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EC number: 214-787-5 | CAS number: 1194-65-6
- 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
Effects on fertility
Description of key information
The NOEL for the test material was determined to be 3 mg/kg bw/day according to a two generation rat study performed in line with EPA Guideline OPP 83-4.
Link to relevant study records
- Endpoint:
- two-generation reproductive toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 30 July 1987 to 21 April 1989
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- EPA OPP 83-4 (Reproduction and Fertility Effects)
- Deviations:
- yes
- Remarks:
- (actual relative humidity was 20-94%; three incorrect pups were selected for the F1 generation; in addition, the following protocol deviation was also reported; on three occasions test diets were prepared in advance and stored frozen)
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- other: Crl:CD(SD)BR
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: (P) approxaimtely 6 wks; (F1) nominally 4 wks
- Weight at study initiation: (P) Males: 139.7-217.4 g; Females: 107.7-149.9 g;
- Housing: stainless steel wireless cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 12 days
ENVIRONMENTAL CONDITIONS
- Temperature: 19-25 °C
- Humidity: 40-70 %
- Air changes: minimum 15 per hour
- Photoperiod: 12 hours light/12 hours dark - Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- DIET PREPARATION
- Rate of preparation of diet (frequency): weekly (excpet on three occassions when the diet was prepared in advance and frozen) - Details on mating procedure:
- - M/F ratio per cage: 1/1
- Length of cohabitation: up to 15 days
- Proof of pregnancy: sperm in vaginal smear - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples were taken from the diet formulations prepared in weeks 1, 13, 26 and 36 and analysed by shaking samples with hexane and water (low dose groups) or hexane only (high dose groups). Hexane solutions are further diluted and analysed using GC.
- Duration of treatment / exposure:
- Two generations
- Frequency of treatment:
- Daily
- Details on study schedule:
- - F1 parental animals not mated until 10 weeks after selected from the F1 litters.
- Dose / conc.:
- 60 ppm
- Dose / conc.:
- 350 ppm
- Dose / conc.:
- 2 000 ppm
- No. of animals per sex per dose:
- Thirty (P); twenty-five (F1 generation)
- Control animals:
- yes, plain diet
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily
BODY WEIGHT: Yes
- Time schedule for examinations: weekly except for mated females which were weighed on days 0, 6, 12, 15 and 20 of gestation and days 1, 4, 7, 14 and 21 of lactation.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined: Yes (weekly)
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes - Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, maximum of 8 pups/litter (sex distribution as equal as possible); excess pups were killed and discarded.
PARAMETERS EXAMINED
The following parameters were examined in F1 / F2 offspring:
stillbirths, live births, postnatal mortality, litter weights, and clinical condition of pups
GROSS EXAMINATION OF DEAD PUPS:
yes - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals (at time of weaning of F1 generation).
- Maternal animals: All surviving animals (at time of weaning of F1 generation).
GROSS NECROPSY
- Gross necropsy was performed.
HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues were removed: ovaries, uterus, cervix, vagina, lesions, pituitary, testes, epididymides, seminal vesicles, prostate and coagulating gland. - Postmortem examinations (offspring):
- SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at time of weaning.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows:
GROSS NECROPSY
- Gross necropsy was performed.
- Number of implantation sites were counted and recorded for F1 females. - Statistics:
- Using nested analysis of variance for normally distributed errors or by non-parametric techniques for non-normally distributed errors.
The standard deviation obtained from analysis of variance was used for 't' tests between control and treatment groups. Where necessary, data were transformed before analysis.
Non-parametric testing was performed using the Kruskal-Wallis test for a treatment-related response.
Significant differences between control and treatment groups were determined using the Wilcoxon rank sum test. - Reproductive indices:
- Median pre-coital time = time by which half the females had mated
Fertility index = (no. of pregnant females / no. of paired females) x 100
Fecundity index = (no. of pregnant females / no. of mated females) x 100
Gestation index = (no. of females with live pups / no. of pregnant females) x 100 - Offspring viability indices:
- Post-implantation survival index (F1 only) = (no. of pups born / no. of implantation sites) x 100
Live birth index = (no. of pups alive on day 1 / no. of pups born) x 100
Viability index 1 = (no. of pups alive on day 4 before culling / no. of pups alive on day 1) x 100
Viability index 2 = (no. of pups alive on day 7 / no. of pups alive on day 4 after culling) x 100
Viability index 3 = (no. of pups alive on day 14 / no. of pups alive on day 7) x 100
Viability index 4 = (no. of pups alive on day 21 / no. of pups alive on day 14 x 100) - Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Clinical observations of P generation adults were restricted to those commonly seen in this strain of rat in these laboratories e.g. occasional instances of rough hair coat, slight hair loss, fur staining and chronnodacryorrhoea. Incidence of fur staining and slight hair loss was slightly increased at 2000 ppm in P generation females during late gestation.
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- Treatment did not adversely affect mortality. One P generation male was found dead during week 14; necropsy revealed a liver mass. This death was not attributable to treatment. There were no other adult deaths.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Body weight gains were lower in males and females at 2000 ppm; body weight gain in females during gestation was also lower at 2000 ppm.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Food consumption was lower than controls in males and females at 2000 ppm. Initial lowering of food consumption in P generation animals was so marked as to suggest adverse palatability of the test material in the diet.
- Food efficiency:
- no effects observed
- Description (incidence and severity):
- Food conversion efficiency was similar in all groups, with the exception of week 1 for the highest dose level.
- 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
- Description (incidence and severity):
- There were no significant histopathological effects on either the pituitary or reproductive tract attributable to test material administration.
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- no effects observed
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- Mating performance, fertility, fecundity, pregnancy rate and duration of gestation were not adversely affected by treatment.
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 60 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- other: equivalent to 3 mg/kg bw/day Based on lower bodyweight gain in offspring in both adults and pups, no effects on fertility were noted
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Clinical observations of F1 generation adults were restricted to those commonly seen in this strain of rat in these laboratories e.g. occasional instances of rough hair coat, slight hair loss, fur staining and chronnodacryorrhoea.
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- mortality observed, non-treatment-related
- Description (incidence and severity):
- Offspring survival was not adversely affected by treatment. One F1 generation male was killed during week 12 following accidental injury to the snout. This death was not attributable to treatment. There were no other adult deaths.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Body weight gains were lower in males and females at 2000 ppm; body weight gain in females during gestation was also lower at 2000 ppm. Body weight gain was lower than controls in F1 males at 350 ppm.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Food consumption was lower than controls in males and females at 2000 ppm.
- Food efficiency:
- no effects observed
- Description (incidence and severity):
- Food conversion efficiency was similar in all groups.
- 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:
- no effects observed
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- Necropsy findings of weaned offspring were not adversely affected by treatment.
- Histopathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- There were no significant histopathological findings for either the pituitary or reproductive tract attributable to test material administration. Hyaline droplet nephropathy was recorded in the kidneys of three high dose male. This finding was considered related to test material administration.
- Other effects:
- not examined
- Behaviour (functional findings):
- not examined
- Developmental immunotoxicity:
- not examined
- Key result
- Dose descriptor:
- NOEL
- Generation:
- F1
- Effect level:
- 60 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- other: equivalent to 3 mg/kg bw/day Based on lower bodyweight gain in offspring in both adults and pups, no effects on fertility were noted
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 2 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No observed adverse effects
- Critical effects observed:
- not specified
- Reproductive effects observed:
- not specified
- Conclusions:
- Under the conditions of the test, administration of the test material to rats over two generations at dietary concentrations up to 2000 ppm did not adversely affect adult reproduction or offspring survival. Body weight gains were lower in adults and offspring at 2000 ppm and to a lesser extent at 350 ppm. Food consumption was also reduced in adults at 2000 ppm. No adverse effects of treatment were seen at the low level of 60 ppm which is considered to be the NOEL (equivalent to 3 mg/kg bw/day).
- Executive summary:
In a GLP compliant study conducted in line with standardised guideline EPA OPP 83-4, the effect of the test material on reproductive toxicity was determined in the rat.
Rats were administered the test material by oral (diet) at 0, 60, 350 and 2000 ppm.
Adult reproduction or offspring survival was not adversely affected. Body weight gains were lower in adults and offspring at 2000 ppm and to a lesser extent at 350 ppm. Food consumption was also reduced in adults at 2000 ppm. No adverse effects of treatment were seen at the low level of 60 ppm which is considered to be the NOEL (equivalent to 3 mg/kg bw/day).
Reference
Table 1: Summary of adult performance
Dose group (ppm) | ||||||||
0 | 60 | 350 | 2000 | |||||
P | F1 | P | F1 | P | F1 | P | F1 | |
Males | ||||||||
In group | 30 | 25 | 30 | 25 | 30 | 25 | 30 | 25 |
Dead: post pairing | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
Failing to induce pregnancy | 1 | - | 2 | - | 2 | - | 1 | - |
Females | ||||||||
In group | 30 | 25 | 30 | 25 | 30 | 25 | 30 | 25 |
Pregnant/% | 29/96.7 | 25/100 | 28/93.3 | 20/80 | 28/93.3 | 24/96 | 29/96.7 | 25/100 |
With total resorption | 1 | - | 0 | - | 0 | - | 0 | - |
Total litter loss | 4 | 4 | 3 | 4 | 3 | 4 | 5 | 2 |
With live pups at day 21 post-partum | 24 | 21 | 25 | 16 | 25 | 20 | 24 | 23 |
Table 2: Group mean body weight gain (g)
Dose group (ppm) | |||||||||
0 | 60 | 350 | 2000 | ||||||
Time interval | Sex | P | F1 | P | F1 | P | F1 | P | F1 |
0 -5 | M | 199.9 | 260.6 | 192.0 | 256.7 | 192.7 | 242.6 | 148.1 | 201.9 |
F | 90.5 | 120.5 | 91.9 | 122.1 | 88.0 | 111.5 | 67.1 | 98.7 | |
6 -10 | M | 88.9 | 104.6 | 98.8 | 113.6 | 83.5 | 93.8 | 68.8 | 71.0 |
F | 32.1 | 40.3 | 31.0 | 37.7 | 34.5 | 39.4 | 23.8 | 33.3 | |
11 -13 | M | 33.2 | 44.7 | 23.3 | 43.8 | 29.5 | 37.6 | -6.1 | 41.7 |
F | 100 | 112 | 109 | 115 | 109 | 108 | 88 | 85 | |
14 -16 | M | 29.8 | 31.8 | 29.3 | 41.8 | 30.7 | 48.3 | 53.7 | 42.6 |
F | 29 | 46 | 40 | 36 | 53 | 45 | 65 | 60 |
*14-17 weeks for males of the F1 generation
Table 3: Group mating data
Dose group (ppm) | ||||||||
0 | 60 | 350 | 2000 | |||||
Mating indices | P | F1 | P | F1 | P | F1 | P | F1 |
Number of paired females | 30 | 25 | 30 | 25 | 30 | 25 | 30 | 25 |
Number of mated males | 30 | 25 | 30 | 22 | 29 | 24 | 29 | 25 |
Number of pregnant females | 29 | 25 | 28 | 20 | 28 | 24 | 29 | 25 |
Fertility index (%) | 96.7 | 100 | 93.3 | 80 | 93.3 | 96 | 96.7 | 100 |
Fecundity index (%) | 96.7 | 100 | 93.3 | 90.9 | 96.6 | 100 | 100 | 100 |
Table 4: Group mean pup weights (g)
Dose group (ppm) | ||||||||
0 | 60 | 350 | 2000 | |||||
Day | P | F1 | P | F1 | P | F1 | P | F1 |
1 (combined) | 6.1 | 5.7 | 5.7 | 5.9 | 5.5 | 5.9 | 5.6 | 5.8 |
4 (combined) | 8.6 | 7.9 | 7.9 | 8.4 | 7.2 | 7.7 | 6.9 | 7.8 |
7 (combined) | 13.8 | 13.2 | 13.1 | 13.7 | 12.1 | 12.8 | 10.4 | 12.0 |
14 (combined) | 29.8 | 30.0 | 29.1 | 29.8 | 27.4 | 27.4 | 21.9 | 24.4 |
21 (combined) | 49.8 | 50.9 | 49.5 | 49.7 | 46.7 | 45.98 | 38.2 | 39.9 |
21 (males) | 51.2 | 51.8 | 50.3 | 51.0 | 49.1 | 47.2 | 39.5 | 40.6 |
21 (females) | 49.6 | 49.6 | 48.7 | 48.5 | 44.7 | 45.9 | 37.9 | 38.9 |
% weight changes | 716 | 793 | 4768 | 742 | 749 | 678 | 582 | 588 |
Table 5: Group incidence histopathology findings
P generation | F1 generation | ||||||||
Dose group* and sex | Dose group* and sex | ||||||||
0 ppm M | 2000 ppm M | 0 ppm F | 2000 ppm F | 0 ppm M | 2000 ppm M | 0 ppm F | 2000 ppm F | ||
Animals examined | 30 | 30 | 30 | 30 | 25** | 24** | 25** | 25** | |
Animals unremarkable | 10 | 10 | 19 | 23 | 8 | 9 | 15 | 17 | |
Skin | Acanthosis | 0 | 1 | 3 | 3 | 1 91) | 1 (2) | 9 (9) | 7 (7) |
Dermatitis | 2 | 0 | 3 | 0 | 0 (1) | 1 (2) | 2 (9) | 0 (7) | |
Adnexal atrophy | - | - | - | - | 0 (1) | 0 (2) | 0 (9) | 1 (7) | |
Liver | Necrosis (lobar) | 0 | 1 | 0 | 0 | 1 (1) | - | - | - |
Kidneys | Focal nephropathy | 0 | 10 | 0 | 0 | - | - | - | - |
Hydroneophrosis | 2 | 0 | 0 | 0 | 1 (1) | 1 (3) | - | - | |
Nephroblastoma | 0 | 0 | 0 | 1 | - | - | - | - | |
Hyaline droplets | - | - | - | - | 0 (1) | 3 (3) | - | - | |
Basophilic tubules | - | - | - | - | 0 (1) | 3 (3) | - | - | |
Casts | - | - | - | - | 0 (1) | 3 (3) | - | - | |
Cyst | - | - | - | - | 0 (1) | 1 (3) | - | - | |
Pituitary | Altered cell focus | 0 | 2 | 0 | 0 | - | - | - | - |
Cyst | 0 | 3 | 0 | 0 | 1 | 0 | 0 | 0 | |
No sample | 0 | 0 | 1 | 0 | - | - | - | - | |
Oral cavity | Necropsy finding/ no equivalent finding | 2 | 1 | 2 | 2 | - | 1 (1) | - | - |
Stomatitis | - | - | - | - | - | 1 (1) | - | - | |
Nasal cavity | Rhinitis | - | - | - | - | - | 1 (1) | - | - |
Abdominal cavity | Necropsy finding/ no equivalent finding | 0 | 1 | 0 | 0 | - | - | - | - |
Lungs | Inflammatory cell foci | - | - | - | - | 1 (1) | - | - | - |
Congestion/heamorrhage | 2 | 1 | 0 | 1 | 1 (1) | - | - | - | |
Foamy histiocytes | 2 | 1 | 0 | 0 | - | - | - | - | |
Lymphoid hyperlasia | 1 | 1 | 0 | 0 | - | - | - | - | |
Pneunomitis | 2 | 1 | 0 | 0 | - | - | - | - | |
Skull | Exostoses | 1 | 1 | 0 | 0 | - | - | - | - |
Foot | Arthritis | 1 | 0 | 0 | 0 | - | - | - | - |
Dermatitis | 0 | 1 | 0 | 0 | - | - | - | - | |
Tail | Dermatitis/folliculitis | 0 | 3 | 0 | 0 | 1 (1) | - | - | - |
Mandiubular lymph node | Hyperplasia | - | - | - | - | ||||
Ear | Chondritis | - | - | - | - | ||||
Testis | Atrophy | 1 | 1 | - | - | 2 | 2 | - | - |
Sperm granuloma | - | - | - | - | 0 | 1 | - | - | |
Epididymis | Inflammatory cell foci | 0 | 1 | - | - | 1 | 0 | - | - |
Oligospermia | 0 | 1 | - | - | 0 | 2 | - | - | |
Seminal vesicle | Not remarkable | 30 | 30 | - | - | 24 | 25 | - | - |
Coagualting gland | One sample | 4 | 3 | - | - | 0 | 1 | - | - |
Protstate | Inflammatory cell foci | - | - | - | - | 6 | 6 | - | - |
Prostatitis | 10 | 10 | - | - | 3 | 4 | - | - | |
Ovary | Not remarkable | - | - | 30 | 30 | - | - | 25 | 25 |
One sample | - | - | - | - | - | - | 1 | 0 | |
Uterus | Arteritis | - | - | 1 | 0 | - | - | 0 | 0 |
Oestrus stage | - | - | 1 | 1 | - | - | 0 | 0 | |
Cervix | Not remarkable | - | - | - | - | - | - | 0 | 0 |
Vagina | Not remakrable | - | - | 30 | 30 | - | - | 0 | 0 |
Cause of death | Liver lesion | 1 | |||||||
Upper respiratory infection/ stomatitis | 1 |
If less animals were examined, the real number examined is presented between brackets.
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Species:
- rat
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
A two-generation reproduction toxicity study in rats with dose levels up to 2000 ppm did not adversely affect adult reproduction or offspring survival. Body weight gains were lower in adults and offspring at 2000 ppm and to a lesser extent at 350 ppm. Food consumption was also reduced in adults at 2000 ppm. No adverse effects of treatment were seen at the low level of 60 ppm; this dose therefore constitutes a NOEL (corresponding to 3 mg/kg bw/day).
Effects on developmental toxicity
Description of key information
The NOAEL for both maternal and embryo/foetotoxicity for the test material was determined to be 45 mg/kg bw/day according to a study performed in line with OCED Guideline 414 and EPA Guideline OPP 83-3.
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 24 March 1988 to 15 August 1989
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- yes
- Remarks:
- 18 mated females instead of 20 were used in the study
- Qualifier:
- according to guideline
- Guideline:
- EPA OPP 83-3 (Prenatal Developmental Toxicity Study)
- Deviations:
- yes
- Remarks:
- 18 mated females instead of 20 were used in the study
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rabbit
- Strain:
- New Zealand White
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Weight at study initiation: 3.00-4.48 kg at mating
- Housing: individually in stainless steel cages
- Diet: ad libitum
- Water: mains water ad libitum
- Acclimation period: at least 19 days before mating
ENVIRONMENTAL CONDITIONS
- Temperature: 16-22 °C
- Humidity: 40-70 %
- Air changes: minimum of 15 per hour
- Photoperiod: 14 hours light/10 hours dark - Route of administration:
- oral: gavage
- Vehicle:
- other: 1 % gum tragacanth
- Details on exposure:
- Suspensions of the test material in vehicle were prepared weekly and dispensed as daily aliquots
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples of each test formulation were taken from the first and second weekly preparations for analysis.
- Details on mating procedure:
- Each female was mated with one proven stud New Zealand White buck.
- Duration of treatment / exposure:
- To mated females from days 7 to 19 of gestation.
- Frequency of treatment:
- Once daily
- Duration of test:
- Animals were killed on day 29 of gestation.
- Dose / conc.:
- 15 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 45 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 135 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 18
- Control animals:
- yes, concurrent vehicle
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily during gestation
BODY WEIGHT: Yes
- Time schedule for examinations: days 0, 7, 13, 19, 23 and 28 of gestation.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined: days 0-7, 7-13, 13-19, 19-23, and 23-29 of gestation. - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number and intrauterine position of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: pregnancy status - Fetal examinations:
- - External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [all per litter]
- Skeletal examinations: Yes: [all per litter]
- Head examinations: Yes: [all per litter] - Statistics:
- Levene's test was used to test for equality of variances between groups for body weight gain (except days 7-13), food intake, uterus weight and mean litter weight. Where there was a significant difference between groups using one-way analysis of variance, pairwise t-tests between treated groups and the control were conducted. Where Levene's test was significant (p<0.05), non-parametric tests were performed.
Major and minor external/visceral defects and major skeletal defects were analysed by comparing the proportion of litters in the treated groups with one defect to the proportion in the control group using the Fisher exact test.
Kruskal-Wallis non-parametric analysis of variance was performed on all other parameters. Where there was a significant overall difference between groups (p<0.05), the Wilcoxon Rank Sum Test was performed for each treated group against the controls. - Indices:
- Percentage pre-implantation loss = ((no. of corpora lutea - no. of implantation sites) / no. of corpora lutea) x 100
Percentage of post-implantation loss = ((no. of implantation sites - no. of live young) / no. of implantation sites) x 100
Females as % of males = (no. of females / no. of males) x 100
Fertility index = (no. of females pregnant / no. of females mated) x 100 - Clinical signs:
- no effects observed
- Description (incidence and severity):
- The clinical condition of surviving animals was generally comparable in all groups.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- Four of the treatment animals died or were killed, two in the low dose and one in both the median and high dose groups. The distribution between the treated groups did not indicate an effect of treatment.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Group mean body weight gain of the high dose animals was significantly lower than the controls. The majority of high dose animals lost weight from day 7 to day 13 of gestation. In three animals the loss persisted until treatment ceased. There was no adverse effect of treatment on weight gain at the low or intermediate dose level.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Food intake of high dose animals was significantly lower than controls over the treatment period. No significant differences were observed at the low and intermediate dose levels.
- 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:
- not examined
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- Necropsy revealed no treatment-related lesions.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- Necropsy revealed no treatment-related lesions.
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
- Number of abortions:
- not examined
- Pre- and post-implantation loss:
- effects observed, treatment-related
- Description (incidence and severity):
- The number of corpora lutea and implantations per dose were comparable in all groups. Pre-implantation loss was within the expected range in all groups. Post-implantation loss was higher than controls in the high dose group. The increase was mainly attributable to two atypical litters (number 66 and 72) and was not statistically significant. The number of foetuses per litter was correspondingly reduced. The incidence of intrauterine deaths in the low and intermediate dose groups was lower than controls and litter size was marginally increased.
- Total litter losses by resorption:
- not examined
- Early or late resorptions:
- not examined
- Dead fetuses:
- not examined
- Changes in pregnancy duration:
- no effects observed
- Description (incidence and severity):
- The number of pregnant animals surviving to day 29 of gestation was between 14 and 16 in every group.
- Changes in number of pregnant:
- no effects observed
- Description (incidence and severity):
- Pregnancy incidence was 100 % in the low dose and 94.4 % in all other groups.
- Other effects:
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 45 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Fetal body weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Foetal weight was lower than controls in the high dose group. The reduction was not statistically significant and was attributable to three atypical litters (number 66, 71, and 72). There was no adverse effect on foetal weight in the low and intermediate dose groups.
- Reduction in number of live offspring:
- not examined
- Changes in sex ratio:
- not examined
- Changes in litter size and weights:
- not examined
- Changes in postnatal survival:
- not examined
- External malformations:
- effects observed, treatment-related
- Description (incidence and severity):
- The incidence of litters containing foetuses showing major defects was significantly higher than controls in the high dose group. Again the increase was mainly attributed to litters 66, 71, and 72 suggesting that these were mediated by maternal toxicity. There was no adverse effect of treatment on the incidence of major defects in the low or intermediate dose groups. The incidence of minor defects or variations did not indicate an effect of treatment at any of the dose levels investigated.
- Skeletal malformations:
- not specified
- Visceral malformations:
- not specified
- Other effects:
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 45 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: embryotoxicity
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 45 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: fetotoxicity
- Abnormalities:
- not specified
- Developmental effects observed:
- not specified
- Conclusions:
- Under the conditions of the test, administration of the test material at 135 mg/kg bw/day elicited maternal toxicity, characterised by maternal weight loss at the onset of dosing and reduced food intake over the treatment period. In three animals, the reaction was so severe as to elicit corresponding foetal effects. The litters of these animals showed reduced foetal weight and an increased incidence of intrauterine deaths and major abnormalities. In the remaining litters, the incidence of foetal effects did not greatly differ from normal values. There was no adverse effect of treatment, maternal or foetal, at 15 or 45 mg/kg/day in either this or the previous study (Barker, 1989b). The NOAEL for both maternal and embryo/foetotoxicity in this study is 45 mg/kg bw/day.
- Executive summary:
In a GLP compliant study conducted in line with standardised guidelines OECD 414 and EPA OPP 83-3, the effect of the test material on developmental toxicity was determined in the rabbit.
Rabbits were administered the test material by oral (gavage) at 0, 15, 45 and 135 mg/kg bw/day. Administration of the test material at 35 mg/kg bw/day elicited maternal toxicity, characterised by maternal weight loss at the onset of dosing and reduced food intake over the treatment period. In three animals, the reaction was so severe as to elicit corresponding foetal effects. The litters of these animals showed reduced foetal weight and an increased incidence of intrauterine deaths and major abnormalities. In the remaining litters, the incidence of foetal effects did not greatly differ from normal values. There was no adverse effect of treatment, maternal or foetal, at 15 or 45 mg/kg/day in either this or the previous study (Barker, 1989b).
The NOAEL for both maternal and embryo/foetotoxicity in this study is 45 mg/kg bw/day.
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 19 September 1983 to 26 January 1984
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: 13 weeks
- Weight at study initiation: 182 to 237 g
- Housing: suspended steel cages
- Diet: stock diet ad libitum
- Water: tap water ad libitum
- Acclimation period: seven days
ENVIRONMENTAL CONDITIONS
- Temperature: 23 ± 2 °C
- Humidity: >40 %
- Photoperiod (hrs dark / hrs light): 12 hours light/12 hours dark - Route of administration:
- oral: gavage
- Vehicle:
- other: 1 % tragacanth gum
- Analytical verification of doses or concentrations:
- not specified
- Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/2
- Length of cohabitation: overnight
- After 1 day of unsuccessful pairing replacement of first male by another male with proven fertility.
- Breeding continued until the desired number of females was obtained. - Duration of treatment / exposure:
- From day 6 up to and including day 15 of pregnancy
- Frequency of treatment:
- Daily
- Duration of test:
- Up to day 21 of gestation
- Dose / conc.:
- 20 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 60 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 180 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- Twenty five pregnant females
- Control animals:
- yes, concurrent vehicle
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations checked: general condition and behaviour
DETAILED CLINICAL OBSERVATIONS: No
BODY WEIGHT: Yes
- Time schedule for examinations: day 0, 6, 16 and 21 of pregnancy
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined: day 0 to day 6, day 6 to day 16 and day 16 to day 21 of pregnancy - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: foetal length, placenta weight of live foetuses, empty uterus weight - Fetal examinations:
- - External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [half per litter]
- Skeletal examinations: Yes: [half per litter] (all groups except 20 mg/kg bw/day)
- Head examinations: No - Statistics:
- Student's t-test was used to determine the differences in degree of ossification between test and control groups to transformed ossification values (DgOt) expressed in degrees and calculated by:
DgOt = √DgOº
Differences in body weight, food consumption, organ weights, litter data, foetus weights and lengths and placenta weights were analysed by applying analysis of (co)-variance followed by Dunnett's multiple comparison test whereas skeletal and visceral anomaly were evaluated by Chi-square test. - Indices:
- Percentage pre-implantation loss (PRIL) = ((no. of corpora lutea - no. of implantation sites) / no. of corpora lutea) x 100
Percentage of post-implantation loss (POIL) = ((no. of implantation sites - no. of live young) / no. of implantation sites) x 100
Degree of ossification of foetus skeletons (DgO) = no. of bones without ossification (or with incomplete ossification) / no. of bones examined - Clinical signs:
- no effects observed
- Description (incidence and severity):
- No abnormalities in condition or behaviour of the animals were observed.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Description (incidence):
- No deaths of the animals were observed.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Weight gain of animals in the 60 and 180 mg/kg dose group was reduced during the treatment period.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Food intake of animals in the 60 and 180 mg/kg dose group was reduced during the treatment period.
- 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):
- no effects observed
- Description (incidence and severity):
- No abnormalities in behaviour of the animals were observed.
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- not examined
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
- Number of abortions:
- not examined
- Pre- and post-implantation loss:
- not examined
- Total litter losses by resorption:
- not examined
- Early or late resorptions:
- not examined
- Dead fetuses:
- not examined
- Changes in pregnancy duration:
- no effects observed
- Description (incidence and severity):
- The gestation index was 100 in all groups.
- Changes in number of pregnant:
- no effects observed
- Description (incidence and severity):
- Maternal performance was comparable in all groups and the fertility indices ranged from 84.0 in the high dose, 88.0 in the 60 mg/kg does and 92.0 in both the control and low dose group.
- Other effects:
- not examined
- Dose descriptor:
- NOAEL
- Effect level:
- 20 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- food consumption and compound intake
- other: maternal toxicity
- Fetal body weight changes:
- not specified
- Reduction in number of live offspring:
- not specified
- Changes in sex ratio:
- not specified
- Changes in litter size and weights:
- not specified
- Changes in postnatal survival:
- not specified
- External malformations:
- not specified
- Skeletal malformations:
- no effects observed
- Description (incidence and severity):
- Skeletal examination of the foetuses did not indicate any embryo/foetotoxic or teratogenic effects that could be related to treatment. The slightly increased incidence of supernumerary thoracic ribs in the 180 mg/kg dose group was not considered to be of toxicological significance.
- Visceral malformations:
- no effects observed
- Description (incidence and severity):
- Visceral examination of the foetuses did not indicate any embryo/foetotoxic or teratogenic effects that could be related to treatment.
- Other effects:
- no effects observed
- Description (incidence and severity):
- Autopsy findings, organ weights and litter data did not reveal any embryo- or foetotoxic effect of the test material.
- Dose descriptor:
- NOAEL
- Effect level:
- 180 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: embryotoxicity
- Dose descriptor:
- NOAEL
- Effect level:
- 180 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: fetotoxicity
- Abnormalities:
- not specified
- Developmental effects observed:
- not specified
- Conclusions:
- Under the conditions of the test, weight gain and food intake in maternal animals was reduced in 60 and 180 mg/kg bw/day dose groups but no effects on fertility indices were seen. Autopsy findings, organ weights, litter data and visceral and skeletal examination of the foetuses did not reveal any embryotoxic, foetotoxic or teratogenic effects that could be related to the test material. The NOAEL for maternal toxicity was determined to be 20 mg/kg bw/day; the NOAEL for embryo/foetotoxicity was determined to be 180 mg/kg bw/day.
- Executive summary:
In a GLP compliant study conducted in line with sound scientific principles (and stated as being similar to standardised guideline OECD 414), the effect of the test material on developmental toxicity was determined in the rat.
Rats were administered the test material by oral (intra-oesophagic intubation) at 0, 20, 60 and 180 mg/kg bw/day.
Weight gain and food intake in maternal animals was reduced in the 60 and 180 mg/kg bw/day dose groups but no effects on fertility indices were seen. Autopsy findings, organ weights, litter data and visceral and skeletal examination of the foetuses did not reveal and embryotoxic, foetotoxic or teratogenic effects that could be related to the test material.
The NOAEL for maternal toxicity was determined to be 20 mg/kg bw/day; the NOAEL for embryo/foetotoxicity was determined to be 180 mg/kg bw/day.
Referenceopen allclose all
Table 1: Mean weight (kg), body weight gain (kg) and food intake (g)
Dose group (mg/kg bw/day) | |||||
Day | Parameter | 0 | 15 | 45 | 135 |
0 | Body weight | 3.63 | 3.61 | 3.76 | 3.68 |
7 | Body weight | 3.78 | 3.77 | 3.91 | 3.84 |
Body weight gain | 0.15 | 0.16 | 0.15 | 0.16 | |
Food intake | 201 | 204 | 212 | 212 | |
13 | Body weight | 3.83 | 3.84 | 3.97 | 3.70*** |
Body weight gain | 0.05 | 0.07 | 0.06 | -0.14 | |
Food intake | 175 | 184 | 184 | 115*** | |
19 | Body weight | 3.94 | 3.97 | 4.08 | 3.80 |
Body weight gain | 0.11 | 0.13 | 0.11 | 0.10 | |
Food intake | 168 | 171 | 170 | 124* | |
23 | Body weight | 4.03 | 4.0 | 4.16 | 3.85 |
Body weight gain | 0.09 | 0.04 | 0.08 | 0.05 | |
Food intake | 148 | 141 | 158 | 132 | |
29 | Body weight | 4.16 | 4.03** | 4.23 | 4.00 |
Body weight gain | 0.13 | 0.02 | 0.07 | 0.15 | |
Adjusted body weight | 3.58 | 3.48 | 3.68 | 3.51 | |
Food intake | 127 | 92 | 118 | 122 | |
Total mean | Body weight gain | 0.53 | 0.42 | 0.47 | 0.32 |
Food intake | 166 | 161 | 171 | 144 |
*P<0.05; ***P<0.001
Table 2: Group incidence of foetuses with defects
Dose group (mg/kg bw/day) | |||||
Observation | 0 | 15 | 45 | 135 | |
Number of foetuses examined | 142 | 154 | 146 | 115 | |
External and visceral effects | Major | 0 | 1 | 1 | 11** |
Minor | 5 | 14 | 2 | 12 | |
Variants | 46 | 47 | 70 | 39 | |
Skeletal | Major | 1 | 0 | 0 | 24 |
Minor | 33 | 45 | 36 | 16 | |
Variants | 128 | 141 | 130 | 106 | |
Total number of foetuses showing major defects | 1 | 1 | 1 | 26 |
** P<0.01
Table 1: Mean maternal body weight, body weight gain and food intake (g)
Dose group (mg/kg bw/day) | |||||
Day | Parameter | 0 | 20 | 60 | 180 |
0 | Body weight | 202.1 | 201.7 | 201.3 | 204.5 |
6 | Body weight | 226.1 | 225.1 | 224.5 | 229.6 |
Body weight gain | 24.0 | 23.4 | 23.3 | 25.0 | |
Food intake | 17.3 | 17.3 | 17.8 | 18.3 | |
16 | Body weight | 267.0 | 262.1 | 253.5** | 255.6* |
Body weight gain | 40.9 | 37.0 | 29.0** | 26.0** | |
Food intake | 19.5 | 18.2 | 16.5** | 15.4** | |
21 | Body weight | 326.9 | 323.5 | 313.1 | 322.3 |
Body weight gain | 59.9 | 60.6 | 59.6 | 66.2 | |
Food intake | 21.2 | 21.6 | 22.2 | 23.5** | |
Total | Body weight gain | 124.8 | 121.5 | 111.9 | 117.9 |
* P<0.05; **P<0.01
Table 2: Statisitically significant alterations
Dose group (mg/kg bw/day) | |||||
Observation | 0 | 20 | 60 | 180 | |
Number of litters examined | 23 | 22 | 22 | 21 | |
umber of foetuses examined | 279 | 272 | 248 | 266 | |
Visble alterations | Small focal subcutaneous haemorrhage or petachia | 0 | 2 | 3 (2) | 3 (3) |
Dysmature appearance | 0 | 0 | 0 | 1 | |
Number of litters examined | 23 | n.d | 22 | 21 | |
Number of foetuses examined | 134 | n.d. | 114 | 129 | |
Skeletal alterations | Malformations | 0 | 0 | 0 | 0 |
Minor anomalies | 18 | 10 | 12 | ||
Variants | 25 | 24 | 37* | ||
Number of litters examined | 23 | n.d. | 22 | 21 | |
Number of foetuses examined | 134 | n.d. | 114 | 129 | |
Ossification asent (in degrees) | Forelimb phalanges | 65.49 | 53.55*** | 72.74* | |
Hindlimb phalanges | 56.59 | 53.95 | 60.11 | ||
Cervical vertebrae bodies | 37.99 | 29.33* | 42.28 | ||
Sternebrae | 0.59 | 0 | 7.03** | ||
Ossification incomplete (in degrees) | Forelimb phalanges | 12.88 | 12.31 | 9.66 | |
Hindlimb phalanges | 17.12 | 13.72 | 21.75** | ||
Cervical vertebrae bodies | 26.53 | 18.07** | 22.82 | ||
Sternebrae | 10.94 | 8.75 | 18.49** | ||
Number of litters examined | 23 | 22 | 22 | 21 | |
Number of foetuses examined | 145 | 140 | 131 | 135 | |
Visceral | Malformations | 1 | 0 | 0 | 3 (2) |
Minor anomalies | 14 (10) | 27* (13) | 23 (10) | 26* (17) | |
Variants | 14 (10) | 24 (14) | 27* (17) | 25* (14) |
Number of affected litters between brackets
n.d. = not determined
* P<0.05; **P<0.01; ***P<0.001
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 45 mg/kg bw/day
- Species:
- rabbit
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Additional information
A combined embryotoxicity/teratogenicity study in rats showed that the weight gain and food intake of animals in the 60 and 180 mg/kg dose groups was reduced during the treatment period. The only other effect found was the slightly increased incidence of supernumerary thoracic ribs in the 180 mg/kg group, however this was considered to be of no toxicological significance. The NOAEL for maternal toxicity is 20 mg/kg bw/day and the NOAEL for embryo/fetotoxicity is 180 mg/kg bw/day.
The available teratology studies in rabbits revealed that the administration of the test material at 135 mg/kg bw/day elicits maternal toxicity, characterised by maternal weight loss at the onset of dosing and reduced food intake over the treatment period. The NOAEL for both maternal and embryo/fetotoxicity is 45 mg/kg bw/day.
Justification for classification or non-classification
In accordance with the criteria for classification as defined in Annex I, Regulation (EC) No 1272/2008, the substance is considered to be unclassified for toxicity to reproduction.
Additional information
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