Aluminium tri-sec-butanolate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

two-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1975

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Study was performed prior to GLP or OECD guidelines and followed rats for two-generations through to weaning. The F2 pups were not necropsied but instead placed into a chronic, carcinogenicity study. F1b generation was produced for teratologic examination.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)

Deviations:

yes

Remarks:

F2 pups were not necropsied

Principles of method if other than guideline:

The P animals were re-mated and F1b fetuses were produced and examined in a teratology study. The F2 pups were produced and followed through weaning, but not necropsied. F1a pups were reared and mated and then necropsied as adults. The F1b fetuses were necropsied for a complete teratological examination.

GLP compliance:

no

Remarks:

study was prior to GLP

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

Rats (30/sex/group) were housed individually in mesh-bottom cages in an air-conditioned room and provided food and water ad libitum. Food and fluid intake, and body weights were measured on a weekly basis.

Route of administration:

oral: drinking water

Vehicle:

water

Details on exposure:

Animals were provided with drinking water via stainless steel sipper tubes containing 0.3, 1.0, or 3.0% (approximately 538, 1644, or 5089 mg/kg/dayfor males; and 594, 1771, and 4571 mg/kg/day for females) secondary butanol. On day 10 post-partum of the F1 pups, the top dose was lowered to 2.0% (approximately 3000 mg/kg/day) due to clear loss in body weight of the dams and lower birthweight of the pups.

The average daily intake in mg/kg/day at the 2% exposure level was not reported by the study investigators, but was reported by the USEPA in their 2003 IRIS assessment of MEK as average daily intakes of 3,384 mg/kg/day in males and 3,122 mg/kg/day in females based on a linear regression analysis of the reported average intakes for males and females at drinking water concentrations of 0, 0.3, 1, and 3%.

Negative controls were provided with tap water.

Details on mating procedure:

For the P1 mating, after 9 weeks on test, one male was co-housed with one female until a vaginal sperm plug was observed or sperm were evident in a vaginal smear. Females were transferred to separate cages on gestation day 17 or 18, and allowed to carry their litters to term. Dams having more than 8 pups had the number of pups randomly culled to a maximum litter size of 8. Pup and dam weights were recorded on day 4 and 21 of lactation.

For the P2 mating, after separation from their weaned F1 litters, dams were allowed a two-week rest interval (no treatment), then placed back on treatment and re-mated as before until the first 20 dams showed evidence of pregnancy.

For the F1 mating, at 12 weeks of age, matings were accomplished as per the P1 method described above.

Analytical verification of doses or concentrations:

no

Details on analytical verification of doses or concentrations:

Not applicable

Duration of treatment / exposure:

F0 animals: 9 weeks premating exposure, 18 days gestation, 21 days lactation
F1 animals: 21 days lactation, 8 weeks premating exposure, 18 days gestation, 21 days lactation
F2 animals: 21 days lactation.

Second mating of the P-generation:
Two-week "rest period" then remating. Exposure through day 20 gestation.

Frequency of treatment:

Continuous (P, F1)
A two week rest interval occurred between the first and the second matings of the P generation.

Details on study schedule:

Rats (30/sex/group) were exposed continuously via drinking water to SBA concentrations of 0, 0.3, 1.0, or 3.0% for 9 weeks and then mated until evidence of pregnancy achieved. After the birth of the F1a generation, on day 10 of lactation, the top dose was lowered to 2.0% for all subsequent stages of the study. The F1a pups were reared to day 28, and then transferred to individual cages and continued on treatment until 12 weeks of age, when they were mated to form an F2 generation, which was brought to term and followed through day 21 weaning.

P animals were re-mated (20 dams/group) to generate F1b fetuses which were necropsied for teratological examination.

Remarks:

Doses / Concentrations:
Controls
Basis:
nominal in water
0

Remarks:

Doses / Concentrations:
Low dose
Basis:
nominal in water
0.3 % (538 - 594 mg/kg/day)

Remarks:

Doses / Concentrations:
Mid dose
Basis:
nominal in water
1.0 % (1644 - 1771 mg/kg/day)

Remarks:

Doses / Concentrations:
High dose - P1 generation only
Basis:
nominal in water
3.0 % (5089 - 4571 mg/kg/day)

Remarks:

Doses / Concentrations:
High dose - P2 and F1 generations only
Basis:
nominal in water
2.0 % (approximately 3000 mg/kg/day)

No. of animals per sex per dose:

30 dams + 30 males (reproduction)
20 dams (teratology)

Control animals:

yes

Details on study design:

An F1b generation was produced in a second mating of 20 of the dams/group from the P generation, exposed to secondary butanol at concentrations of 0, 0.3, 1.0, or 2.0 %. This F1b generation was necropsied for teratological evaluation (1/3 of the pups for visceral, and 2/3 of the pups for skeletal examinations).

F1a Litters were weaned at 21 days and housed together for an additional 6 days under the same treatment as the dams. Pups from these litters (30 males and females aged 28 days) were selected for the F1 mating.

Positive control:

Not applicable

Parental animals: Observations and examinations:

Body weight (weekly) and daily food and water consumption up to 8 weeks.
Calculated test material intake.

Oestrous cyclicity (parental animals):

No data

Sperm parameters (parental animals):

No data

Litter observations:

% viable at birth, 4 days, and 21 days. (viability and lactation indices)
Body weight day 4 and day 21.
Number of live/dead pups were ascertained as soon as possible following delivery, and completed by day 4.

Postmortem examinations (parental animals):

All animals received a gross necropsy. Uteri were examined. Ten animals per sex/group received histopathological evaluations and organ weight measurements on spleen, adrenals, pituitary, gonads, and heart. Twenty animals/sex/group were examined histologically for lesions and organ weights measured for the liver and kidney. Any gross lesions noted were examined histologically.

Teratology portion reproductive parameters:
* Corpora lutea
* Implant sites
* Resorptions
* Live fetuses
* Dead fetuses

Clinical Chemistry: fasting blood sugar, urea nitrogen, serum glutamic oxaloacetic transaminase (SGOT), serum alkaline phosphatase, serum ornithine carbamyl transferase (SOCT), total serum proteins.

Haematology: hematocrit, hemoglobin, erythrocyte count, total and differential leucocyte counts, and prothrombin time.

Urinalysis: Semi-quantitative for sugar, protein, ketone bodies, specific gravity, and microscopic characterization of the centrifuged sediment.

Postmortem examinations (offspring):

* Live/dead fetuses
* Sex of live fetuses

Teratology:
1) Soft tissue (visceral) examination:

2) Skeletal examination:
* Sternebrae
* ribs
* vertebrae
* extremities
* skull
* hyoid

Statistics:

Not reported

Reproductive indices:

Fertility
Gestation

Offspring viability indices:

Viability
Lactation

Clinical signs:

not specified

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Other effects:

effects observed, treatment-related

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

effects observed, treatment-related

Body weight gain was depressed at 3.0% (4571 - 5089 mg/kg/day) secondary butanol, but efficient food utilisation was not affected, indicating the effect was due to depressed appetite.

Fertility rate for the P animals treated with 3.0% SBA was 73%, which is below historical norms for the rat colony. After lowering the top dose to 2.0% secondary butanol (3384 and 3122 mg/kg/day in males and females, respectively), no effect on fertility was observed in the F1 matings.

No hematologic, urinary, or clinical biochemical alterations were seen in the sacrificed adult animals of either generation.

Males had slightly elevated liver and kidney weights, and females had elevated liver weights at 2.0% secondary butanol, but these increases were not statistically significant using a t-test.

In all dose groups, a high rate of respiratory and renal disease were noted upon microscopic evaluation. These findings were assessed as being typical of rat colonies not barrier maintained.

In the lungs of animals in all groups, a progressive hypertrophy of lymphoid tissue around bronchi, bronchioles, and often blood vessels, and in the mucosa of the trachea and bronchi were typically seen. Later changes include chronic interstitial inflammation of the alveolar walls, and loci of acute and subacute inflammation of the bronchial and tracheal mucosa, which precedes the development of bronchiectasis and abscess formation or atelectasis.

A low incidence of worms and the parasite (Trichosomoides crassicauda) was found in the renal pelvis of two animals (not related to treatment).

All of the above changes were considered to be expected findings in rat colonies from this era and not treatment-related.

Findings that were unexpected, and potentially treatment-related included the following four:

i) Nonreactive tubular degeneration in the outer medullary zone, probably involving mainly the thick ascending limb of the loop of Henle. The
epithelium shows loci of pycnosis, cytoplasmic granulation, increased eosinophilia, and, sometimes, desquamation with downstream
intraluminal clusters of free cells. In this study the change observed in female animals showed equal extent and intensity in animals of all groups. However, among the males, the change is two to three times more prominent in the high level test group (2% secondary butanol) than in the water control.

2) Tubular casts were found in five of the 2% group only. This excludes (a) the marked scarring and cast formation in the two animals with polyarteritis nodosa; and (b) a solitary small cast that might be seen in an occasional animal of any group.

3) Foci of tubular regeneration to a notable extent in eight 2% secondary butanol animals, and in only one water control animal, one low dose secondary butanol animal and in two mid dose secondary butanol animals. Some of these foci apparently are regenerating epithelium, and others have recently regenerated.

4) Microcysts in the tip of the renal papilla were found in 2% secondary butanol animals but in no water controls. These presumbably are dilatations of collecting ducts just before they open into the renal pelvis. Some of these "cysts" were empty, others were more or less filled with homogeneous eosinophilic material that resembles plasma, and may have been fluid during life, with component proteins that were fixed in place by formalin.

Of the above unexpected renal findings, none were regarded as having clear pathologic significance.

Compared to water, 2% secondary butanol evoked changes in kidneys of rats (males more than females) including an accelerated
appearance of tubular casts and focal tubular regeneration, development of microcysts in the apices of renal papillae, and
possibly epithelial degeneration in tubules in the outer medullary zone.

Dose descriptor:

NOAEL

Effect level:

10 000 mg/L drinking water

Sex:

male/female

Basis for effect level:

other: No changes in clinical signs, organ weights, histopathology, or fertility indices. Equivalent to 1644 and 1771 mg/kg/day for males and females, respectively.

Dose descriptor:

LOAEL

Effect level:

20 000 mg/L drinking water

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Sexual maturation:

no effects observed

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Histopathological findings:

not examined

Fetotoxicity as measured by a significant reduction in pup viability at birth, a reduced birthweight, and reduced survival to day 21 was seen at 3.0% SBA in the F1a generation. No treatment-related effects were seen on corpora lutea or resorptions.

No skeletal or soft tissue abnormalities or terata were observed with SBA treatment. Fetotoxicity as reduced birthweight was also seen in the F2 pups exposed to 2.0% SBA.

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

10 000 mg/L drinking water

Sex:

male/female

Basis for effect level:

other: Based on no observed fetotoxicity, viability or teratogenicity. Equates to 1644 and 1771 mg/kg/day for males and females, respectively

Dose descriptor:

LOAEL

Generation:

F1b

Effect level:

20 000 mg/L drinking water

Sex:

male/female

Basis for effect level:

other: Decreased fetal weights

Reproductive effects observed:

not specified

Table 1. Summary of Reproduction Parameters in the P/F1b generation

Parameter	Water	0.3% SBA	1.0% SBA	2.0% SBA
Number of pregnancies	29	28	30	29
Number of pregnancies to term	29	28	30	29
Corpora lutea (total)	392	357	422	383
Corpora lutea (per dam)	13.1	11.9	14.1	12.8
Live litters (total)	29	27	30	29
Implant sites (total)	344	312	372	322
Implant sites (per dam)	11.9	11.1	12.4	11.1
Resorptions (total)	5	11	1	10
Resorptions (1 or more per dam)	5	8	1	6
Resorptions (complete litter)	0	0	0	0
% partial resorptions	17.2	28.6	3.33	20.7
Live fetuses (total)	339	300	371	312
Live fetuses (per dam)	11.7	10.7	12.4	10.8
Sex ratio (M/F)	0.99	1.08	0.91	0.89
Dead fetuses (total)	0	1	0	0
Dams with all dead fetuses	0	1	0	0
% all dead	0	3.57	0	0
Average fetal weight (g)	4.14	4.16	4.38	3.74
Net body weight gain (P males)	269	274	261	229
Net body weight gain (P females)	154	158	155	130

Table 2. Summary of Reproduction and Lactation Parameters (P generation)

Parameter	Water	0.3% SBA	1.0% SBA	3.0% SBA
Number of matings	30	30	30	30
Number of pregnancies	29	27	29	27
Number of litters:
Born alive	29	27	29	26
Alive at 4 days	29	27	29	25
Alive at 21 days	28	24	29	23
Number of pups:
Born alive	300	289	311	220
Born dead	2	6	3	23
Number of pups:
Alive at 4 days	300	283	309	203
Alive at 21 days	215	180	225	153
Number of pups/litter:
Born alive	10.3	10.7	10.7	8.5
Alive at 4 days	10.3	10.5	10.7	8.1
Culled to at 4 days	7.8	7.6	7.9	6.8
Alive at 21 days	7.7	7.5	7.8	6.8
Mean pup body weight:
at 4 days	10.3	10.2	10.0	8.2
at 21 days	49.5	47.2	44.4	28.4
Indices:
Fertility	96.7	90.0	96.7	90.0
Gestation	100.0	100.0	100.0	96.3
Viability	100.0	97.9	99.4	92.3
Lactation	95.6	88.2	97.8	89.5

Table 3. Summary of Reproduction and Lactation Parameters (F1/F2 generation)

Parameter	Water	0.3%	1.0%	2.0%
Number of matings	30	30	30	30
Number of pregnancies	29	29	28	27
Number of litters:
Born alive	29	29	28	27
Alive at 4 days	28	28	27	24
Alive at 21 days	27	28	25	23
Number of pups:
Born alive	296	302	267	272
Born dead	4	3	2	4
Number of pups:
Alive at 4 days	282	293	236	241
Alive at 21 days	200	209	170	166
Number of pups/litter:
Born alive	10.2	10.4	9.54	10.1
Alive at 4 days	10.1	10.5	8.74	10.0
Culled to at 4 days	7.54	8.00	7.00	7.46
Alive at 21 days	7.41	7.46	6.80	7.22
Mean pup body weight (g)
At 4 days	10.0	9.74	9.56	9.48
At 21 days	40.1	39.2	39.1	34.9
Indices:
Fertility	96.7	96.7	93.3	90.0
Gestation	100	100	100	100
Viability	95.3	97.0	88.7	88.6
Lactation	94.8	93.3	90.0	92.7

Conclusions:

Secondary butyl alcohol, administered in drinking water to rats over two generations did not affect reproductive parameters or cause fetotoxicity up to a concentration of 1.0% (approximately 1700 mg/kg/day). A decrease in pup viability was seen at 3.0% and a slight decrease in fetal body weight was seen at 2.0% (3122 mg/kg/day in females). Kidney pathology in adult rats exposed to the highest doses of 3.0 and 2.0% were typical of kidney lesions seen in rats with aging.

Executive summary:

Secondary butyl alcohol, administered in drinking water to rats over two generations did not affect reproductive performance or cause developmental toxicity up to a concentration of 1.0% (1644 mg/kg/day). Adult rats exposed to 2.0% SBA (3122 mg/kg/day) showed significant kidney histopathology in the form of renal tubular degeneration/regeneration, renal tubular casts, microcysts on the tip of the papilla. Pup viability was reduced at 3.0% (4571 mg/kg/day). Fetal body weights were slightly lower at 2.0%. The NOAEL in the study for general systemic, reproductive, and fetotoxic effects was 10000 mg/L (1644 mg/kg/day).

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 644 mg/kg bw/day

Study duration:

chronic

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

Aluminium tri-sec-butylate hydrolyses immediately to 2-butanol and aluminium hydroxide / oxy hydroxide. Therefore, effects on fertility by oral exposure can be assessed by assessing the oral fertility effects of aluminium3+ cationic compounds and 2-butanol.

The reproductive toxicity of 2-butanol (SBA) was assessed in a study equivalent to the OECD test guideline 416 (two-generation reproduction toxicity study). In this study SBA produced a reduction in fertility when administered at 3% in drinking water, a concentration which clearly exceeded the maximum tolerated dose level, causing significant maternal toxicity and reduced pup survival (Cox, 1975). The non-specific systemic effects on the dams and pups noted at 3% (4571 mg/kg/day) included significant maternal body weight loss, kidney and liver histopathology, reduced fetal body weight and pup survival and reduced fertility. When the highest concentration was lowered to 2% (equivalent to 3384 and 3122 mg/kg/day for males and females, respectively) for 2 subsequent matings (P and F1), no effect on fertility or reproduction was observed. Adult rats exposed to 2.0% SBA showed significant kidney histopathology; however, no adverse systemic effects were found at a dose of 1% (equivalent to 1644 and 1771 mg/kg/day for males and females, respectively). Thus, the overall NOAEL for the study was 1644 mg/kg/day. This study was conducted prior to the GLPs and was similar to OECD test guideline 416.

Aluminium compounds investigated were Aluminium chloride, aluminium lactate and aluminium citrate, all targeted to achieve maximum solubility/bioavailability of aluminium cations.

In the repro-screen study according to OECD 422 using aluminium chloride no reproduction, breeding and early post-natal developmental toxicity was observed in rats at 1000 mg/kg body weight for males and females. Based on the reported results, a NOAEL for reproduction, breeding and early post-natal developmental toxicity was suggested at a level of 1000 mg/kg bw.

The non-guideline study on aluminium lactate investigated the long-term motor and cognitive effects of developmental exposure to aluminium (Al) in diet administered to mice at doses 100, 500 and 1000 μg Al/g diet or 10, 50, and 100 mg Al/kg bw/day through development (from conception to 35 days of age) and the influence of less than optimal diets on developmental toxicity of Al. Thus, this non-guideline test cannot be regarded as a classical developmental toxicity test but nevertheless showed no general toxic effects on dams (weigh gain during pregnancy, food intake) and on studied gestational parameters (number of animals completing pregnancy, gestation length, and litter size at birth). The decrease in weight gain during lactation (males, females, 50 and 100 mg Al/kg bw) and motor activity in adulthood (males, 50 mg Al/kg ) could eventually also be attributable to the deficiency in diet composition and therefore was not considered solely aluminium specific.

The study with aluminium citrate was a combined developmental neurotoxicity study and was dosed up to 3225 mg/kg bw/d aluminium citrate (300 mg Al/kg bw/d). Regards developmental effects delayed sexual maturation, measured as delayed vaginal opening in females and delayed preputial separation in males, was observed in the high dose Al-citrate group of this study. The same effect, although somewhat less pronounced, was also seen in the sodium citrate control group. Based on the observed upward deviations from the target dose in the Al citrate groups and the data on water consumption seen in the first weeks after weaning, it is possible that both in the pre- and post-weaning stage, the animals in the Al citrate groups received considerably more citrate than the sodium citrate control group. Moreover, the calculated Al dose during the immediate post-weaning period was more than twice the target dose, which may have contributed to post-natal systemic toxicity due to exposure to the test substance. As such, no Al-based LOAEL/NOAEL can be suggested based on the sexual maturation results in this study.

In conclusion, neither 2-butanol nor soluble aluminium species tested for fertility/developmental toxicity showed significant effects on fertility in absence of maternal toxicity and thus such effects are not expected upon exposure of aluminium tri-sec-butylate as described above.

For explanation for using surrogate data in a weight of evidence approach see section 13 IUCLID.

Short description of key information:
Aluminium tri-sec-butylate hydrolyses immediately to 2-butanol and aluminium hydroxide / oxi hydroxide. Therefore, effects on fertility by oral exposure can be assessed by assessing the oral fertility effects of aluminium 3+ cationic compounds and 2-butanol.
A 2-generation reproductive toxicity study in rats has provided information on the reproductive toxicity of 2-butanol. The oral drinking water dosed study, equivalent to the OECD test guideline 416, reported a NOAEL for parental toxicity of 1644 mg/kg bw/day (10000 mg/l drinking water). The NOAEL for reproductive effects was also 1644 mg/kg bw/day.
Studies investigating effects on development by aluminium chloride, lactate and citrate also failed showing evidence of impairment of fertility.
Thus, effects on fertility upon exposure to aluminium tri-sec-butylate are not expected.

Effects on developmental toxicity

Description of key information

Aluminium tri-sec-butylate hydrolyses immediately to 2-butanol and aluminium hydroxide / oxy hydroxide. Therefore, effects on fertility by oral exposure can be assessed by assessing the oral fertility effects of aluminium hydroxide and sec-butanol.
Secondary butanol (SBA) was studied for developmental toxicity by the oral and inhalation routes of exposure in prenatal development toxicity studies similar in design to OECD Guideline 414. An oral prenatal development toxicity study in rats, predating the GLPs, identified a NOAEL for maternal and developmental toxicity of 1644 mg/kg bw/day (1% in drinking water). An inhalational prenatal development toxicity study of SBA in rats reported a NOAEL for developmental toxicity of 3,500 ppm (10605 mg/m3). A maternal NOAEL was not identified in the inhalation study on the basis of decreased maternal food consumption and reduced body weight gain at all dose levels.
Supportive information was available from an inhalation study conducted with the read across substance for SBA, methyl ethyl ketone (MEK), in mice. No evidence of teratogenicity was observed in these studies in mice or rats.. Embryotoxic and fetotoxic effects only occurred at maternal toxic doses in these studies.
Aluminium hydroxide was investigated in a developmental toxicity study according to OECD Test Guideline 414 without indication of teratogenicity or embryotoxicity up to 768 mg/kg bw/d (equivalent to 266 mg Al/kg bw/d).
Thus, it can be concluded that developmental toxicity is not expected upon exposure to aluminium tri-sec-butylate.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no adverse effect observed

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Aluminium tri-sec-butylate hydrolyses immediately to 2-butanol and aluminium hydroxide / oxy hydroxide. Therefore, effects on fertility by oral exposure can be assessed by assessing the oral fertility effects of aluminium hydroxide and 2-butanol.

The effects of orally administered secondary butanol (SBA) on development were evaluated in a prenatal development toxicity study that is comparable in design to OECD Guideline 414, and predates the GLPs (Cox, 1975). This study was part of a multi-generation reproductive toxicity study. Both F1 males and female Wistar rats were treated with 0 (water), 0.3, 1.0, or 2.0% SBA in drinking water pre-mating through to gestation day 20. Increased maternal kidney weight and renal pathology including tubular casts, tubular degeneration, and eosinophilia at 2% (3122 mg/kg bw/day) were reported. Fetal body weights were also reduced at 2%. No treatment-related skeletal or visceral malformations or variations were seen at any dose. No treatment-related maternal or developmental toxicity was observed at an SBA concentration of 1% (NOAEL = 1644 mg/kg/day).

The effects of inhaled SBA on development was evaluated in a prenatal development toxicity study similar in design to OECD Guideline 414 (GLP status not provided) (Nelson et al.,1989). Sprague-dawley rats were exposed to SBA concentrations of 0, 3500, 5000, or 7000 ppm 7 hours/day from gestation days 0 through 20. Maternal toxicity (evidenced by reduced food intake and reduced body weight gain) was noted at all dose levels. An increase in resorptions and reduced fetal weight were seen at 5000 and 7000 ppm, respectively. There were no teratogenic effects reported at any dose level. The NOAEC for embryotoxicity and fetotoxicity was 3500 ppm (10,605 mg/m3). An estimated internal absorbed dose of 350 mg/kg/day was calculated to correspond to the 3500 ppm concentration in the study. No NOAEC was identified for maternal toxicity in the study.

Supportive information was provided by a study conducted with the read across substance, methyl ethyl ketone (MEK). An inhalation teratology study in Swiss mice of MEK reported slight maternal toxicity in form of increased relative liver and kidney weights and fetotoxicity in form of reduced male fetal weights and increased incidence of the variation misaligned vertebrae at 3000 ppm (Schwetz, 1991). Some additional variations and malformations occurred in the study that were not normally encountered in contemporary controls, but there was no clear dose-response relationship for these findings. The NOAEC for fetotoxic and maternal toxicity in this study was 1000 ppm (2940 mg/m3).

Overall, the data suggests that SBA is not teratogenic and it does not cause fetotoxicity at doses that do not also cause maternal toxicity.

Aluminium hydroxide was investigated in a developmental toxicity study according to OECD Test Guideline 414 without indication of teratogenicity or embryotoxicity up to 768 mg/kg bw/d (equivalent to 266 mg Al/kg bw/d, highest dose group).

Thus, it can be concluded that developmental toxicity is not expected upon exposure to aluminium tri-sec-butylate.

Justification for classification or non-classification

The substance does not meet the criteria for classification and labelling for reproductive toxicity as set out in Regulation (EC) No. 1272/2008 (CLP) respectively DSD (Directive 67/548/EEC). Also, effects via lactation were not observed in any of the studies.