83 mg a.i./kg bw/day) in males and 67-106 mg/kg bw/day (or 54-86 mg a.i./kg bw/day) in females
- Key result
- Dose descriptor:
- NOEL
- Remarks:
- reproductive toxicity
- Effect level:
- 2 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no reproductive toxicity observed
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Remarks:
- i.e., equivalent to 100-188 mg/kg bw/day (or 81-152 mg a.i./kg bw/day) in males and 139-198 mg/kg bw/day (or 113-161 mg a.i./kg bw/day) in females
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 2 000 ppm
- System:
- other: body weight
- Treatment related:
- yes
- Dose response relationship:
- yes
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- There were no signs of toxicity in the F1 or F2 animals.
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- no mortality observed
- Description (incidence and severity):
- There was no effects of treatment on postnatal deaths.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- The F1 litters exhibited reduced body weight per litter on postnatal Days 21 and 28 at 2000 ppm. F1 pup body weight gain was reduced during lactation Days 14-21 and 21-28.
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- There were no treatment-related observations or histopathological findings in either the F0 or F1 adult animals at any dose. There were no treatment-related findings in the F1 or F2 pups that died during lactation or randomly selected F1and F2 pups at necropsy.
- Histopathological findings:
- no effects observed
- Description (incidence and severity):
- There were no treatment-related observations or histopathological findings in either the F0 or F1 adult animals at any dose. There were no treatment-related findings in the F1 or F2 pups that died during lactation or randomly selected F1and F2 pups at necropsy.
- Behaviour (functional findings):
- not examined
- Developmental immunotoxicity:
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- general toxicity
- Generation:
- F1
- Effect level:
- 1 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- Remarks on result:
- other: i.e., equivalent to 51-102 mg/kg bw/day (or 41-83 mg a.i./kg bw/day) in males and 67-106 mg/kg bw/day (or 54-86 mg a.i./kg bw/day) in females
- Key result
- Dose descriptor:
- NOEL
- Remarks:
- developmental toxicity
- Generation:
- F1
- Effect level:
- 2 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no effects observed
- Remarks on result:
- other: i.e., equivalent to 100-188 mg/kg bw/day (or 81-152 mg a.i./kg bw/day) in males and 139-198 mg/kg bw/day (or 113-161 mg a.i./kg bw/day) in females
- Key result
- Critical effects observed:
- no
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- There were no signs of toxicity in the F1 or F2 animals.
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- no mortality observed
- Description (incidence and severity):
- There was no effects of treatment on postnatal deaths.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- F2 pup weights per litter were reduced at 2000 ppm on postnatal Day 28. Pup weight gain was also reduced at 2000 ppm during lactation Days 14-21 and for Days 21-28.
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- There were no treatment-related observations or histopathological findings in either the F0 or F1 adult animals at any dose. There were no treatment-related findings in the F1 or F2 pups that died during lactation or randomly selected F1and F2 pups at necropsy.
- Histopathological findings:
- no effects observed
- Behaviour (functional findings):
- not examined
- Developmental immunotoxicity:
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- general toxicity
- Generation:
- F2
- Effect level:
- 1 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- Remarks on result:
- other: i.e., equivalent to 51-102 mg/kg bw/day (or 41-83 mg a.i./kg bw/day) in males and 67-106 mg/kg bw/day (or 54-86 mg a.i./kg bw/day) in females
- Key result
- Dose descriptor:
- NOEL
- Remarks:
- developmental toxicity
- Generation:
- F2
- Effect level:
- 2 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no effects observed
- Remarks on result:
- other: i.e., equivalent to 100-188 mg/kg bw/day (or 81-152 mg a.i./kg bw/day) in males and 139-198 mg/kg bw/day (or 113-161 mg a.i./kg bw/day) in females
- Key result
- Critical effects observed:
- no
- Key result
- Reproductive effects observed:
- no
- Conclusions:
- Based on the results of the read across study, the rat NOAEL (systemic toxicity) for both parental generation (P0 and F1) and offspring (F1 and F2) was considered to be at 1000 ppm (in diet), equivalent to 51-102 mg a.i./kg bw/day in males and 67-106 mg/kg bw/day for female, respectively. The rat NOEL (reproductive toxicity) although not specified by the authors in the study report, can be considered to be at the highest tested dose 2000 ppm (in diet), equivalent to 100-188 mg/kg bw/day for males and 139-198 mg/kg bw/day in females.
- Executive summary:
A two-generation study was conducted to determine the toxicity to reproduction of the read across substance, C12-16 ADBAC (81.09% active in aqueous/ethanol solution) according to US EPA OPP 83-4, in compliance with GLP. The read across substance was orally administered to Sprague-Dawley CD rats (28/sex/group) at dose levels of 0, 300, 1000 or 2000 ppm read across substance (equivalent to average doses of 0, 16-31, 51-102, and 100-188 mg/kg bw/day for males and 0, 21-32, 67-106 and 139-198 mg/kg bw/day in females) in the diet. Following a 10-week pre-breed exposure period, the P0 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, twenty-eight (28) F1 weanling/sex/group were randomly selected and exposed to the same dietary concentration of the read across substance as their parents for 10 weeks. After their pre-breed exposure, F1/P1 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 P0 and F1 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. Remaining non-selected F1 and F2 pups at weaning were euthanised and discarded.
Reduced body weights in F0 males (but no F0 males or F1 males and females), reduced weight gain in F0 males and females and F1 males (but not F1 females) and reduced food consumption in F0 males and females and F1 males (but not F1 females) during the ten-week pre-breed exposures was observed. With the exception of body weights and food consumption in F0 females, reductions in the pre-breed parameters appeared transitory, disappearing after one or two weeks. Reproductive parameters were not affected in either of the two breeds (F1 or F2). At initiation of the gestational period, body weights of the F0 (but not F1) females at 2000 pp, were reduced; weight gains through-out gestation for both breeds were normal. Reduced gestations food consumption was observed in F1 females only.
F1 litters at 2000 ppm exhibited reduced body weights at weaning; both F1 and F2 generations of pups exhibited reduced body weights on Day 28 postpartum, one week subsequent to weaning. Body weight gains in both F1 and F2 litters were reduced for corresponding time intervals (lactational days 14-21 and 21-28) as well. The reduction in pup body weights (and weight gain) at 2000 ppm was considered to be treatment related as it corresponded to the time when the pups began to rely solely on the read across substance diet as their source of nutrition. While the statistical reductions were observed only for female pup body weight gains on lactation days 21-28 in F1 litters and for male pups on days 14-21 in F2 litters, body weight gain reductions were apparent in both sexes of pups during these time periods. There were no treatment-related observations or histopathological findings in either the F0 or F1 adult animals at any dose. There were no treatment-related findings in the F1 or F2 pups that died during lactation or randomly selected F1and F2 pups at necropsy. Under the conditions of the study, it can be stated that, dietary administration of the read across substance at dose levels of 0, 300, 1000 and 2000 ppm for two generations to Sprague-Dawley rats was well tolerated and no sign of reproductive toxicity was observed at any dose level. Also, there was no increased risk to the offspring in the absence of indications of maternal toxicity. The rat NOAEL (systemic toxicity) for both parental generation (P0 and F1) and offspring (F1 and F2) was considered to be at 1000 ppm (in diet), equivalent to 51-102 mg a.i./kg bw/day in males and 67-106 mg/kg bw/day for female, respectively. The rat NOEL (reproductive toxicity) although not specified by the authors in the study report, can be considered to be at the highest tested dose 2000 ppm (in diet), equivalent to 100-188 mg/kg bw/day for males and 139-198 mg/kg bw/day in females (Neeper-Bradley, 1990).
Referenceopen allclose all
For further details, see under Any other information on results incl. tables.
The mean achieved dosages of the test
substance for the dose-levels of 250, 1000 and 2000 ppm of test
substance were as follows:
F0 generation
- males (Days 1 to 106): 16, 61 and 123 mg/kg bw/day, respectively,
- females:
during premating period (Days 1 to 71): 19, 74 and 154
mg/kg bw/day, respectively,
during pregnancy period (Days 0 to 20 p.c.): 18, 69 and 145 mg/kg
bw/day, respectively,
during lactation period (Days 1 to 21 p.p.): 37, 159 and 326 mg/kg
bw/day, respectively.
F1 generation
- males (Days 1 to 120): 24, 96 and 202 mg/kg bw/day, respectively,
- females:
during premating period (Days 1 to 64): 32, 127 and 269 mg/kg
bw/day, respectively,
during pregnancy period (Days 0 to 20 p.c.): 21, 83 and 164 mg/kg
bw/day, respectively,
during lactation period (Days 1 to 21 p.p.): 41, 162 and 323 mg/kg
bw/day, respectively.
The actual intake of test substance for both males and females given
250, 1000 and 2000 ppm throughout the study is approximately
16-25, 61-101 and 123-208 mg/kg bw/day, respectively for the
F0 generation and 24-31, 96-123 and 202-252 mg/kg bw/day for
the F1 generation.
Details on results:
Parent males (F0):
No effects:mortality, clinical signs, mating and fertility indices, seminology parameters, macroscopic post-mortem examination and histopathology.
Body weight:
During the first week of dosing, the body weight gains were slightly low at the low and mid dose-levels (-13% and -11%, p<0.01, p<0.05, respectively) and moderately low at the high dose-level (days 1 to 8, -24%, p<0.001). This effect on body weight gain was observed over all the dosing period (days 1 to 106, - 11%, p<0.01; -8%, non-statistically significant and -20%, p<0.001, at 250, 1000 and 2000 ppm, respectively).
At all dose-levels, when compared to controls, body weights were marginally lower for the low and mid dose-levels (between -5 and -7%, p<0.01) and slightly lower for the high dose-level during most of the dosing period (-13%, p<0.001).
Food consumption:the food consumption during the premating period was marginally low at 250 and 1000 ppm reaching statistical significance during the first weeks of dosing (weeks 1, 3 and 4) and sporadically during 5 or 7 weeks (between -7% and -10%, p< 0.01, p<0.001). This effect was more marked at 2000 ppm and was statistically significant during the whole dosing period (between -7 and -14%, p<0.01, p<0.001).
Organ weights (expressed in %)
Lower absolute and body weight-related liver weights in the males given 1000 or 2000 ppm were statistically significant. In addition, the absolute value of the differences observed was of higher magnitude than that observed for the differences in body weights and the absolute and body weight-related differences were dose-related in the males. These differences were considered to be due to the treatment with the test substance, C12-16 ADBAC. It is worth mentioning that similar differences in liver weight without histomorphological changes were observed in the previous 90-day study.
Parent females F0
No effects:mortality, clinical signs, mating and fertility indices, estrous cycle, pregnancy and parturition data (implantation, fecundity, post-implantation, and neo-natal losses, gestation and delivery parameters) and histopathology.
Body weight:The body weight gain was unaffected by treatment at 250 and 1000 ppm. A moderately, statistically significantly, low body weight gain was observed at 2000 ppm during the first and the fourth week of premating (-31%, p<0.001 and -38%, p<0.01, respectively) and over all pregnancy (-13%, p<0.01) while it increased during the lactation period (24 g vs. 0 g, p<0.001). At this latter dose-level, body weights were lower during most of the dosing period (ranging between -4 and -9%, p<0.05, p<0.01) but returned to values comparable to controls at the end of the lactation period (316 g vs. 325 g in controls).
Food consumption:
The food consumption was unaffected by the treatment at 250 and 1000 ppm while it was slightly reduced at 2000 ppm, reaching statistical significance during the first week of dosing (-11%, p<0.001), during 2 weeks of the premating period (days 22 to 29 and days 64 to 71, -5% p<0.01) and during 2 weeks of the pregnancy period (days 0 to 7 p.c., -4%, p<0.05 and days 7 to 14,
-8%, p<0.001).
During the first week of the lactation period, group mean food consumption was slightly increased in the group given 2000 ppm and values were thereafter comparable to controls until the end of lactation.
Organ weights (expressed in %)
Lower absolute and body weight-related liver weights in females given 1000 or 2000 ppm were statistically significant. In addition, the absolute value of the differences observed was of higher magnitude than that observed for the differences in body weights. These differences were considered to be due to the treatment with the test item BKC. It is worth mentioning that similar differences in liver weight without histomorphological changes were observed in the previous 90-day study.
Macroscopic post-mortem examination
Some segments of the intestinal tract were distended with faeces at necropsy with higher incidence in the females given 2000 ppm, compared with their respective controls.
Although no microscopic finding could be correlated, considering the higher incidence of this finding in the test item-treated females compared with their respective controls, distension of intestinal tract was considered to be related to treatment with the test item. This included:
- ileum in 1/25 females given 1000 ppm and 5/25 females given 2000 ppm vs. none control female,
- coecum in 1/25 females given 250 ppm, 8/25 given 1000 ppm and 12/25 females given 2000 ppm vs. 2/25 control females,
- colon in 1/25 females given 1000 ppm and 2/25 females given 2000 ppm vs. none control female.
F1 males
No effects:mortality, clinical signs, neurobehavioral tests, mating and fertility indices, seminology parameters and histopathology.
Body weight:On day 1 (post-natal day 22), the body weight was slightly lower at 2000 ppm (-13%, p<0.001) while it was minimally, but not statistically significantly,
affected at 1000 ppm (-5%) and was similar to controls at 250 ppm. During the whole dosing period, the body weight was generally slightly (for the low and mid-dose levels) to moderately (for the high dose-level), but statistically significantly, lower. The body weight gain was statistically significantly lower during the two first weeks of dosing at all dose-levels and remained markedly lower over all the dosing period at the high dose-level (days 1 to 120, - 18%,p<0.001).
Food consumption:
In the males, group mean food consumption was slightly to moderately lower at all dose-levels (ranging between -7 and -21%, p<0.05, p<0.01, p<0.001) reaching statistical significance during many periods at the low and mid dose- levels and during all recorded periods at the high dose-level (p<0.01, p<0.001).
Sexual development
The mean age at preputial separation (cleavage of the balanopreputial gland) was unaffected by the treatment at 250 and 1000 ppm (i.e occurred at 49.6 and
50.1 day old, respectively vs. 47.8 day old in controls) while, when compared to the male control group, a significant difference was observed in males given 2000 ppm (52.80 ± 6.02 vs. 47.76 ± 2.62 days, p<0.0019). It was not statistically significant when body weight was considered as a covariate, which suggests that this effect was the consequence of a lower body weight rather than a direct effect on sexual development.
Organ weights (expressed in %)
Lower absolute and/or body weight-related liver weights in the males given 250, 1000 or 2000 ppm were observed, with statistical significance. In addition, the absolute value of the differences observed was of higher magnitude than that observed for the differences in body weights. These differences were therefore considered to be due to treatment with the test item, BKC. It is worth mentioning that similar differences in liver weight without histomorphological changes were observed in the previous 90-day study and similar differences in liver weights were also noted in the F0 generation.
Macroscopic post-mortem examination
The coecum was distended with faeces in 1/25 males given 1000 ppm and in 4/25 males given 2000 ppm.
Although no microscopic finding could be correlated (at least for the macroscopic abnormalities which were examined), considering the previous observations made in the intestinal tract in the females of the F0 generation, this finding reported in a few test item-treated animals of both sexes, was considered to be most probably related to treatment with the test item.
F1 females
No effects:mortality, clinical signs, neurobehavioral tests, mating and fertility indices, oestrous cycle, pregnancy and parturition data (with the exception of number of implantation sites and number of live foetuses), and histopathology.
Body weight:On day 1 (post-natal day 22), the body weight was statistically significantly lower at 1000 and 2000 ppm (-6%, p<0.005 and -13%, p<0.001, respectively) and remained lower over all the premating and pregnancy periods until the second week of lactation. The body weight gain was marginally reduced (-9%, not statistically significant and -15% p<0.001, for the low and mid-dose-levels, respectively) to markedly reduced (-41%, p<0.001 for the high dose-level) during the first week of premating and over the pregnancy periods (-10%, -11%, -19%, respectively, p<0.01 or p<0.001) while it was increased when compared to controls during the lactation period.
Food consumption:
In the females, group mean food consumption was unaffected by the treatment at the low and mid dose-groups while it was lower at 2000 ppm during premating and pregnancy, reaching statistical significance during most of the recorded periods (ranging between -9 and -14%, p<0.01, p<0.001). No effect was noted during the lactation period.
Sexual development
The mean age for vaginal opening was unaffected by the treatment, i.e. occurred on days 34.1, 33.7, 35.4 for pups from the control, 250 and 1000 ppm groups, respectively while it was delayed for 4 days at 2000 ppm.
When compared to the female control group, a significant difference was observed in females given 2000 ppm (38.40 ± 5.16 vs. 34.12 ± 2.19 in controls p<0.0001), however it was not statistically significant when body weight was considered as a covariate which suggests that this effect was the consequence of a lower body weight rather than a direct effect on sexual development.
Furthermore, animals that had values outside the range of individual control values had the lowest weight at sexual maturity which confirm that this effect was the consequence of reduced body weight and not a direct effect on sexual development.
Pregnancy and parturition data
The statistically significantly lower number of implantation sites and the lower number of live foetuses (-13%, p<0.001 for both parameters) in females given 2000 ppm when compared to controls, were considered to be treatment- related, although these values were within the range of historical control data.
Organ weights (expressed in %)
Lower absolute and/or body weight-related liver weights in the females given 250, 1000 or 2000 ppm were observed, with statistical significance and dose- relationship in the females. In addition, the absolute value of the differences observed was of higher magnitude than that observed for the differences in body weights. These differences were therefore considered to be due to treatment with the test item, BKC. It is worth mentioning that similar differences in liver weight without histomorphological changes were observed in the previous 90-day study and similar differences in liver weights were also noted in the F0 generation.
Macroscopic post-mortem examination
The cecum was distended with feces in 2/25 females given 2000 ppm. Although no microscopic finding could be correlated (at least for the macroscopic abnormalities which were examined), considering the previous observations made in the intestinal tract in the females of the F0 generation, this finding reported in a few test item-treated animals of both sexes, was considered to be most probably related to treatment with the test item.
F2 males
No effects:viability and lactation indices, clinical signs, gross external abnormalities, assessment of reflex development (surface righting, cliff avoidance and air righting) and macroscopic post-mortem examination.
Body weight:No effects on body weight or body weight gain were noted at 250 and 1000 ppm while slightly lower body weight gain was observed at 2000 ppm between day 4 and day 21 post-partum (-8%, p<0.05).
Although this difference in body weight gain was slight, it was considered to be possibly related to the treatment.
Organ weights (expressed in %)
Considering that the differences in absolute and body weight-related weights of the spleen of the animals given 1000 or 2000 ppm were dose-related in the two sexes and that the absolute value of the difference in the absolute spleen weight was marginally higher than that observed for the difference in body weight at necropsy, a relationship to treatment could not be excluded, as similar changes were observed in the spleen weights of the pups of the F1 generation.
Macroscopic post-mortem examination
The cecum was distended with feces in 2/25 females given 2000 ppm. Although no microscopic finding could be correlated (at least for the macroscopic abnormalities which were examined), considering the previous observations made in the intestinal tract in the females of the F0 generation, this finding reported in a few test item-treated animals of both sexes, was considered to be most probably related to treatment with the test item.
F2 females
No effects:viability and lactation indices, clinical signs, gross external abnormalities, assessment of reflex and physical development (surface righting, cliff avoidance and air righting) and macroscopic post-mortem examination.
Body weight:No effects on body weight or body weight gain were noted at 250 and 1000 ppm while slightly lower body weight gain was observed at 2000 ppm between day 4 and day 21 post-partum (-8%, p<0.05).
Although this difference in body weight gain was slight, it was considered to be possibly related to the treatment.
Organ weights (expressed in %)
Considering that the differences in absolute and body weight-related weights of the spleen of the animals given 1000 or 2000 ppm were dose-related in the two sexes and that the absolute value of the difference in the absolute spleen weight was marginally higher than that observed for the difference in body weight at necropsy, a relationship to treatment could not be excluded, as similar changes were observed in the spleen weights of the pups of the F1 generation.
Offspring of F0 parents (F1 pups)
No effects:viability and lactation indices, clinical signs and gross external abnormalities, assessment of reflex development and macroscopic post-mortem examination.
Body weight:At birth, pup body weights were unaffected by the treatment at all dose-levels. During the lactation period, pup body weight and body weight gain were not affected at 250 ppm.
At 1000 and 2000 ppm, pup body weight gains were statistically significantly lower during the last week of lactation (-9%, p<0.05 and -11%, p<0.01) while body weight was statistically significantly lower on day 21 post-partum for the high-dose only (-7%, p<0.05). This effect was considered to be most probably related to pup food intake (which normally started during the last week of lactation) and was therefore considered to be related to the treatment.
Organ weights (pups sacrificed at weaning)
Dose-related lower absolute and body weight-related spleen weights were observed in the male and female pups given 1000 or 2000 ppm. This achieved statistical significance for the absolute weight for the animals given 2000 ppm. Almost all the individual weights were within the control range for the test item-treated animals; however they were gathered at the lower limit of the range, especially at the high dose-level.
For the differences in spleen weights, a relationship to treatment with the test item cannot be ruled out, as the same trend was observed in the pups of the F1 generation. However, they might be stress-related, considering the young age of the animals and/or the consequence, at least in part, of the decrease in body weight.
Results for F0 and F1 generation summarised according to dose groups:
The following results were obtained:
F0 generation (during premating, mating, pregnancy and lactation until day 21 post-partum of F0 parents and post-natal day 21 for their progeny)
Group 4: 2000 ppm
- no treatment related clinical signs or mortality were noted,
- for the parent males, over all the dosing period, statistically significantly low food consumption (between -7 and -14%, p<0.01 and p<0.001), low body weights (-6 and -13%, p<0.001) and reduced body weight gains (- 20%, p<0.001) were noted,
- for the parent females, the food consumption was reduced during the first week of the premating period (-11%, p<0.001) and during the 2 first weeks of pregnancy (-9% and -8%, respectively). This was associated with lower body weight gain during the first week of the premating period (-31%, p<0.001), during the pregnancy period (-13%, p<0.01) and lower body weights over all the premating and pregnancy periods (between -4% and -9%, p<0.05, p<0.01). The food consumption and the body weight gains were slightly increased during the first week of lactation,
- no effect on mating, male and female fertility (including estrous cycle and seminology parameters) or on the progress of pregnancy or delivery,
- no effect on pup survival (F1 generation pups) while reduced pup body weight gain was noted during the last week of lactation (-11%, p<0.01),
- necropsy of parents revealed dilatation of ileum in 5/25 females, dilatation of cecum in 12/25 females and of the colon in 2/25 females,
- lower absolute and body weight-related liver weights in parental males (respectively, -23%, -11%, p<0.01) and females (respectively, -16 % and
- 11%, p<0.01) and lower absolute and relative spleen weights of their progeny (respectively, -16%, p<0.05 and -9% for the males, -14%, p<0.05 and -8% for the females),
- no histopathological findings were noted at microscopic examination of the different organs (including reproductive organs).
Group 2 and 3: 250 and 1000 ppm
- no treatment related deaths or clinical signs were observed,
- for the parent males, the food consumption was marginally low during the first week of dosing and sporadically during 4 or 5 weeks (between -7% and -10%, p<0.01, p<0.001) and was associated with a slightly low body weight gain during the first week of dosing (-13% and -11%, p<0.01, p<0.05, respectively) and over all the dosing period (-11%, p<0.05; -8%, respectively at both dose-levels),
- for the parent females, the food consumption and body weight gains were unaffected by the treatment,
- no effect on mating, male and female fertility (including estrous cycle and seminology parameters), gestation, fecundity or delivery,
- no effect on progeny survival from delivery until weaning (F1 generation pups),
- necropsy of parental males and females given 1000 ppm revealed dilatation of the cecum with feces in 8/25 females and dilatation of the ileum and the colon in 1/25 females,
- at 1000 ppm, there were lower absolute and body weight-related liver weights of parental males (respectively, -12%, p<0.05 and -7%, p<0.05) and females (-14% and -11%, p<0.01) and marginal, non-statistically significant, lower absolute and body weight-related progeny spleen weights (-7% and -4% for the males and -9% and -6% for the females),
- at 250 ppm, no effect was noted on parents or progeny‟ organ weights,
- no histopathological findings were noted at microscopic examination of the different parental organs (including reproductive organs) at either dose-level.
F1 generation (from post-natal day 22, during mating, pregnancy and lactation until day 21 post-partum)
Group 4: 2000 ppm
- no treatment-related clinical signs or mortality in parental males or females,
- for the males, the food consumption was lower during the whole dosing period (between -12 and -21%, p<0.0001) and the body weight and body weight gain were moderately lower over all the dosing period (-18%, p<0.001),
- for the females, reduced food consumption was noted during the premating and pregnancy periods (ranging between -9% and -14%, p<0.01 and p<0.001). This was associated with lower body weight from the first day of the premating period until the second week of lactation and lower body weight gain during the first week of premating (-41%, p<0.001) and over all the premating and pregnancyperiods,
- the mean age of preputial separation and vaginal opening was delayed for approximately 5 and 4 days, respectively (52.8 vs. 47.76 day old for preputial separation and 38.4 vs. 34.12 day old for vaginal opening) as a consequence of lower body weight, while no effect was noted on their locomotor activity or on neurobehavioralparameters,
- no effects were noted on mating or parental fertility (including number of pregnant females with liveborn, estrous cycle and seminology parameters), however, the number of implantation sites and the litter size at birth were reduced (13 vs. 14.9 and 12.4 vs. 14.2, p<0.01, respectively),
- the pup weight gain of the progeny of the F1 generation (F2 generation pups) was slightly lower during the lactation period (-8%,p<0.05),
- necropsy of the F1 generation revealed dilatation of the cecum with feces in 4/25 males and 2/25females,
- lower absolute and body weight-related liver weights of parental males (respectively, -28% and -12%, p<0.01) and females (respectively, -25% and -18%, p<0.01) and decreased absolute and relative spleen weights of their progeny (-23%, p<0.01 and -10% for the males, -26% and -14%, p<0.01 for the females),
- no histopathological findings were noted at microscopic examination of the different organs (including reproductiveorgans).
Group 3: 1000 ppm
- no treatment-related clinical signs in parental males andfemales,
- for the males, the food consumption was statistically significantly lower during many dosing periods (between -6% and -11%, p<0.05, p<0.01, p<0.001) and was associated with a slightly lower body weight and body weight gain over all the dosing period (-7%),
- for the females, the body weight and food consumption were slightly lower during the first week of premating and during pregnancy (body weight: -15%, p<0.001 and -11%, p<0.01, food consumption: between -9 and -14%, p<0.01,p<0.001),
- no effect on mating, parental fertility (including estrous cycle and seminology parameters), gestation, fecundity ordelivery,
- no effect on pup development and progeny survival from delivery until weaning,
- no effect on locomotor activity and neurobehavioural parameters of the progeny,
- necropsy of the parents revealed dilatation of coecum with faeces in 1/25 males,
- lower absolute and body weight-related liver weights of parental males (respectively, -13%, p<0.05 and -6%, not statistically significant) and females (respectively, -17% and -14%, p<0.01) and marginally lower absolute and body weight-related spleen weight of their progeny (-3% for the males and -11 and -10%, respectively for the females),
- no histopathological findings were noted at microscopic examination of the different organs (including reproductive organs).
Group 2: 250 ppm
- no effects at clinical examination of the male and female parents,
- for the males, body weight and body weight gain were slightly, but statistically significantly, lower during most of the dosing period (-9%, p<0.05) while the food consumption was transiently lower,
- for the females, the body weight gain was slightly lower during pregnancy (days 0 to 20 p.c., -10%, p<0.01) while no effect was noted on food consumption,
- no effect on mating, male and female parental fertility (including estrous cycle and seminology parameters), gestation, fecundity or delivery,
- no effect on sexual development or on neurobehavioral parameters,
- no effect on the development of the progeny from delivery until weaning,
- no macroscopic findings in parental males and females or their progeny,
- lower absolute and body weight-related liver weights of parental males (respectively, -14%, p<0.05 and -6%, not statistically significant) and females (respectively, -14% and -12%, p<0.01) but no effect was observed on organ weights of the progeny,
- no microscopic findings for male and female parents.
For result tables, kindly refer to the attached background material section of the IUCLID.
Effect on fertility: via oral route
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 16 mg/kg bw/day
- Study duration:
- subchronic
- Experimental exposure time per week (hours/week):
- 168
- Species:
- rat
- Quality of whole database:
- Guideline compliant read across studies. No specific reproductive toxicity or true systemic effects
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
Study 1: A two-generation study was conducted to determine the toxicity to reproduction of the read across substance, C12 -16 ADBAC (49.9% active in water) according to OECD Guideline 416, in compliance with GLP. In this study, the substance was administered in the diet to male and female Sprague-Dawley rats at dose levels of 0, 250, 1000 and 2000 ppm (i.e., equivalent to 0, 16-25, 61-101 and 123- 208 mg a.i./kg bw/day, respectively for the F0 generation and 24-31, 96-123 and 202-252 mg a.i./kg bw/day for the F1 generation respectively). Doses were administered before and throughout mating and gestation until the end of the lactation period in both F0 and F1 generations.
At 2000 ppm, 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 dilatation 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 1000 ppm, P0 (males) and P1 (both sexes) showed 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 250 ppm (corresponding to approximately 16-25 mg a.i./kg bw/day for F0 males and females and 24-31 mg a.i./kg bw/day 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.
The lower food intake, which was most pronounced in period of start of intake as well in F0 as in F1 animals, indicated that the intake was influenced by palatability of the compound and not by a toxic mechanism. At 250 ppm, the small effects on body weight, body weight changes and absolute and relative organ weights were considered to be resulting from reduced food intake. Similar was the case for the 1000 ppm group. As this was not considered to be an adverse toxic effect from exposure to the read across substance, 250 ppm was considered to be the NOAEL for parental systemic toxicity. The NAOEL for mating behaviour, fertility and gestation of each generation was considered to be 2000 ppm. The marginally lower absolute and body weight-related spleen weight of the F2 progeny at 1000 ppm was also considered to be indirectly caused by the lower food intake of F1 parents, and therefore was not considered to be an adverse toxic effect from exposure to the read across substance. Therefore, the NOAEL for development, growth and survival of each progeny was considered to be at 1000 ppm. Under the conditions of the study, the NOAELs for parental, reproductive and development toxicity were established at 250, 2000 and 1000 ppm respectively (Foulon, 2008).
Study 2: A two-generation study was conducted to determine the toxicity to reproduction of the read across substance, C12-16 ADBAC (81.09% active in aqueous/ethanol solution) according to US EPA OPP 83-4, in compliance with GLP. The read across substance was orally administered to Sprague-Dawley CD rats (28/sex/group) at dose levels of 0, 300, 1000 or 2000 ppm read across substance (equivalent to average doses of 0, 16-31, 51-102, and 100-188 mg/kg bw/day for males and 0, 21-32, 67-106 and 139-198 mg/kg bw/day in females) in the diet. Following a 10-week pre-breed exposure period, the P0 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, twenty-eight (28) F1 weanling/sex/group were randomly selected and exposed to the same dietary concentration of the read across substance as their parents for 10 weeks. After their pre-breed exposure, F1/P1 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 P0 and F1 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. Remaining non-selected F1 and F2 pups at weaning were euthanised and discarded.
Reduced body weights in F0 males (but no F0 males or F1 males and females), reduced weight gain in F0 males and females and F1 males (but not F1 females) and reduced food consumption in F0 males and females and F1 males (but not F1 females) during the ten-week pre-breed exposures was observed. With the exception of body weights and food consumption in F0 females, reductions in the pre-breed parameters appeared transitory, disappearing after one or two weeks. Reproductive parameters were not affected in either of the two breeds (F1 or F2). At initiation of the gestational period, body weights of the F0 (but not F1) females at 2000 pp, were reduced; weight gains through-out gestation for both breeds were normal. Reduced gestations food consumption was observed in F1 females only.
F1 litters at 2000 ppm exhibited reduced body weights at weaning; both F1 and F2 generations of pups exhibited reduced body weights on Day 28 postpartum, one week subsequent to weaning. Body weight gains in both F1 and F2 litters were reduced for corresponding time intervals (lactational days 14-21 and 21-28) as well. The reduction in pup body weights (and weight gain) at 2000 ppm was considered to be treatment related as it corresponded to the time when the pups began to rely solely on the read across substance diet as their source of nutrition. While the statistical reductions were observed only for female pup body weight gains on lactation days 21-28 in F1 litters and for male pups on days 14-21 in F2 litters, body weight gain reductions were apparent in both sexes of pups during these time periods. There were no treatment-related observations or histopathological findings in either the F0 or F1 adult animals at any dose. There were no treatment-related findings in the F1 or F2 pups that died during lactation or randomly selected F1and F2 pups at necropsy. Under the conditions of the study, it can be stated that, dietary administration of the read across substance at dose levels of 0, 300, 1000 and 2000 ppm for two generations to Sprague-Dawley rats was well tolerated and no sign of reproductive toxicity was observed at any dose level. Also, there was no increased risk to the offspring in the absence of indications of maternal toxicity. The rat NOAEL (systemic toxicity) for both parental generation (P0 and F1) and offspring (F1 and F2) was considered to be at 1000 ppm (in diet), equivalent to 51-102 mg a.i./kg bw/day in males and 67-106 mg/kg bw/day for female, respectively. The rat NOEL (reproductive toxicity) although not specified by the authors in the study report, can be considered to be at the highest tested dose 2000 ppm (in diet), equivalent to 100-188 mg/kg bw/day for males and 139-198 mg/kg bw/day in females (Neeper-Bradley, 1990).
The biocides assessment reports available from RMS Italy on C12-16 ADBAC and Coco TMAC, overall concluded similarly that these substances do not indicate a concern for reproduction toxicity. However, the corrected dietary doses were slightly different in the C12-16 ADBAC biocides assessment report, where the NOAELs for parental and offspring toxicity were both reported be >50 and >30 mg/kg bw/day and the NOAELs for effects on fertility was reported to be >100 and >52 mg/kg bw/day for the Foulon, 2008 and Neeper-Bradley, 1990 studies respectively (ECHA biocides assessment report, 2015, 2016). The assessment report on Coco TMAC, which contained only the Foulon 2008 study however corresponded to the NOAELs summarized in this dossier. Nevertheless, due to the absence of specific reproductive toxicity and the fact that the observed effects in parents relate to general toxicity which are secondary to local effects, the parental NOAELs (16 mg/kg bw/day) were not considered to be relevant to the determination of a systemic DNELs.
In line with the biocides assessment report, the NOAELs from the 2-generation reproductive toxicity studies in rats have not been considered further for systemic risk assessment.
Effects on developmental toxicity
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no study available
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
Based on the results of the read across two-generation reproductive toxicity studies in rats, the test substance does not warrant a classification according to the EU CLP criteria (Regulation 1272/2008/EC).
Additional information
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