Cyclododeca-1,5,9-triene

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Oral

2002: According to OECD 422; GLP; 10 Sprague Dawley rats; 30, 100, 300 mg/kg bw/day; no mortality; NOAEL males and females: 300 mg/kg bw/day, reproduction. (K1)

Link to relevant study records

Reference

Endpoint:

one-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Version / remarks:

1986

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

other: Crl:CD (SD)IGS BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ORGANISMS
- Age: males 59 days, females 52 days (approximately)

Route of administration:

oral: gavage

Details on exposure:

ADMINISTRATION / EXPOSURE
- Vehicle: corn oil
- Concentration in vehicle: 6, 20, 60 mg/ml
- Total volume applied: 5 ml/kg bw/dose

Details on mating procedure:

MATING PROCEDURES: 
- mating period approximately 1-2 weeks, beginning after  approximately four weeks of dosing.

Duration of treatment / exposure:

Exposure period: males through test day 55; females 4 weeks premating through 4-day lactation period
Premating exposure period (males): approximately 4 weeks
Premating exposure period (females): approximately 4 weeks
Duration of test: approximately 60 days

Frequency of treatment:

daily

Dose / conc.:

30 mg/kg bw/day

Dose / conc.:

100 mg/kg bw/day

Dose / conc.:

300 mg/kg bw/day

No. of animals per sex per dose:

Number of animals: 10 per sex and per dose group

Control animals:

yes, concurrent vehicle

Parental animals: Observations and examinations:

- Clinical signs: at least once daily
- Mortality: at least twice daily
- Body weight: weekly, for females also on lactation days 0 and 4
- Food consumption: weekly
- Ophthalmoscopic examination: Both eyes of all rats prior to study and  on test day 24, prior to clinical pathology evaluation (surviving rats).
- Clinical pathology evaluation on all rats after 4 weeks of dosing, and  on male rats at the time of scheduled sacrifice:   
- hematology / coagulation: erythrocyte count, total leukocyte count,  platelet count, hemoglobin concentration, hematocrit, differential  leukocyte count, mean corpuscular volume, mean corpuscular hemoglobin,  mean corpuscular hemoglobin concentration, absolute reticulocyte counts,  red cell distribution width, microscopic blood examination, activated  partial thromoboplastin time, prothrombin time.   
- clinical chemistry: alkaline phosphatase, alanine aminotransferase,  aspartate aminotransferase, sorbitol dehydrogenase, glucose, urea  nitrogen, calcium, inorganic phosphorus, total bilirubin, cholesterol,  triglyceride, creatinine, total protein, albumin, globulin, sodium,  potassium, chloride.  
- urine: volume, specific gravity, urobilinogen, blood, glucose,  protein, appearance (quality, transparency, color), pH, bilirubin,  ketones, sediment microscopy.
- Other: Neurobehavioral Functional Observational Battery (FOB) on all  study rats prior to exposure and following approximately 4 weeks of test  substance administration.

Litter observations:

OFFSPRING: gestation length, mating index, gestation index, fecundity  index, implantation site numbers, implantation efficiency, sex ratio,  pups born alive, viability index

Postmortem examinations (parental animals):

ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC):
- Time: Sacrifice and necropsy of males on day 56 and of females on days  56-64.
- Organ weights P: liver, kidneys, adrenal glands, thymus, brain, spleen,  heart, testes, epididymides. Calculation of ratios to final body and  brain weights.
- Histopathology P:    all high dose and control rats: testes, epididymides, ovaries, gross  lesions;   5 high dose and 5 control rats per sex: additional 37 tissues   5 females from other groups with >= 1 offspring: liver

Postmortem examinations (offspring):

Implantation site number and efficiency, sex ratio, mean pup weights, pups born alive,  viability index

Statistics:

STATISTICAL METHODS: 
- All weight parameters (P, not F), gestation length, clinical pathology,  grip strength, foot splay: One-way analysis of variance followed with  Dunnett's test or Kruskal-Wallis test; followed with Dunn's test.
- Incidence of clinical and FOB observations; mating, gestation,  fecundity indexes: Sequential application of Cochran-Armitage test for  trend
- Implantation site number and efficiency, sex ratio, pups born alive,  viability index: Jonckheere's test
- Mean pup weights: Linear contrast of the least square means
- Motor activity: Levene's and Shapiro-Wilk tests followed by repeated  measures analysis of variance followed by contrasts of Jonckheere's trend  test.

Clinical signs:

no effects observed

Description (incidence and severity):

There were no test substance-related effects on clinical observations

Mortality:

mortality observed, non-treatment-related

Description (incidence):

One high-dose male was sacrificed in extremis due to a dosing-related injury. One high-dose female was found dead on day 57 from dystocia. No other deaths occured during the study.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Decreased body weight gain was observed and considered to be compound-related and of biological significance: 300 mg/kg males (-19 % for days 1-56, not statistically significant; weight -7%); 100 and 300 mg/kg females (only during gestation: gains -13% and -20%, weights -7% and -12%, respectively, statistically significant).

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Increased food consumption was observed and considered to be compound-related and of biological significance: 300 mg/kg males (+19%) 100 mg/kg (+7%, not statistically significant) and 300 mg/kg females (+13%, statistically significant) during gestation.

Food efficiency:

effects observed, treatment-related

Description (incidence and severity):

As a consequence, food efficiency was significantly reduced: 300 mg/kg males (-33%) 100 and 300 mg/kg females during gestation (+14 and +29%, respectively, statistically significant).

Ophthalmological findings:

no effects observed

Description (incidence and severity):

no test substance-related effects

Haematological findings:

no effects observed

Description (incidence and severity):

no test substance-related effects

Clinical biochemistry findings:

no effects observed

Behaviour (functional findings):

no effects observed

Description (incidence and severity):

There were no test substance-related effects in neurobehavioral parameters or motor activity.

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

no test substance-related adverse effects

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Description (incidence and severity):

- Fertility index: no test substance-related effects
- Duration of gestation: no test substance-related effects
- Gestation index: no test substance-related effects
- Number of implantations: no test substance-related effects
- Mating index: no test substance-related effects;
- Implantation efficiency: no test substance-related effects

NOAEL (NOEL), LOAEL (LOEL):    
- NOAEL  30 mg/kg for females, 100 mg/kg for males    
- LOAEL 100 mg/kg for females, 300 mg/kg for males 

Dose descriptor:

NOAEL

Effect level:

300 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reproductive performance

other: no adverse effects observed

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day

Sex:

male

Basis for effect level:

body weight and weight gain

food consumption and compound intake

food efficiency

Dose descriptor:

NOAEL

Effect level:

30 mg/kg bw/day

Sex:

female

Basis for effect level:

body weight and weight gain

food consumption and compound intake

food efficiency

Critical effects observed:

no

Mortality / viability:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Body weights of pups in the 300 mg/kg group were significantly decreased (-17% on lactation day 4)

Other effects:

no effects observed

Description (incidence and severity):

- Sex and sex ratios: no test substance-related effects
- Pups born alive: no test substance-related effects

- NOAEL  100 mg/kg for pups  
- LOAEL  300 mg/kg for pups

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

100 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

Critical effects observed:

no

Reproductive effects observed:

no

Summary of reproductive outcomes:

 

- Dose (mg/kg) 0 30 100 300

- Mating Index(%): 80.0 90.0 100.0 100.0

- Fertility Index (%): 87.5 77.8 70.0 70.0

- Gestation Length (days): 22.0 22.0 22.0 22.0

- Implantations (mean/litter): 16.0 15.6 16.3 16.1

- Implantation efficiency (%): 92.1 96.2 92.0 89.5

- Gestation Index: 100.0 100.0 100.0 100.0

- Mean % Born Alive: 98.3 99.1 99.2 99.0

- 0-4 Day Viability (%): 98.0 99.0 98.2 98.3

- Sex Ratio (males): 0.45 0.50 0.49 0.45

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

60 mg/kg bw/day

Study duration:

subacute

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

Oral

A combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (no limit test) was performed according to OECD 422 and in compliance with GLP. Ten Sprague Dawley rats per sex per dose were treated daily orally by gavage with 30, 100, or 300 mg/kg bw/day of the test substance equivalent to 6, 20, and 60 mg/ml concentration in vehicle, respectively. The vehicle used was corn oil. The total volume applied was 5 ml/kg bw/dose. Males and females were exposed through test day 55 and from four weeks pre-mating through 4-day lactation period, respectively. Control animals were included and received concurrent vehicle treatment. General toxicity has been stated in the endpoint summary of chapter 7.5. Subsequently, only reproductive and developmental effects are presented. No effects regarding fertility, duration of gestation, gestation index, number of implantations, mating index, or implantation efficiency were observed in parental animals. No effects on viability of pups was observed. Body weights of pups in the 300 mg/kg/day group were significantly decreased (-17% on lactation day 4). No substance related changes were reported for sex and sex ratio and pups born alive. The NOAEL in pups was 100 mg/kg/day, based on decreased body weights of pups in the 300 mg/kg/day group during gestation (2000, K1).

In addition, a combined repeated dose/reproductive developmental toxicity study in Sprague Dawley rats treated orally with test substance was only available in the original study language (Japanese) and an IUCLID dossier entry available on the NIHS Japan was used (2007, K4). Results obtained in this study are similar to those retrieved by Malley et al. (2002). However, effects on the liver were here regarded as adverse. It has to be noted that no historical ranges of the control were given and results were not properly discussed in the IUCLID dossier entry. Thus, it may be assumed that effects on the liver were adaptive and a non-adverse reaction as has been concluded for effects on the liver by Malley et al. (2002). In addition, the significant low value of the number of liveborn pups at 300 mg/kg bw/day was regarded as adverse. However, the basis for effect level (here: significant lower value of the number of liveborn pups at 300 mg/kg bw/day) does not take the number of stillborn pups into account which are higher in the control group than in the 300 mg/kg bw/day group. Thus, a live birth index of 100% in the 300 mg/kg bw/day group was achieved compared to 98.7% in the control group. Taking the live birth index into account, the finding of decreased liveborn pups was not considered as test substance-related and adverse.

Effects on developmental toxicity

Description of key information

Inhalation:

2003: No guideline followed; GLP; whole body inhalation; 22 Sprague Dawley rats; 10, 25, 67 ppm; Decreased fetal body weight and increase in delayed sternebral ossification at 67 ppm; NOEC maternal and fetal developmental toxicity: 67 ppm and 25 ppm (K1)

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Version / remarks:

1981

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OTS 798.4900 (Prenatal Developmental Toxicity Study)

Version / remarks:

1987

Deviations:

no

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

other: Crl:CD (SD)BR

Details on test animals or test system and environmental conditions:

TEST ORGANISMS
- Source: Charles River Breeding Laboratories, Raleigh (North Carolina,  USA)
- females; age: 51-70 days when received (at 1, 2, or 3 days of gestation); 5, 4,  or 3 days acclimation
- Number of animals: 22 per exposure concentration

Route of administration:

inhalation: mixture of vapour and aerosol / mist

Type of inhalation exposure (if applicable):

whole body

Vehicle:

air

Details on exposure:

ADMINISTRATION / EXPOSURE
- Type of exposure: whole-body
- Concentrations: 10 / 25 / 75 ppm (target)
- Type or preparation of particles: Controlled flows of high-pressure air  and liquid test substance through heated mixing flask (approx. 240 °C),  dilution with additional air, total airflow 60 l/min (target; measured:  59 - 62 l/min).
- Exposure chamber temperature: target 22 +/- 2 °C; measured 22 - 27 °C

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

- Concentration monitoring:   known volume samples from breathing zone at 60 minute intervals;   passage through glass fiber filter followed by glass impinger with  hexane as collection medium;   weighing of filter before and after sampling;   GC / FID analysis of hexane solution, quantification with standard  curve.
- Particle size (high test concentration, 3 measurements): MMAD 5.4 / 1.5  / 0.76 µm, mean 2.6 µm, with 13-56% of the particles < 1 µm; 35-89% < 3  µm; 66-99% < 10 µm.
-further details: see references

Details on mating procedure:

-mated by supplier

Duration of treatment / exposure:

days 6-20 of gestation

Frequency of treatment:

6 hours/day

Duration of test:

Duration of test: 16 days

Dose / conc.:

10 ppm (nominal)

Remarks:

67.5 mg/m311, 10 +/- 0.27 ppm (analytical concentration)

Dose / conc.:

25 ppm (nominal)

Remarks:

169 mg/m3; 25 +/- 0.33 ppm (analytical concentration)

Dose / conc.:

67 ppm (nominal)

Remarks:

452 mg/m3; 67 +/- 1.9 ppm (analytical concentration)

No. of animals per sex per dose:

22 per exposure concentration

Control animals:

yes, concurrent vehicle

Details on study design:

- Rationale for animal assignment: Exposure concentrations were based on results of a 14-day inhalation study with the test substance. Groups of 10 non-pregnant female rats were exposed to either 18, 40, or 85 ppm (6 h/day) for 5 days. Slight effects (body weight gain reductions) were seen at 40 and 85 ppm.
- Sex: female

Maternal examinations:

PARAMETERS ASSESSED DURING STUDY:
- Body weight gain: days 0, 6, 8, 10, 12, 14, 16, 18, 20, 21
- Food consumption: days 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 21
- Clinical observations: once daily (before onset of exposure; including  day 21), on exposure days also 1 h after exposure

ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC): Study  terminated on day 21
- Macroscopic: Organs of the thoracic and abdominal cavities

Ovaries and uterine content:

- Examination of uterine content: type (live and dead fetuses, and  resorptions) and relative positions 

Fetal examinations:

- Examination of fetuses: body weight, sex, and external alterations;  visceral alterations and stages of renal papillary development (live  fetuses 1, 3, 5 etc. for each litter), skeletal alterations (all live  fetuses)

Statistics:

STATISTICAL METHODS: 
- Maternal weight, weight change, food consumption: parametric linear  contrast of means
- Incidence data (pregnancy, clinical observations): Cochran-Armitage test
- Reproductive outcome data and fetal alteration data: Jonckheere's test;  at > 75 % ties: permutation methodology
- Mean fetal weight, sex ratio: Analysis of variance (ANOVA), applying a  parametric linear contrast of least square means

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

10 ppm: no effect; 25 ppm: increase in facial staining; 67 ppm: diminished response to alerting stimulus; stained and/or wet fur, staining was considered to be the result of increased lacrimation and salivation and decreased grooming.

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Statistically significant effects in both absolute and adjusted (terminal body weight minus the products of conception) were observed at 25 and 67 ppm. Reductions were first noted on day 8 of gestation and persisted until study termination. The magnitude of the reductions from control values ranged from 5 to 6% and 11 to 16% at 25 ppm and 67 ppm, respectively. During the first week of exposure some occasionally statistically significant weight change intervals at 10 ppm were observed, however, were minimal in magnitude (3-4% lower than controls) and transient. Thus, were not considered to be adverse.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

The maternal weight data corresponded to food consumption values, which were reduced at 25 (-9%) and 67 (-28%) ppm but unaffected at 10 ppm.

Number of abortions:

no effects observed

Description (incidence and severity):

Number aborting: none

Pre- and post-implantation loss:

no effects observed

Description (incidence and severity):

none

Early or late resorptions:

no effects observed

Description (incidence and severity):

- Number of resorptions (mean): 0 ppm: 1.0; 10 ppm: 0.7; 25 ppm: 0.4; 67 ppm: 0.7 ==> no effect

Changes in number of pregnant:

no effects observed

Description (incidence and severity):

- Number pregnant per dose level = number of litters: 0 ppm: 21; 10 ppm: 20; 25 ppm: 22; 67 ppm: 20. ==> no effect

Other effects:

no effects observed

Description (incidence and severity):

- Number of implantations (mean): 0 ppm: 14.1; 10 ppm: 14.1; 25 ppm: 13.3; 67 ppm: 13.8 ==> no effect
- Number of corpora lutea (mean): 0 ppm: 15.6; 10 ppm: 15.4; 25 ppm: 14.8; 67 ppm: 15.0 ==> no effect

Dose descriptor:

NOEC

Effect level:

10 ppm

Based on:

test mat.

Basis for effect level:

body weight and weight gain

Remarks on result:

other: more than 10% reduction in body weight implies maternal toxicity

Abnormalities:

no effects observed

Reduction in number of live offspring:

no effects observed

Description (incidence and severity):

- Number viable: all live

Changes in sex ratio:

no effects observed

Description (incidence and severity):

male/total = 0.53 / 0.52 / 0.50 / 0.49 ==> no effect

Changes in litter size and weights:

effects observed, treatment-related

Description (incidence and severity):

- Litter size and weights (mean): 0 ppm: 13.1 fetuses (6.9 males + 6.2 females) with 5.68 g mean weight 10 ppm: 13.4 fetuses (7.1 males + 6.4 females) with 5.63 g mean weight 25 ppm: 13.0 fetuses (6.6 males + 6.4 females) with 5.55 g mean weight 67 ppm: 13.1 fetuses (6.5 males + 6.7 females) with 4.93 g mean weight ==> statistically significant effect on weight (-13.2%) at 67 ppm

External malformations:

no effects observed

Skeletal malformations:

effects observed, treatment-related

Description (incidence and severity):

Compound related, statistically significant increase in incidence of delayed skeletal ossification:
- sternebrae: 0 ppm: -; 10 ppm: 1 fetus; 25 ppm: 2 fetuses (2 litters); 67 ppm: 8 fetuses (5 litters): considered compound-related and consistent with reduced fetal weight.
- vertebrae: 0 ppm: 113 fetuses (21 litters) 10 ppm: 123 (20); 25 ppm: 134 (22); 67 ppm: 136 (20): not considered toxicologically relevant based on high background incidence; well within the control range of four studies from the same time: 128-161 fetuses in 23-25 litters.

Visceral malformations:

no effects observed

Dose descriptor:

NOEC

Effect level:

25 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

fetal/pup body weight changes

other: significant increase in delayed sternebral ossification at 67 ppm

Abnormalities:

effects observed, treatment-related

Localisation:

other: delayed sternebral ossification

Description (incidence and severity):

8 fetuses (5 litters)

Developmental effects observed:

yes

Lowest effective dose / conc.:

67 ppm (nominal)

Treatment related:

yes

Relation to maternal toxicity:

developmental effects as a secondary non-specific consequence of maternal toxicity effects

Dose response relationship:

no

Table 1: Maternal body weights in rats exposed to the test substance by inhalation on days 6 to 20 of gestation

concentration (ppm)

Days of gestation	0 N=2l	10 N=20	25 N=22	67 N=20
0	239.7 (10.1)a,b	240.8 (9.9)	240.4 (12.0)	240.4 (10.1)
4	252.7 (14.0)	249.2 (15.4)	253.5 (14.2)	254.7 (13.1)
6	262.7 (13.8)	257.3 (16.1)	263.1 (16.6)	256.4 (16.6)
8	267.6 (12.7)	255.9 (14.3)d	253.7 (12.9)d	239.3 (12.4)d
10	277.0 (13.9)	267.5 (11.l)d	264.5(13.4)d	245.2 (10.9)d
12	289.6 (13.7)	279.5 (11.8)d	275.8 (15.2)d	251.5 (12. l )d
14	302.7 (15.3)	293.6 (14.2)	285.8 ( 16.6)d	260.2 (12.8)d
16	322.8 (16.8)	315.2 (15.1)	306.8 (17.4)d	275.5 (14.9)d
18	350.8 (17.9)	344.3 (16.3)	332.8 (17.9)d	295.4 (16.l)d
20	383.7 (20.7)	374.8 (19.0)	360.4 (21.4)d	320.4 (18.6)d
21	416.9 (22.9)	408.0 (20.9)	395.0 (22.5)d	355.2 (22.6)d
21C	323.4 (19.6)	313.5 (15.1)	305.2 (17.4)d	274.9 (18.9)d
6-21	154.3 (21.4)	150.8 (17.2)	131.9 (23.8)d	98.8 (23.4)d
6-2lc	60.8 (17.9)	56.3 (14.4)	42.1 (18.2)d	18.5 (21.l)d

 a = Data from non-pregnant females were excluded

b = Standard deviation is presented in parentheses

c = Weight calculated using the final body weight minus the products of conception

d = Significant trend (linear contrast of means); p < 0.05

Conclusions:

Developmental toxicity was only observed after exposure concentrations producing signs of maternal toxicity and thus, the test substance was not considered to be a selective developmental toxicant in the rat under the conditions chosen.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

165.79 mg/m³

Study duration:

subacute

Experimental exposure time per week (hours/week):

42

Species:

rat

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Inhalation

In a developmental toxicity study (no limit test), 22 Sprague Dawley rats were exposed whole body to a mixture of aerosol and vapor of the test substance at concentrations of 10, 25, and 67 ppm. Females were mated by the supplier and exposed from gestation day 6 throughout day 20 six hours per day each day. The duration of the test was 16 days. Control animals receiving the concurrent vehicle (air) were included. Parameters examined were body weight, food consumption, uterine content, and clinical observations. Necropsy has been performed at study termination on day 21. An examination of the fetuses was conducted on body weight, sex, external alterations, visceral alterations, stages of renal papillary development, and skeletal alterations. No mortality or clinical signs were observed in maternal animals. Reduced maternal body weight was first noted on day 8 of gestation at 25 and 67 ppm and the reductions persisted until study termination. The magnitude of reductions from control values ranged from 5 to 6% at 25 ppm and 11 to 16% at 67 ppm. Although there were some occasionally statistically significant weight change intervals at 10 ppm during the first week of exposures they were minimal in magnitude (3-4% lower than controls) and transient and thus, were not considered to be adverse. The maternal weight data corresponded to food consumption values, which were reduced at 25 (-9%) and 67 (-28%) ppm but unaffected at 10 ppm. In maternal animals, no developmental toxicity was observed. Developmental toxicity was seen only at 67 ppm limited to a slight but statistically significant reduction in fetal body weight. In addition, a significant increase in delayed sternebral ossification that was consistent with the reduction in mean fetal body weight was observed. Litter sizes, viability, and sex ratios were unaffected. No gross external, visceral, or skeletal malformations were observed in fetuses. There was no evidence of fetal developmental toxicity at either 10 or 25 ppm. Thus, the NOEC for maternal developmental toxicity and fetal developmental toxicity was concluded to be 67 ppm and 25 ppm, respectively (2003, K1).

However, small reduction in fetal body weight and retardation of ossification where directly associated with high reduction of body weight of maternal animals (above 10% reduction) and regarded as secondary to maternal toxicity. Thus, no classification for developmental effects were warranted according to Regulation (EC) 1272/2008.

Justification for classification or non-classification

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance is not considered to be classified for reproductive toxicity under Regulation (EC) No. 1272/2008.